Stereoselective Convergent Synthesis of Tetrahydro-5H-benzo[c

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Stereoselective Convergent Synthesis of Tetrahydro-5Hbenzo[c]fluorene via Nine-Membered Ring-Closing Metathesis and Transannular Acid-Mediated Cyclization/Nucleophilic Addition Anek Lekky, Tanachote Ruengsatra, Somsak Ruchirawat, and Poonsakdi Ploypradith J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00263 • Publication Date (Web): 14 Mar 2019 Downloaded from http://pubs.acs.org on March 17, 2019

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The Journal of Organic Chemistry

Stereoselective Convergent Synthesis of Tetrahydro-5H-benzo[c]fluorene via NineMembered

Ring-Closing

Metathesis

and

Transannular

Acid-Mediated

Cyclization/Nucleophilic Addition Anek Lekky, † Tanachote Ruengsatra,† Somsak Ruchirawat,†,‡,§ and Poonsakdi Ploypradith†,‡,§,* † ‡

Program in Chemical Biology, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, and Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6

Road, Laksi, Bangkok, Thailand 10210 §

Centre of Excellence on Environmental Health and Toxicology, Commission on Higher

Education (CHE), Ministry of Education, Thailand E-mail: [email protected]

Abstract

The diene methyl ethers or acetates, constructed from the Li-Br exchange/addition reactions of 2vinylbenzaldehydes and 2-(but-3-en-1-yl)bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda-Grubbs II as catalyst to provide the corresponding benzannulated (Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular

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cyclization/nucleophilic

addition

at

C7

furnished

the

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corresponding

tetrahydro-5H-

benzo[c]fluorenes as single streoisomers with the exclusive cis stereochemistry at the ring junction (C5-C6) and trans at the site of nucleophilic attack (C6-C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrate. Thus, tetrahydro-5H-benzo[c]fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.

Introduction Tetrahydrobenzofluorenes are a group of tetracyclic ring systems consisting of an indane fused with a tetrahydronaphthalene. Because some derivatives with the tetrahydrobenzo[a]fluorene core 1 were identified as selective estrogen receptor modulators (SERMs), their synthesis was investigated

and

reported

(Figure

1).1

However,

synthesis

of

the

corresponding

tetrahydrobenzo[b]fluorene core 2 and tetrahydrobenzo[c]fluorene core 3 has received much less attention; to the best of our knowledge, there has been no report on their preparation. Interestingly, the core 3 can be considered as the isosteric carba analog of the corresponding tetrahydroindeno[2,1-c]chromene core 4 of brazilin (5), a naturally-occurring red pigment isolated from the alcoholic extracts of the heartwood of Caesalpinia sappan L. and found to exhibit anticancer as well as anti-inflammatory activities,2,3 and hematoxylin (6), a natural product which serves as a platform for developing novel derivatives as anti-HIV-1 agents.4


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Figure 1. Tetrahydrobenzofluorene cores 1-3, tetrahydroindeno[2,1-c]chromene core 4, brazilin (5), and hematoxylin (6).

As shown retrosynthetically in Scheme 1, we envisioned that the tetrahydro-5H-benzo[c]fluorene 7 could be obtained most straightforwardly from the nine-membered ring precursor 8 via a onepot acid-mediated transannular cyclization with a concomitant nucleophilic addition.5,6 The benzannulated cyclononene 8, in turn, was anticipated to arise directly from the ring-closing metathesis (RCM) of the corresponding diene 9 which could be assembled from the 2vinylbenzaldehyde 10 and 2-bromoarene 11 via Li-Br exchange/addition reaction. Both 2vinylbenzaldehyde 10 and 2-bromoarene 11 could then be obtained from a common 2bromobenzaldehyde 12.



Scheme 1. Retrosynthesis of the Tetrahydro-5H-benzo[c]fluorene 7

Results and discussion Due to commercial availability and structural simplicity, 2-bromostyrene 13a and 2bromobenzyl bromide 14a were used as starting materials as shown in Scheme 2. Lithiumbromine exchange of 13a followed by addition of N,N-dimethylformamide (DMF) furnished the corresponding 2-formylstyrene 15a in 70% yield. Allylation of 14a using allyl Grignard gave the corresponding 2-(but-3-en-1-yl)bromobenzene 16a in 93% yield. Subsequently, 16a underwent Li-Br exchange using n-BuLi and the corresponding lithiated arene then reacted with 15a to furnish the diarylmethanol diene 17a in 90% yield.

Scheme 2. Synthesis of the Diarylmethanol Diene 17a

With the diarylmethanol diene 17a in hand, we next turned our attention to the key step of ringclosing metathesis (RCM) of the nine-membered ring. From previous literature on RCM, the desired nine-membered ring closure could be challenging; the formation of the nine-membered ring via RCM has been found to be entropically and enthalpically less favorable than the RCM of other medium-sized rings (7-12).7,8a In addition, the presence of at least one heteroatom (N, O, P, or S) as one of the nine-membered ring atoms was frequently necessary to facilitate the RCM by providing cyclic conformational constraint for the otherwise flexible diene substrates.9,10 We anticipated that the presence of two aromatic rings in 17a connecting the two terminal olefin


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units could provide similar effects to facilitate the desired RCM.8 Different commercially available ruthenium-based RCM catalysts (Grubbs I, II as well as Hoveyda-Grubbs (HG) I, II; 530 mol%) were attempted to affect the nine-membered RCM of 17a under various conditions (toluene and 1,2-dichloroethane (DCE) as solvent at 45–90 °C for 18–48 h); however, no desired product 18a could be observed. After some experimentation, the hydroxy group of 17a was converted to the corresponding acetate 19a and methyl ether 20a in 94% and 98% yields, respectively; both 19a and 20 were then subjected to Ru(II)-catalyzed nine-membered ringclosing metathesis to furnish the corresponding benzannulated (Z)-cyclononene acetate 21a and methyl ether 22, respectively (Scheme 3).

Scheme 3. Ru(II)-Catalyzed RCM to Furnish the Nine-Membered Ring Benzannulated (Z)Cyclononene Acetate 21a and Methyl Ether 22

As shown in Table 1, Grubbs II and HG-I catalysts (up to 30 mol%) did not provide the desired (Z)-cyclononene products 21a or 22a (entries 1–4). With 19a as substrate, using 5 mol% HG-II as catalyst gave 21a in 3% yield along with 80% recovery of 19a (entry 5). Increasing the amount of the catalyst (up to 30 mol%) gave better yields of 21a (entries 6–9). Using 10 mol% of the catalyst gave 21a in 16% yield with 62% recovery of 19a (entry 6); dramatic improvement



was observed when 20 mol% of the catalyst was employed, providing the product 21a in 68% yield with only 13% recovery of the starting material (entry 7). Using 30 mol% of the catalyst led to complete consumption of the starting material while giving the product in 70% yield (entry 8). The best isolated yield of 71% could be achieved when using 20 mol% of the catalyst and 1,2-dichloroethane (DCE) as solvent instead of toluene (entry 9). It should be noted also that using DCE as solvent led to fewer side products from the RCM. In addition, the optimized condition was also effective for converting the diene methyl ether 20 to the corresponding product 22 (entries 10–11). The desired RCM occurred with excellent stereocontrol to generate both cyclononenes exclusively with the Z geometry which was established on the basis of NOE of the two olefinic protons of 21a.

Table 1. Optimization of the Nine-Membered RCM of 19a and 20a entry diene catalyst (mol%)b

product

yield (%)c

1

19a

A (5–30)

21a

trace

2

19a

B (5–30)

21a

0d

3

20

A (5–30)

22

trace

4

20

B (5–30)

22

0d

5

19a

C (5)

21a

3 (80)e

6

19a

C (10)

21a

16 (62)e

7

19a

C (20)

21a

68 (13)e

8

19a

C (30)

21a

70

9

19a

C (20)

21a

71f

10

20

C (20)

22

74f


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11 a

20

C (30)

22

75

Unless otherwise noted, reactions were performed in toluene at 80 °C for 18 h. bA = Grubbs II;

B = Hoveyda-Grubbs I; C = Hoveyda-Grubbs II. cIsolated yields. dA complex mixture was obtained in each case. No desired product was observed spectroscopically by 1H NMR of the crude mixture. eThe numbers in parenthesis are percent recovery of 19a. fDCE was used as solvent.

With 21a and 22 in hand, we then turned our attention to the transannular acid-mediated cyclization with concomitant nucleophilic addition to join the central 5/6-membered ring-fused system. After screening some Lewis/Brønsted acids (BF3·Et2O, CF3CO2H, and p-TsOH immobilized on silica (PTS-Si)) and experimentation for the hydrosilane (Et3SiH) reaction, it was found that the use of BF3⸱Et2O gave the best results; both 21a and 22 smoothly underwent the desired one-pot

cyclization/addition of hydride to

provide the tetrahydro-5H-

benzo[c]fluorene 23a in 94% and 86% yields, respectively (Figure 2).11 Due to the better yield of 23a from 21a, the scope of other nucleophiles was investigated using 21a as substrate. In case of TMSN3, the corresponding product 21b could be obtained along with a side-product arising from the direct substitution reaction of the azide on the acetate (the ratio was ca. 1.7:1 favoring 21b). In addition, various electron-rich aromatics smoothly underwent this BF3·Et2O-mediated cyclization/nucleophilic addition to furnish the products 23c-k in moderate to good yields (5489%). Even 1,3,5-trimethylbenzene, a moderately electron-rich aromatic, gave the desired product 23k in 56% yield. The regioselectivity with respect to the aromatics could be rationalized by the electrophilic aromatic substitution-type mechanism whereby the electrophilic species, generated from the (Z)-cyclononene 21a upon complexation with BF3·Et2O, attacked the electron-rich aromatics exclusively on the position either ortho or para to the electron-donating substituents.12 Interestingly, in case of phenol as a nucleophile, two separable products arising



from C- and O-alkylation could be obtained in 66% and 12% yields, respectively.13 In sharp contrast, no product could be obtained when electronically neutral benzene was employed as nucleophile. All products 23b-k were obtained as single isomers. Relative stereochemistry at C5, C6, and C7 could be assigned as 5,6-cis and 6,7-trans on the basis of extensive NOE studies.14,15

Figure 2. Scope of nucleophiles. aA combined yield of the two inseparable azide products. bA 2:1 mixture of isomers. cThe corresponding O-alkylated product was also obtained in ca. 12% yield.


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To demonstrate the generality of our developed strategy for the substrates bearing different methoxylated patterns on the aromatic rings, the diarylmethanol dienes 17b-i, the diene acetates 19b-i, and the benzannulated (Z)-cyclononene acetates 21b-i were prepared from the corresponding 2-vinylbenzaldehydes 15a-c and 2-bromoarenes 16a-c as shown in Table 2. The requisite coupling partners 15a-c and 16a-c, when they were not commercially available, could be straightforwardly prepared from their common starting material benzaldehydes 24a-b in good to excellent overall yields (74-91% over 2-3 steps; Scheme 4).

Scheme 4. Preparation of the Methoxylated 2-Vinylbenzaldehydes 15b-c and 2-Bromoarenes 16b-c from Common Starting Material Benzaldehydes 24a-b

The developed method was rather general; moderate to good yields of the products from each step could be readily obtained regardless of the different methoxylated patterns. Overall, the benzannulated (Z)-cyclononene acetates 21b-i could be obtained in moderate to good yields (4362%) over three steps from the corresponding 2-vinylbenzaldehydes 15a-c and 2-bromoarenes 16a-c.

Table 2. Scope of Different Methoxylated Substrates



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yield (%)a

coupling partners entry 2-vinylbenzaldehyde

2-bromoarene

diene alcohol diene acetate

(Z)-cyclononene acetate

1

16b

17b (83)

19b (96)

21b (66)

17c (89)

19c (95)

21c (64)

17d (92)

19d (96)

21d (70)

17e (86)

19e (91)

21e (64)

17f (90)

19f (94)

21f (62)

17g (91)

19g (96)

21g (54)

17h (84)

19h (93)

21h (65)

15a

(R1 = OMe; R2, R3, R4 = H) 2

15a

16c

(R2 = OMe; R1, R3, R4 = H) 3

15b

16a

(R4 = OMe; R1, R2, R3 = H) 4

15b

16b

(R1, R4 = OMe; R2, R3 = H) 5

15b

16c

(R2, R4 = OMe; R1, R3 = H) 6

15c

16a

(R3 = OMe; R1, R2, R4 = H) 7

15c

16b

(R1, R3 = OMe; R2, R4 = H)


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8

15c

16c

17i (89)

19i (94)

21i (51)

(R2, R3 = OMe; R1, R4 = H) a

Isolated yields.

On the basis of the results shown in Figure 2, three nucleophilic species (Et3SiH, 1,2,4trimethoxybenzene, and 1,3-dimethoxybenzene) were chosen and they were used in the final step of BF3·Et2O-mediated transannular cyclization/nucleophilic addition for the benzannulated (Z)cyclononene acetates 21b-i. The results are summarized in Figure 3. The regioselective attack of the electron-rich aromatics was similar to that observed for 23d and f. Substrates 21b-c and 21g-i all gave the corresponding tetracyclic products 25a-f and 25p-x in moderate to excellent yields (36-96%). For these substrates, the position of the methoxy group (R1 vs R2) on the aromatic ring B affects the yields; those with the methoxy group at R1 generally gave the products in higher yields (25a vs 25d; 25b vs 25e; 25s vs 25v). In addition, the substrates with the methoxy group at R3 (21g-i) furnished the desired products in higher yields (44-96%) than other substrates albeit requiring

longer

reaction

times.

Interestingly,

all

of

these

substrates

underwent

cyclization/addition reaction with 1,2,4-trimethoxybenzene smoothly, providing the products in good to excellent yields (71-90%; 25c, 25f, 25r, 25u, and 25x). In contrast, those substrates with the methoxy group at R4 (21d-f) furnished mixtures of products arising from the direct displacement of the acetate and cyclization/nucleophilic addition for hydride and 1,3dimethoxybenzene. Moderate yields (41, 49, and 44%) could be obtained from the reactions employing 1,2,4-trimethoxybenzene as the nucleophile (25i, 25l, and 25o). NOEs were once again employed to determine the stereochemistry at C5, C6, and C7 as 5,6-cis and 6,7-trans.14,15



Figure 3. Substrate scope for the transannular BF3·Et2O-mediated cyclization/nucleophilic addition. aFor each substrate and nucleophile, an inseparable mixture of the corresponding products arising from the direct substitution on the acetate and the BF3-mediated cyclization/nucleophilic addition was obtained. bThese reactions required 6-18 h to complete.


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A plausible mechanism to account for the stereoselective cyclization is depicted in Scheme 5. Initial ionization upon complexation of the benzannulated (Z)-cyclononene acetates with BF3·Et2O generated the bisbenzylic carbocation intermediate A which may undergo direct nucleophilic attack by some nucleophiles (e.g. azide) to furnish the benzannulated cyclononene as the by-product B (path a). On the other hand, the -electrons of the (Z)-olefin of the benzannulated cyclononene may help stabilize the carbocation A through the - electrons of the aromatic ring A; this is represented as the pentadienyl cation-like intermediate C.16 The ensuing transannular cyclization of the (Z)-olefin onto the carbocation A (path b) then generated the indanyl carbocation D. Subsequent nucleophilic attack onto the indanyl cation D occurs with exclusive trans stereoselectivity relative to the nearby stereogenic center (C6-C7) because the attack can only take place from the convex face of the carbocation D, resulting in the 5,6-cis and 6,7-trans relative stereochemistry in the tetracyclic products (E).15

Scheme 5. A Plausible Mechanism

The effects of each methoxy group at R1, R2, R3, and R4 on the reaction and also the type of products could be rationalized as followed. On the aromatic ring B, the methoxy group at R1 may



assist the formation of the initial bisbenzylic carbocation A by providing additional stabilization through the aromatic -bond as follows. The methoxy group at R2 cannot provide such stabilization; this could account for the higher yields of the products bearing the methoxy group at R1 when compared to those with the methoxy group at R2. On the aromatic ring A, the presence of the methoxy group at R4, while also providing stabilization to the bisbenzylic cation A, favors the nucleophilic addition to this cation (path a), leading to the generation of the sideproduct benzannulated (Z)-cyclononene B. This mode of competing reactions can be observed clearly for the reactions of the cyclononene acetates 21d-f, especially when triethylsilane and 1,3-dimethoxybenzene were employed as nucleophilic agents to generate the corresponding products (25g, 25h, 25j, 25k, 25m, and 25n) as mixtures arising from the competitive reactions. The methoxy group at R3 may increase the nucleophilicity of the (Z)-olefin of the styrene moiety, promoting the formation of the desired product. In general, higher yields of the products were obtained from those substrates containing R3 as the methoxy group (25g-i). With the substrate 21h containing the methoxy groups at R1 and R3 on both aromatic rings, all three cyclized products 25s-25u were obtained in good to excellent yields (80-96%), possibly due to the promoting effects of the methoxy group at R1 for the formation of the initial carbocation and that at R3 for the cyclization.

Conclusion In summary, a novel highly stereoselective strategy for the tetrahydro-5H-benzo[c]fluorene core from simple 2-bromobenzaldehydes has been developed for the first time. The strategy features HG-II-catalyzed nine-membered ring closure followed by BF3-mediated transannular cyclization/nucleophilic addition of hydride, azide, and various electron-rich aromatics. The


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products were obtained exclusively with the 5,6-cis and 6,7-trans relative stereochemistry at the three consecutive stereogenic centers as a result of the highly stereoselective cyclization of the putative pentadienyl cation-like intermediate.16 Over four steps spanning the Li-Br exchange, acetylation, HG-II catalyzed RCM, and BF3-mediated transannular cyclization/nucleophilic addition, the desired tetrahydro-5H-benzo[c]fluorenes were obtained in good yields (up to 56%). Application of a similar strategy to affect the formation and cyclization of other smaller as well as larger ring sizes towards the synthesis of natural products or biologically active compounds with relevant cores are being pursued in our laboratory and will be reported in due course.

Experimental General Experimental Methods Unless otherwise noted, reactions were run in oven-dried round-bottomed

flasks.

Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl or purified by the solvent purification system while dichloromethane (CH2Cl2) was also purified by the solvent purification system prior to use. All other compounds were used as received from the suppliers; PTS-Si (pTsOH immobilized on silica) employed in these experiments possessed the surface area of 500 m2/g as indicated by the supplier. The crude reaction mixtures were concentrated under reduced pressure by removing organic solvents on rotary evaporator. Column chromatography was performed using silica gel 60 (particle size 0.06-0.2 mm; 70-230 mesh ASTM). Analytical thinlayer chromatography (TLC) was performed with silica gel 60 F254 aluminum sheets. Chemical shifts for 1H nuclear magnetic resonance (NMR) spectra were reported in parts per million (ppm,) downfield from tetramethylsilane.

Splitting patterns are described as singlet (s),

doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), doublet of doublet (dd), doublet of



triplet (dt), and doublet of doublet of doublet (ddd). All 13C NMR data were obtained with the use of broadband decoupling (13C{1H}) and reported as proton-decoupled data. Resonances for infrared (IR) spectra were reported in wavenumbers (cm-1 ). Low resolution (LRMS) mass spectra were obtained either using electron ionization (EI) or time-of-flight (TOF) while high resolution (HRMS) mass spectra were obtained using time-of-flight (TOF) via the atmosphericpressure chemical ionization (APCI) or electrospray ionization (ESI). Melting points were uncorrected.

General Procedure for the Synthesis of 2-Vinylbenzaldehydes 15a-c To a stirred solution of the corresponding bromostyrene (1 equiv) in dry THF (5 mL/1 mmol) at 78 °C under argon atmosphere was added n-BuLi (1.6 M in hexane; 1.1 equiv). The reaction mixture was stirred at -78 °C for 15 min; DMF (3 equiv) was then added. The reaction was further stirred at -78 °C for 30 min and then slowly warmed up to room temperature at which it was stirred for 3 h. Saturated NaHCO3 and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica gel to furnish the desired product.

2-Vinylbenzaldehyde (15a). Following the general procedure and purification by column chromatography on silica gel (2% EtOAc/hexane), the product was obtained as yellow oil (505 mg, 3.82 mmol, 70%). IR (UATR): max 2924, 2853, 1693, 1599, 1456, 1259, 1119, 1014, 924, 761 cm-1. 1H NMR (400 MHz, CDCl3):  10.26 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.56–7.49 (m,


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3H), 7.42–7.38 (m, 1H), 5.68 (dd, J = 17.2, 1.2 Hz, 1H), 5.49 (dd, J = 10.8, 1.2 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3):  192.1, 140.2, 133.6, 133.1, 132.6, 131.0, 127.7, 127.2, 119.1. TOFHRMS calcd for C9H8ONa (M+Na+) 155.0467, found 155.0473.

4-Methoxy-2-vinylbenzaldehyde (15b). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow oil (670 mg, 4.13 mmol, 88%). IR (UATR): max 2930, 2856, 1760, 1679, 1562, 1492, 1287, 1098, 1025, 813 cm-1. 1H NMR (400 MHz, CDCl3):  10.12 (s, 1H), 7.77 (dd, J = 8.7, 1.2 Hz, 1H), 7.55 (dd, J = 17.6, 10.8 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.7, 2.4 Hz, 1H), 5.69 (dd, J = 17.6, 1.2 Hz, 1H), 5.49 (dd, J = 10.8, 1.2 Hz, 1H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  190.7, 163.6, 142.6, 133.9, 133.3, 126.5, 119.0, 113.2, 112.1, 55.4. TOF-HRMS calcd for C10H10O2Na (M+Na+) 185.0573, found 185.0572.

5-Methoxy-2-vinylbenzaldehyde (15c). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow oil (655 mg, 4.04 mmol, 86%). IR (UATR): max 2932, 1603, 1504, 1463, 1208, 1114, 1031, 910, 864, 781 cm-1. 1H NMR (400 MHz, CDCl3 ):  10.30 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 17.2, 11.2 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.8 Hz, 1H), 5.60 (d, J = 17.2 Hz, 1H), 5.43 (d, J = 11.2 Hz, 1H), 3.85 (s, 3H).

13

C{1H} NMR (100 MHz, CDCl3 ):  191.5,

159.2, 133.68, 133.65, 132.1, 128.7, 121.0, 118.0, 112.7, 55.4. TOF-HRMS calcd for C10H10O2Na (M+Na+) 185.0573, found 185.0571.

General Procedure for the Synthesis of 2-Bromoarenes (16a-c)



To a stirred solution of the corresponding 2-bromobenzyl bromide (1 equiv) in dry Et2O (1 mL/1 mmol) at 0 °C under argon atmosphere was added allylmagnesium bromide (1 M in Et2O; 2 equiv). The mixture was stirred at 0 °C and slowly warmed up to room temperature for overnight. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica gel to furnish the desired product.

1-Bromo-2-(but-3-en-1-yl)benzene (16a). Following the general procedure and purification by column chromatography on silica gel (100% hexane), the product was obtained as colorless oil (786 mg, 3.72 mmol, 93%). IR (UATR): max 2932, 1734, 1603, 1495, 1294, 1147, 1021, 951, 892, 717 cm-1. 1H NMR (400 MHz, CDCl3):  7.49 (d, J = 8.0 Hz, 1H), 7.17–7.14 (m, 2H), 7.01– 6.97 (m, 1H), 5.90–5.79 (m, 1H), 5.06–4.96 (m, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.34 (dd, J = 15.2, 7.6 Hz, 2H).

13

C{1H} NMR (100 MHz, CDCl3 ):  140.9, 137.5, 132.6, 130.2, 127.4, 127.2,

124.3, 115.1, 35.5, 33.7. These spectroscopic data are in good accordance with the commercialized compound.

1-Bromo-2-(but-3-en-1-yl)-4-methoxybenzene (16b). Following the general procedure and purification by column chromatography on silica gel (2% EtOAc/hexane), the product was obtained as pale yellow oil (844 mg, 3.50 mmol, 98%). IR (UATR): max 2937, 2835, 1604, 1490, 1283, 1037, 911, 857, 807, 775 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.37 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 1H). 5.91–5.81 (m, 1H), 5.08–4.97 (m, 2H), 3.72 (s, 3H), 2.77–2.73 (m, 2H), 2.37–2.31 (m, 2H).

13

C{1H} NMR (100 MHz, CDCl3 ): 


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158.7, 141.8, 137.4, 133.0, 115.9, 115.1, 114.7, 112.9, 55.2, 35.7, 33.6. TOF-HRMS calcd for C11H1379BrO (M+) 240.0144, found 240.0150 and C11H1381BrO (M+) 242.0124, found 242.0126.

2-Bromo-1-(but-3-en-1-yl)-4-methoxybenzene (16c). Following the general procedure and purification by column chromatography on silica gel (2% EtOAc/hexane), the product was obtained as pale yellow oil (844 mg, 3.50 mmol, 98%). IR (UATR): max 3000, 2934, 1594, 1470, 1278, 1239, 1160, 912, 867, 705 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.08–7.06 (m, 2H), 6.67 (dd, J = 8.4, 2.8 Hz, 1H), 5.89–5.79 (m, 1H), 5.06–4.96 (m, 2H), 3.72 (s, 3H), 2.75–2.72 (m, 2H), 2.34–2.29 (m, 2H).

13

C{1H} NMR (100 MHz, CDCl3):  158.2, 137.6, 132.8, 130.5,

124.3, 117.7, 115.0, 113.3, 55.3, 34.6, 34.0. TOF-HRMS calcd for C11H1379BrO (M+) 240.0144, found 240.0151 and C11H1381BrO (M+) 242.0124, found 242.0127.

General Procedure for the Synthesis of the Dienes (17a-i) To a stirred solution of 2-bromoarenes (16a-c) (1.2 equiv) in dry THF (5 mL/1 mmol) at -78 °C under argon atmosphere was added n-BuLi (1.6 M in hexane; 1.2 equiv). The reaction mixture was stirred at -78 °C for 30 min before a solution of 2-vinylbenzaldehydes (15a-c) (1 equiv) in dry THF (1 mL/1 mmol) was added. The resulting mixture was then stirred at -78 °C for 30 min and slowly warmed up to room temperature for overnight. Saturated NaHCO3 and EtOAc were added, and the two phases were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2 SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica gel to furnish the desired product.



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(2-(But-3-en-1-yl)phenyl)(2-vinylphenyl)methanol (17a). Following the general procedure and purification by column chromatography on silica gel (3% EtOAc/hexane), the product was obtained as colorless sticky residue (540 mg, 2.04 mmol, 90%). IR (UATR): max 3308, 3064, 1639, 1480, 1450, 1202, 1175, 994, 911, 758 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.46 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.26–7.16 (m, 6H), 6.96 (dd, J = 17.2, 10.8 Hz, 1H), 6.26 (s, 1H), 5.85–5.72 (m, 1H), 5.61 (dd, J = 17.2, 1.2 Hz, 1H), 5.29 (dd, J = 10.8, 1.2 Hz, 1H), 4.96–4.91 (m, 2H), 2.66–2.55 (m, 2H), 2.30–2.23 (m, 1H), 2.21–2.10 (m, 1H).

13

C{1H} NMR

(100 MHz, CDCl3):  140.3, 139.8, 139.2, 137.9, 136.6, 134.1, 129.4, 127.88, 127.85, 127.6, 127.0, 126.7, 126.3, 126.1, 117.0, 114.9, 69.3, 34.8, 31.6. TOF-HRMS calcd for C19H20ONa (M+Na+) 287.1398, found 287.1399.

(2-(But-3-en-1-yl)-4-methoxyphenyl)(2-vinylphenyl)methanol (17b). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (185 mg, 0.63 mmol, 83%). IR (UATR): max 3345, 2922, 1604, 1570, 1489, 1288, 1164, 1028, 911, 760 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.46 (d, J = 6.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.28–7.24 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 17.2, 10.8 Hz, 1H), 6.74 (s, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.21 (s, 1H), 5.88–5.76 (m, 1H), 5.60 (d, J = 17.2 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 5.00–4.94 (m, 2H), 3.77 (s, 3H), 2.73–2.62 (m, 2H), 2.34–2.28 (m, 1H), 2.24–2.18 (m, 1H), 2.10 (br s, 1H). 13C{1H} NMR (100 MHz, CDCl3):  158.9, 141.1, 140.2, 137.9, 136.4, 134.2, 132.7, 128.3, 127.8, 127.7, 126.7, 126.3, 116.8, 115.3, 115.0, 110.9, 69.2, 55.1, 34.8, 31.8. TOF-HRMS calcd for C20H22O2Na (M+Na+) 317.1506, found 317.1507.


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(2-(But-3-en-1-yl)-5-methoxyphenyl)(2-vinylphenyl)methanol (17c). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (199 mg, 0.68 mmol, 89%). IR (UATR): max 3359, 2922, 2852, 1604, 1570, 1463, 1235, 1028, 912, 760 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.47 (d, J = 7.6 Hz, 1H), 7.27–7.18 (m, 3H), 7.09–6.99 (m, 3H), 6.78 (dd, J = 8.2, 2.8 Hz, 1H), 6.24 (s, 1H), 5.78–5.70 (m, 1H), 5.64 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.8 Hz, 1H), 4.93–4.89 (m, 2H), 3.74 (s, 3H), 2.58–2.45 (m, 2H), 2.25–2.18 (m, 2H), 2.12–2.04 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):

157.9, 141.7, 139.7, 138.0, 136.7, 134.1, 131.2, 130.5, 128.0, 127.9, 127.0,

126.4, 117.2, 114.9, 112.7, 112.6, 69.3, 55.1, 35.0, 30.8. TOF-HRMS calcd for C20H22O2Na (M+Na+) 317.1506, found 317.1512.

(2-(But-3-en-1-yl)phenyl)(4-methoxy-2-vinylphenyl)methanol (17d). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (333 mg, 1.13 mmol, 92%). IR (UATR): max 3336, 3073, 2936, 1639, 1570, 1452, 1287, 1164, 1014, 856 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.48–7.45 (m, 1H), 7.23–7.20 (m, 2H), 7.17–7.14 (m, 1H), 7.06–6.98 (m, 3H), 6.72 (dd, J = 8.2, 2.8 Hz, 1H), 6.21 (br s, 1H), 5.81–5.70 (m, 1H), 5.61 (dd, J = 17.2, 1.2 Hz, 1H), 5.33 (dd, J = 10.8, 1.2 Hz, 1H), 4.95–4.90 (m, 2H), 3.78 (s, 3H), 2.61–2.48 (m, 2H), 2.27–2.16 (m, 1H), 2.15–2.05 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  159.0, 140.6, 139.0, 138.1, 138.0,

134.1, 132.5, 129.3, 128.6, 127.4, 126.5, 126.0, 117.2, 114.9, 113.1, 111.6, 68.9, 55.1, 34.7, 31.5. TOF-HRMS calcd for C20H22O2Na (M+Na+) 317.1506, found 317.1512.



(2-(But-3-en-1-yl)-4-methoxyphenyl)(4-methoxy-2-vinylphenyl)methanol (17e). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (344 mg, 1.06 mmol, 86%). IR (UATR): max 3337, 2937, 1606, 1572, 1490, 1288, 1162, 1014, 912, 814 cm-1 . 1H NMR (400 MHz, CDCl3):  7.25 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.94 (dd, J = 17.6, 10.8 Hz, 1H), 6.77–6.69 (m, 3H), 6.13 (s, 1H), 5.83–5.73 (m, 1H), 5.60 (dd, J = 17.6, 1.2 Hz, 1H), 5.28 (dd, J = 10.8, 1.2 Hz, 1H), 4.98–4.92 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 2.64–2.53 (m, 2H), 2.30–2.21 (m, 2H), 2.20–2.10 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  158.8, 158.7, 140.7, 137.9, 137.7, 134.1, 133.0, 132.8, 128.3, 128.0, 116.9, 115.1, 114.9, 113.0, 111.4, 110.7, 68.6, 55.1, 55.0, 34.6, 31.6. TOF-HRMS calcd for C21H24O3Na (M+Na+) 347.1617, found 347.1611.

(2-(But-3-en-1-yl)-5-methoxyphenyl)(4-methoxy-2-vinylphenyl)methanol (17f). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (360 mg, 1.11 mmol, 90%). IR (UATR): max 3476, 2933, 1606, 1571, 1287, 1162, 1029, 995, 912, 815 cm-1 . 1H NMR (400 MHz, CDCl3):  7.11–7.07 (m, 5H), 6.78 (dd, J = 8.4, 2.8 Hz, 1H), 6.72 (dd, J = 8.4, 2.8 Hz, 1H), 6.19 (d, J = 3.6 Hz, 1H), 5.77–5.70 (m, 1H), 5.66 (dd, J = 17.2, 1.2 Hz, 1H), 5.36 (dd, J = 10.8, 1.2 Hz, 1H), 4.93–4.89 (m, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 2.53–2.40 (m, 2H), 2.23–2.14 (m, 1H), 2.10–2.01 (m, 2H).

13

C{1H} NMR (100 MHz, CDCl3):  159.1, 157.9, 142.0, 138.2,

138.1, 134.1, 132.3, 130.9, 130.4, 128.6, 117.3, 114.8, 113.2, 112.5, 112.3, 111.6, 68.9, 55.2, 55.1, 34.9, 30.8. TOF-HRMS calcd for C21H24O3Na (M+Na+) 347.1617, found 347.1608.


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(2-(But-3-en-1-yl)phenyl)(5-methoxy-2-vinylphenyl)methanol (17g). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as pale yellow sticky residue (330 mg, 1.12 mmol, 91%). IR (UATR): max 3382, 2853, 1604, 1570, 1463, 1235, 1097, 1028, 912, 760 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.43 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.26–7.16 (m, 3H), 6.88–6.81 (m, 3H), 6.28 (d, J = 4.2 Hz, 1H), 5.86–5.76 (m, 1H), 5.52 (dd, J = 17.2, 1.6 Hz, 1H), 5.18 (dd, J = 10.8, 1.6 Hz, 1H), 5.00–4.94 (m, 2H), 3.74 (s, 3H), 2.76–2.63 (m, 2H), 2.36–2.19 (m, 2H), 2.04 (d, J = 4.2 Hz, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  159.3, 141.5, 140.1, 139.4, 138.0, 133.4, 129.5,

129.1, 127.8, 127.6, 126.8, 126.2, 115.1, 115.0, 113.1, 112.5, 69.4, 55.2, 34.9, 31.6. TOF-HRMS calcd for C20H22O2Na (M+Na+) 317.1506, found 317.1512.

(2-(But-3-en-1-yl)-4-methoxyphenyl)(5-methoxy-2-vinylphenyl)methanol (17h). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (334 mg, 1.03 mmol, 84%). IR (UATR): max 2931, 1731, 1514, 1230, 1210, 1192, 1102, 914, 871, 782 cm-1 . 1H NMR (400 MHz, CDCl3):  7.43 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 6.83–6.67 (m, 4H), 6.20 (s, 1H), 5.91–5.78 (m, 1H), 5.50 (d, J = 17.2 Hz, 1H), 5.15 (d, J = 10.8 Hz, 1H), 5.03– 4.97 (m, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 2.79–2.68 (m, 2H), 2.41–2.23 (m, 2H), 2.12 (br s, 1H). 13

C{1H} NMR (100 MHz, CDCl3):

159.3, 158.9, 141.8, 141.2, 137.9, 133.4, 132.5, 128.8,

128.4, 127.4, 115.3, 115.0, 114.8, 112.9, 112.2, 110.9, 69.1, 55.1, 55.0, 34.8, 31.7. TOF-HRMS calcd for C21H24O3Na (M+Na+) 347.1617, found 347.1622.



(2-(But-3-en-1-yl)-5-methoxyphenyl)(5-methoxy-2-vinylphenyl)methanol (17i). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as yellow sticky residue (354 mg, 1.09 mmol, 89%). IR (UATR): max 3076, 2936, 1606, 1491, 1463, 1235, 1028, 995, 912, 804 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.44 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 17.2, 10.8 Hz, 1H), 6.83–6.77 (m, 3H), 6.22 (d, J = 3.6 Hz, 1H), 5.84–5.74 (m, 1H), 5.54 (dd, J = 17.2, 1.2 Hz, 1H), 5.21 (dd, J = 10.8, 1.2 Hz, 1H), 4.98–4.93 (m, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 2.67–2.52 (m, 2H), 2.31–2.13 (m, 3H).

13

C{1H} NMR (100 MHz, CDCl3):  159.3,

157.8, 141.4, 141.2, 138.1, 133.4, 131.3, 130.4, 129.2, 127.5, 115.1, 114.9, 113.1, 112.73, 112.71, 112.6, 69.2, 55.1, 35.0, 30.8. TOF-HRMS calcd for C21H24O3Na (M+Na+) 347.1617, found 347.1614.

General Procedure for the Synthesis of the Diene Acetates (19a-i) To a stirred solution of the dienes (17a-i) (1 equiv), K2CO3 (1.5 equiv), DMAP (0.1 equiv) in CH2Cl2 (10 mL/1 mmol) at room temperature was added Ac2O (1.1 equiv). The reaction mixture was stirred at room temperature for overnight. Water and CH2Cl2 were added, and the two phases were separated. The aqueous layer was extracted twice with CH2Cl2 . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on Sephadex LH-20 to furnish the desired product.

(2-(But-3-en-1-yl)phenyl)(2-vinylphenyl)methyl acetate (19a). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product


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was obtained as pale yellow solid (562 mg, 1.84 mmol, 97%), mp 68–69 °C. IR (UATR): max 3067, 2935, 1738, 1640, 1483, 1370, 1227, 1017, 968, 871 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.50 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.32–7.18 (m, 6H), 7.10 (d, J = 7.6 Hz, 1H), 7.00 (dd, J = 17.2, 10.8 Hz, 1H), 5.83–5.73 (m, 1H), 5.63 (dd, J = 17.2, 1.2 Hz, 1H), 5.33 (dd, J = 10.8, 1.2 Hz, 1H), 4.97–4.92 (m, 2H), 2.67–2.53 (m, 2H), 2.33–2.25 (m, 1H), 2.18–2.11 (m, 1H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  169.7, 139.5, 137.7, 137.2, 136.9, 136.2, 133.9, 129.6, 128.4, 128.0, 127.7, 127.0, 126.5, 126.0, 117.3, 114.9, 70.8, 34.5, 31.8, 21.0. TOF-HRMS calcd for C21H22O2Na (M+Na+) 329.1512, found 329.1525.

(2-(But-3-en-1-yl)-4-methoxyphenyl)(2-vinylphenyl)methyl acetate (19b). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as pale yellow sticky residue (203 mg, 0.603 mmol, 96%). IR (UATR):

max 2936, 1740, 1608, 1492, 1370, 1290, 1018, 974, 821, 755 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.50 (d, J = 8.6 Hz, 1H), 7.33–7.21 (m, 3H), 7.19–7.12 (m, 2H), 6.93 (dd, J = 17.2, 10.8 Hz, 1H), 6.77–6.70 (m, 2H), 5.86–5.75 (m, 1H), 5.61 (d, J = 17.2 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 5.00–4.94 (m, 2H), 3.79 (s, 3H), 2.70–2.56 (m, 2H), 2.35–2.28 (m, 1H), 2.24–2.17 (m, 1H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3 ):  169.8, 159.2, 141.4, 137.7, 137.0, 136.6, 134.0, 129.0, 128.9, 128.2, 127.7, 127.5, 126.5, 117.1, 115.3, 115.1, 111.0, 70.8, 55.1, 34.5, 31.9, 21.1. TOF-HRMS calcd for C22H24O3Na (M+Na+) 359.1617, found 359.1611.

(2-(But-3-en-1-yl)-5-methoxyphenyl)(2-vinylphenyl)methyl acetate (19c). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as pale yellow sticky residue (215 mg, 0.64 mmol, 95%). IR (UATR): max



2937, 1740, 1608, 1490, 1289, 1225, 1018, 973, 912, 755 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.51 (d, J = 8.4 Hz, 1H), 7.31–7.27 (m, 2H), 7.22–7.18 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 17.2, 10.8 Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 6.81 (dd, J = 8.4, 2.8 Hz, 1H), 5.83–5.71 (m, 1H), 5.64 (dd, J = 17.2, 1.6 Hz, 1H), 5.35 (dd, J = 10.8, 1.6 Hz, 1H), 4.97–4.90 (m, 2H), 3.77 (s, 3H), 2.59–2.45 (m, 2H), 2.31–2.21 (m, 1H), 2.13 (s, 3H), 2.12–2.06 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  169.7, 157.7, 138.2, 137.9, 137.3, 135.9, 133.9, 131.5, 130.6, 128.5, 128.0, 127.7, 126.5, 117.4, 114.9, 113.3, 112.5, 70.7, 55.1, 34.7, 31.0, 21.0. TOF-HRMS calcd for C22H24O3Na (M+Na+) 359.1617, found 359.1612.

(2-(But-3-en-1-yl)phenyl)(4-methoxy-2-vinylphenyl)methyl acetate (19d). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as pale yellow sticky (364 mg, 1.08 mmol, 96%). IR (UATR): max 2937, 1740, 1608, 1370, 1290, 1046, 973, 912, 822, 712 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.39– 7.36 (m, 1H), 7.31 (s, 1H), 7.27–7.22 (m, 2H), 7.19–7.16 (m, 1H), 7.07–6.96 (m, 3H), 6.73 (dd, J = 8.8, 2.2 Hz, 1H), 5.83–5.73 (m, 1H), 5.65 (dd, J = 17.2, 1.2 Hz, 1H), 5.36 (dd, J = 10.8, 1.2 Hz, 1H), 4.97–4.91 (m, 2H), 3.79 (s, 3H), 2.64–2.50 (m, 2H), 2.34–2.25 (m, 1H), 2.17–2.07 (m, 1H), 2.11 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3 ):  169.8, 159.5, 139.2, 138.7, 137.8, 137.2, 133.9, 129.7, 129.6, 128.6, 127.8, 126.5, 126.0, 117.5, 114.9, 113.1, 111.6, 70.5, 55.1, 34.4, 31.8, 21.0. TOF-HRMS calcd for C22H24O3Na (M+Na+) 359.1617, found 359.1614.

(2-(But-3-en-1-yl)-4-methoxyphenyl)(4-methoxy-2-vinylphenyl)methyl acetate (19e). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as pale yellow sticky residue (353 mg, 0.96 mmol, 91%). IR


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(UATR): max 2938, 1606, 1491, 1292, 1243, 1159, 1092, 910, 868, 822 cm-1 . 1H NMR (400 MHz, CDCl3):  7.24–7.20 (m, 2H), 7.05–6.94 (m, 3H), 6.77–6.73 (m, 3H), 5.85–5.75 (m, 1H), 5.62 (dd, J = 17.2, 1.2 Hz, 1H), 5.33 (dd, J = 10.8, 1.2 Hz, 1H), 5.00–4.93 (m, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 2.64–2.53 (m, 2H), 2.34–2.28 (m, 1H), 2.22–2.14 (m, 1H), 2.10 (s, 3H).

13

C{1H}

NMR (100 MHz, CDCl3):  169.8, 159.3, 159.1, 141.0, 138.4, 137.7, 133.9, 129.4, 129.3, 128.9, 128.3, 117.2, 115.2, 114.9, 113.1, 111.5, 110.9, 70.5, 55.1, 55.0, 34.4, 31.9. TOF-HRMS calcd for C21H23O2 (M-OAc)+ 307.1692, found 307.1693.

(2-(But-3-en-1-yl)-5-methoxyphenyl)(4-methoxy-2-vinylphenyl)methyl acetate (19f). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as yellow sticky residue (381 mg, 1.04 mmol, 94%). IR (UATR): max 2937, 1606, 1577, 1491, 1292, 1159, 1091, 1042, 910, 707 cm-1 . 1H NMR (400 MHz, CDCl3):  7.25 (s, 1H), 7.10–6.96 (m, 5H), 6.80 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 5.81–5.71 (m, 1H), 5.65 (d, J = 17.8 Hz, 1H), 5.38 (d, J = 10.4 Hz, 1H), 4.95–4.91 (m, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 2.56–2.42 (m, 2H), 2.30–2.21 (m, 1H), 2.15–2.03 (m, 1H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  169.8, 159.5, 157.8, 138.8, 138.6, 137.9, 133.9, 131.3, 130.6, 129.8, 128.4, 117.5, 114.8, 113.2, 112.9, 112.3, 111.6, 70.4, 55.2, 55.1, 34.6, 31.0, 21.0. TOF-HRMS calcd for C21H23O2 (M-OAc)+ 307.1692, found 307.1690.

(2-(But-3-en-1-yl)phenyl)(5-methoxy-2-vinylphenyl)methyl acetate (19g). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as pale yellow sticky residue (361 mg, 1.07 mmol, 96%). IR (UATR): max 2935, 1739, 1607, 1490, 1370, 1223, 1162, 912, 821, 755 cm-1. 1H NMR (400 MHz, CDCl3): 



Page 28 of 58

7.46 (d, J = 8.4 Hz, 1H), 7.32–7.18 (m, 5H), 6.93–6.82 (m, 2H), 6.67 (d, J = 2.8 Hz, 1H), 5.83– 5.76 (m, 1H), 5.53 (dd, J = 17.2, 1.2 Hz, 1H), 5.22 (dd, J = 10.8, 1.2 Hz, 1H), 4.99–4.93 (m, 2H), 3.71 (s, 3H), 2.66–2.59 (m, 2H), 2.33–2.29 (m, 1H), 2.21–2.12 (m, 1H), 2.13 (s, 3H).

13

C{1H}

NMR (100 MHz, CDCl3):  169.7, 159.1, 139.6, 137.8, 137.7, 136.7, 133.2, 129.8, 129.6, 127.6, 127.1, 126.1, 115.4, 115.0, 113.9, 113.2, 70.7, 55.1, 34.5, 31.8, 21.0. TOF-HRMS calcd for C22H24O3Na (M+Na+) 359.1617, found 359.1609.

(2-(But-3-en-1-yl)-4-methoxyphenyl)(5-methoxy-2-vinylphenyl)methyl acetate (19h). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as yellow sticky residue (351 mg, 0.96 mmol, 93%). IR (UATR): max 2935, 1737, 1514, 1464, 1267, 1105, 1016, 914, 867, 772 cm-1 . 1H NMR (400 MHz, CDCl3):  7.46 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.85–6.70 (m, 5H), 5.88–5.78 (m, 1H), 5.51 (d, J = 17.8 Hz, 1H), 5.20 (d, J = 10.8 Hz, 1H), 5.03–4.96 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.72–2.59 (m, 2H), 2.39–2.19 (m, 2H), 2.12 (s, 3H).

13

C{1H} NMR

(100 MHz, CDCl3):  169.7, 159.3, 159.1, 141.5, 138.1, 137.7, 133.3, 129.5, 128.9, 128.8, 127.6, 115.3, 115.2, 115.1, 113.5, 113.0, 111.1, 70.7, 55.17, 55.13, 34.5, 31.9, 21.0. TOF-HRMS calcd for C23H26O4Na (M+Na+) 389.1722, found 389.1723.

(2-(But-3-en-1-yl)-5-methoxyphenyl)(5-methoxy-2-vinylphenyl)methyl acetate (19i). Following the general procedure and purification by column chromatography on Sephadex LH-20 (100% MeOH), the product was obtained as yellow sticky residue (375 mg, 1.02 mmol, 94%). IR (UATR): max 2935, 1737, 1515, 1464, 1267, 1105, 1016, 963, 867, 772 cm-1 . 1H NMR (400 MHz, CDCl3):  7.45 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.94–6.87 (m,


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2H), 6.84–6.77 (m, 2H), 6.68 (d, J = 2.4 Hz, 1H), 5.82–5.73 (m, 1H), 5.53 (dd, J = 17.2, 1.2 Hz, 1H), 5.23 (dd, J = 11.2, 1.2 Hz, 1H), 4.97–4.91 (m, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 2.57–2.50 (m, 2H), 2.30–2.27 (m, 1H), 2.24–2.10 (m, 1H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  169.6, 159.1, 157.8, 137.9, 137.8, 137.4, 133.2, 131.5, 130.6, 129.8, 127.6, 115.4, 114.9, 114.0, 113.4, 113.2, 112.5, 70.6, 55.1, 34.7, 31.0, 20.9. TOF-HRMS calcd for C23H26O4Na (M+Na+) 389.1722, found 389.1723.

1-(But-3-en-1-yl)-2-(methoxy(2-vinylphenyl)methyl)benzene (20a). To a stirred solution of the diene 17a (0.04 g, 0.15 mmol), NaH (55% dispersion in oil, 7.00 mg, 0.30 mmol), DMAP (0.018 g, 0.15 mmol) in CH2Cl2 (1.5 mL) at room temperature was added MeI (0.047 mL, 0.75 mmol). The reaction mixture was stirred at room temperature for overnight. Water and CH2Cl2 were added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica gel (3% EtOAc/hexane) to furnish the desired product as brown sticky residue (41.0 mg, 0.1473 mmol, 98%). IR (UATR): max 2934, 1480, 1323, 1265, 1186, 1076, 967, 874, 839, 753 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.49 (d, J = 7.8 Hz, 1H), 7.28–7.15 (m, 7H), 6.96 (dd, J = 17.4, 10.8 Hz, 1H), 5.88–5.76 (m, 1H), 5.73 (s, 1H), 5.61 (dd, J = 17.4, 1.2 Hz, 1H), 5.30 (dd, J = 10.8, 1.2 Hz, 1H), 5.00–4.93 (m, 2H), 3.39 (s, 3H), 2.70–2.56 (m, 2H), 2.34–2.24 (m, 1H), 2.21–2.13 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  140.1, 138.0, 137.4, 134.3, 129.5, 127.8, 127.7, 127.65, 127.61, 127.3, 126.3, 125.9, 116.7, 114.8, 78.7, 57.3, 34.9, 31.7. TOF-HRMS calcd for C20H22ONa (M+Na+) 301.1562, found 301.1563.



General Procedure for the Synthesis of (Z)-Cyclononene Acetates (21a-i) To a stirred solution of the diene acetates (19a-i) (1 equiv) in DCE (100 mL/1mmol) at room temperature was added Hoveyda-Grubbs 

(20 mol%). The mixture was stirred at room

temperature for 10 min and then heated to 80 °C for overnight. Then, the reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica gel to furnish the desired product.

(Z)-6,13-Dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21a). Following the general procedure and purification by column chromatography on silica gel (3% EtOAc/hexane), the product was obtained as white solid (361 mg, 1.30 mmol, 71%), mp 139–141 °C. IR (UATR):

max 2868, 1738, 1486, 1450, 1371, 1232, 1019, 967, 742, 727 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.95 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.34–7.24 (m, 2H), 7.19 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 8.8 Hz, 2H), 6.96 (s, 1H), 6.77 (d, J = 10.8 Hz, 1H), 6.20–6.13 (m, 1H), 2.98–2.91 (m, 1H), 2.85–2.80 (m, 1H), 2.59–2.50 (m, 1H), 2.04 (s, 3H), 1.54 (br s, 1H). 13C{1H} NMR (100 MHz, CDCl3):  169.7, 140.6, 139.5, 137.5, 136.1, 134.2, 129.6, 128.2, 127.7, 127.6, 127.5, 127.3, 127.2, 126.6, 125.6, 70.9, 32.2, 28.1, 21.2. TOF-HRMS calcd for C17H15 (M-OAc)+ 219.1168, found 219.1162.

(Z)-3-Methoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21b). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow solid (121 mg, 0.39 mmol, 66%), mp 113–114 °C. IR (UATR): max 1736, 1602, 1498, 1371, 1231, 1186, 1104, 1017, 963, 743 cm-1. 1

H NMR (400 MHz, CDCl3 ):  7.85 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6


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Hz, 1H), 7.18 (td, J = 7.6, 1.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 6.87 (dd, J = 8.6, 2.4 Hz, 1H), 6.75 (d, J = 10.8 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.19–6.11 (m, 1H), 3.76 (s, 3H), 2.93–2.79 (m, 2H), 2.58–2.48 (m, 1H), 2.03 (s, 3H), 1.54 (br s, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  169.7, 158.9, 142.1, 137.9, 135.8, 134.1, 131.8, 128.2, 127.6, 127.43, 127.40, 127.1, 126.8, 114.7, 111.9, 70.6, 55.1, 32.5, 28.0, 21.2. TOF-HRMS calcd for C20H20O3Na (M+Na+) 331.1304, found 331.1302.

(Z)-2-Methoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21c). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow solid (126 mg, 0.41 mmol, 64%), mp 126–127 °C. IR (UATR): max 1736, 1602, 1498, 1371, 1232, 1186, 1036, 1018, 964, 743 cm-1. 1

H NMR (400 MHz, CDCl3 ):  7.78 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.26 (td, J =

7.6, 1.2 Hz, 1H), 7.20 (td, J = 7.6, 1.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.98–6.92 (m, 2H), 6.76–6.71 (m, 2H), 6.18–6.10 (m, 1H), 3.84 (s, 3H), 2.94–2.86 (m, 1H), 2.77–2.71 (m, 1H), 2.56–2.47 (m, 1H), 2.03 (s, 3H), 1.50 (br s, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  169.6,

158.2, 140.6, 137.2, 136.1, 134.4, 133.0, 130.5, 128.2, 127.5, 127.3, 127.2, 112.3, 111.9, 70.8, 55.3, 31.3, 28.4, 21.1. TOF-HRMS calcd for C20H20O3Na (M+Na+) 331.1304, found 331.1301.

(Z)-10-Methoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21d). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow solid (231 mg, 0.75 mmol, 70%), mp 127–128 °C. IR (UATR): max 1736, 1602, 1463, 1371, 1231, 1104, 1018, 963, 930, 743 cm-1. 1

H NMR (400 MHz, CDCl3 ):  7.90 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.30 (td, J =



7.6, 1.2 Hz, 1H), 7.17 (td, J = 7.6, 1.2 Hz, 1H), 7.03 (d, J = 10.8 Hz, 1H), 6.89 (br s, 1H), 6.83 (dd, J = 8.8, 2.8 Hz, 1H), 6.72 (d, J = 10.4 Hz, 1H), 6.57 (d, J = 2.8 Hz, 1H), 6.17–6.10 (m, 1H), 3.72 (s, 3H), 2.97–2.89 (m, 1H), 2.84–2.77 (m, 1H), 2.51–2.48 (m, 1H), 2.02 (s, 3H), 1.54 (br s, 1H), 13C{1H} NMR (100 MHz, CDCl3):  169.6, 158.3, 140.2, 139.7, 137.5, 134.2, 129.9, 129.5, 128.9, 127.5, 127.4, 126.5, 125.3, 114.2, 111.9, 70.7, 55.0, 32.1, 28.0, 21.2. TOF-HRMS calcd for C20H20O3Na (M+Na+) 331.1304, found 331.1303.

(Z)-3,10-Dimethoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21e). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow solid (208 mg, 0.62 mmol, 64%), mp 158–160 °C. IR (UATR): max 1734, 1605, 1497, 1463, 1283, 1236, 1224, 1039, 964, 753 cm-1. 1

H NMR (400 MHz, CDCl3 ):  7.81 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 6.87–6.82 (m,

3H), 6.71 (d, J = 10.8 Hz, 1H), 6.59 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 1.6 Hz, 1H), 6.18–6.10 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.92–2.78 (m, 2H), 2.58–2.48 (m, 1H), 2.02 (s, 3H), 1.56 (br s, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  169.7, 158.8, 158.3, 141.8, 137.3, 134.2, 132.2, 130.5, 128.7, 127.5, 126.6, 114.8, 114.3, 112.0, 111.9, 70.5, 55.1, 32.5, 28.1, 21.2. TOF-HRMS calcd for C21H22O4Na (M+Na+) 361.1410, found 361.1410.

(Z)-2,10-Dimethoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21f). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow solid (218 mg, 0.65 mmol, 62%), mp 107–108 °C. IR (UATR): max 2928, 1734, 1601, 1495, 1233, 1220, 1015, 955, 825, 747 cm-1. 1H NMR (400 MHz, CDCl3):  7.67 (br d, J = 8.4 Hz, 1H), 7.45 (br d, J = 2.0 Hz, 1H), 6.96 (d, J =


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8.4 Hz, 1H), 6.86–6.82 (m, 2H), 6.74–6.69 (m, 2H), 6.57 (d, J = 2.8 Hz, 1H), 6.18–6.10 (m, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 2.94–2.86 (m, 1H), 2.76–2.70 (m, 1H), 2.57–2.47 (m, 1H), 2.03 (s, 3H), 1.51 (br s, 1H).

13

C{1H} NMR (100 MHz, CDCl3):  169.7, 158.4, 158.3, 141.0, 137.6,

134.5, 132.8, 130.5, 129.8, 128.9, 127.3, 114.2, 112.1, 112.0, 111.8, 70.7, 55.3, 55.1, 31.4, 28.4, 21.2. TOF-HRMS calcd for C21H22O4Na (M+Na+) 361.1410, found 361.1406.

(Z)-11-Methoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21g). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow sticky residue (178 mg, 0.58 mmol, 54%). IR (UATR): max 2929, 1740, 1600, 1501, 1369, 1226, 1021, 961, 737, 715 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.84 (d, J = 8.0 Hz, 1H), 7.27–7.22 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 10.8 Hz, 1H), 6.08–6.01 (m, 1H), 3.72 (s, 3H), 2.91–2.83 (m, 1H), 2.77–2.72 (m, 1H), 2.51–2.42 (m, 1H), 1.97 (s, 3H), 1.50 (br s, 1H). 13C{1H} NMR (100 MHz, CDCl3):  169.6, 158.7, 140.8, 139.3, 138.8, 133.8, 129.6, 129.4, 128.8, 127.7, 127.3, 126.7, 125.6, 113.09, 113.06, 70.9, 55.2, 32.2, 28.2, 21.2. TOF-HRMS calcd for C20H20O3Na (M+Na+) 331.1304, found 331.1300.

(Z)-3,11-Dimethoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21h). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow solid (210 mg, 0.62 mmol, 65%), mp 132–133 °C. IR (UATR): max 2929, 1731, 1604, 1493, 1462, 1231, 1202, 1082, 1032, 797 cm-1. 1

H NMR (400 MHz, CDCl3 ):  7.82 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 8.4

Hz, 1H), 6.88–6.84 (m, 2H), 6.76 (dd, J = 8.4, 2.4 Hz, 1H), 6.69 (d, J = 10.4 Hz, 1H), 6.60 (d, J



Page 34 of 58

= 2.8 Hz, 1H), 6.14–6.07 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 2.92–2.78 (m, 2H), 2.57–2.48 (m, 1H), 2.03 (s, 3H), 1.56 (t, J = 8.0 Hz, 1H).

13

C{1H} NMR (100 MHz, CDCl3):  169.6, 158.8,

158.7, 142.3, 139.2, 133.7, 131.6, 129.4, 128.5, 127.3, 126.7, 114.8, 112.9, 112.8, 111.9, 70.6, 55.2, 55.1, 32.5, 28.1, 21.2. TOF-HRMS calcd for C21H22O4Na (M+Na+) 361.1410, found 361.1410.

(Z)-2,11-Dimethoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulen-13-yl acetate (21i). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow sticky residue (176 mg, 0.52 mmol, 51%). IR (UATR): max 2929, 1734, 1601, 1495, 1233, 1230, 1015, 955, 862, 747 cm-1. 1H NMR (400 MHz, CDCl3):  7.46 (d, J = 2.4 Hz, 1H), 7.29 (br d, J = 1.2 Hz, 1H), 7.01–6.96 (m, 2H), 6.89 (s, 1H), 6.79–6.67 (m, 3H), 6.14–6.07 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.94–2.86 (m, 1H), 2.77–2.70 (m, 1H), 2.56–2.47 (m, 1H), 2.05 (s, 3H), 1.53 (br s, 1H).

13

C{1H} NMR (100

MHz, CDCl3):  169.6, 158.7, 158.3, 140.4, 138.6, 134.1, 133.2, 130.6, 129.4, 128.9, 127.1, 113.1, 112.9, 112.2, 112.0, 70.9, 55.3, 55.2, 31.4, 28.5, 21.2. TOF-HRMS calcd for C21H22O4Na (M+Na+) 361.1410, found 361.1409.

(Z)-13-Methoxy-6,13-dihydro-5H-dibenzo[a,d][9]annulene

(22).

Following

the

general

procedure using 20 as substrate and purification by column chromatography on silica gel (3% EtOAc/hexane), the product was obtained as pale yellow sticky residue (27 mg, 0.11 mmol, 74%). IR (UATR): max 2925, 1482, 1448, 1254, 1183, 1077, 1030, 810, 739, 642 cm-1. 1H NMR (400 MHz, CDCl3):  8.00 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.29–7.25 (m, 1H), 7.20–7.15 (m, 2H), 7.04 (t, J = 7.6 Hz, 2H), 6.73 (d, J = 10.8 Hz, 1H), 6.15–


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6.07 (m, 1H), 5.53 (s, 1H), 3.19 (s, 3H), 2.97–2.89 (m, 1H), 2.72–2.66 (m, 1H), 2.56–2.47 (m, 1H), 1.57 (br s, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  140.7, 140.6, 139.3, 136.0, 134.2,

129.5, 128.0, 127.62, 127.60, 127.3, 127.2, 126.74, 126.72, 125.8, 77.9, 56.5, 32.3, 28.1. TOFHRMS calcd for C17H15 (M-OMe)+ 219.1168, found 219.1162.

General Procedure for the Synthesis of Tetrahydro-5H-benzo[c]fluorenes via Lewis AcidMediated Cyclization and Nucleophilic Addition from the Silyl Reagents (23a-b) and from the Electron-Rich Aromatics (23c-k) To a stirred solution of the diene acetate (21a) or the diene methyl ether (22) (1 equiv) in DCM at 0 °C was added the silyl reagents or the electron-rich aromatics (1.2 equiv) prior to the addition of boron trifluoride diethyl etherate (1.2 equiv). The mixture was slowly warmed up to room temperature at which it was stirred for 2 h. Water and CH2Cl2 were added, and the two phases were separated. The aqueous layer was extracted twice with CH2Cl2 . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product which was further purified by column chromatography on silica gel to furnish the desired product.

6,6a,7,11b-Tetrahydro-5H-benzo[c]fluorene (23a). Following the general procedure and purification by column chromatography on silica gel (100% hexane), the product was obtained as yellow sticky residue (14.9 mg, 0.068 mmol, 94%). IR (UATR): max 2925, 1675, 1598, 1488, 1456, 1295, 1237, 1006, 945, 736 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.44 (d, J = 7.6 Hz, 1H), 7.26–7.23 (m, 2H), 7.17–7.09 (m, 5H), 4.32 (d, J = 6.8 Hz, 1H), 3.22 (dd, J = 15.6, 6.8 Hz, 1H), 2.86–2.64 (m, 4H), 1.79–1.72 (m, 1H), 1.59–1.48 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ): 



Page 36 of 58

145.4, 142.3, 137.2, 136.9, 129.9, 128.9, 126.2, 126.0, 125.9, 125.6, 125.0, 124.2, 48.0, 38.66, 38.64, 28.5, 26.1. TOF-HRMS calcd for C17H15 ([M-H2]+H+) 219.1168, found 219.1164.

7-Azido-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (23b). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as yellow sticky residue (15.7 mg, 0.06 mmol, 84%). IR (UATR): max 2927, 2087, 1492, 1316, 1236, 1023, 918, 808, 769, 728 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.45 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.32–7.24 (m, 3H), 7.17 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.66 (d, J = 2.0 Hz, 1H), 4.56 (d, J = 6.8 Hz, 1H), 2.86–2.78 (m, 2H), 2.72–2.65 (m, 1H), 1.96–1.88 (m, 1H), 1.59–1.49 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  145.9, 1387, 136.7, 135.8, 129.9, 129.1, 128.9, 127.1, 126.3, 126.1, 125.4, 125.1, 70.1, 45.9, 45.7, 28.2, 24.8. TOF-HRMS calcd for C17H16N ([M-N2]+H+) 234.1277, found 234.1276 and C17H14N3 ([M-H2]+H+) 260.1182, found 260.1173.

7-(2,4,6-Trimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (23c). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow sticky residue (22.7 mg, 0.06 mmol, 82%). IR (UATR): max 2933, 1591, 1492, 1217, 1203, 1148, 1060, 951, 812, 739 cm-1. 1H NMR (400 MHz, CDCl3):  7.51 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.20–7.16 (m, 1H), 7.12–7.06 (m, 4H), 7.01 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.16 (s, 2H), 6.08 (s, 1H), 4.87 (d, J = 8.0 Hz, 1H), 4.56 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.63 (br s, 3H), 3.24–3.16 (m, 1H), 2.99–2.89 (m, 1H), 2.68–2.60 (m, 1H), 1.85–1.79 (m, 2H).

13

C{1H} NMR

(100 MHz, CDCl3):  161.5, 159.7, 159.6, 147.3, 145.3, 138.8, 138.2, 128.8, 128.5, 126.1, 125.8,


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125.4, 125.3, 124.5, 123.2, 112.7, 92.9, 91.4, 55.8, 55.3, 55.2, 47.1, 43.9, 43.6, 26.6, 26.2. TOFHRMS calcd for C26H27O3 (M+H+) 387.1954, found 387.1963.

7-(2,4,5-Trimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (23d). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale yellow sticky (24.1 mg, 0.063 mmol, 87%). IR (UATR): max 2934, 1603, 1591, 1454, 1217, 1203, 1116, 1039, 951, 738 cm-1 . 1H NMR (400 MHz, CDCl3):  7.47 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.25–7.09 (m, 5H), 7.03 (d, J = 7.2 Hz, 1H), 6.59 (s, 1H), 6.40 (s, 1H), 4.59 (d, J = 5.6 Hz, 1H), 4.42 (d, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H), 2.93–2.86 (m, 1H), 2.79–2.72 (m, 2H), 2.04–1.93 (m, 1H), 1.78–1.70 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  152.0, 148.0, 146.3, 145.2, 142.9,

137.4, 137.1, 129.4, 128.8, 126.7, 126.5, 125.7, 125.5, 124.6, 124.3, 112.6, 97.6, 56.7, 56.6, 56.1, 48.0, 47.8, 46.2, 27.7, 25.5. TOF-HRMS calcd for C26H27O3 (M+H+) 387.1945, found 387.1965.

7-(2,3,4-Trimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (23e). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as colorless sticky residue (24.6 mg, 0.064 mmol, 89%). IR (UATR): max 2835, 1607, 1500, 1457, 1334, 1203, 1037, 1023, 814, 745 cm-1. 1H NMR (400 MHz, CDCl3):  7.46 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.24–7.09 (m, 5H), 7.04 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.48 (d, J = 4.4 Hz, 1H), 4.45 (d, J = 7.2 Hz, 1H), 3.91 (s, 6H), 3.82 (s, 3H), 2.89–2.73 (m, 3H), 2.04–1.95 (m, 1H), 1.79–1.70 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3):  152.18, 152.11, 146.3, 145.2,

142.1, 137.3, 137.1, 130.4, 129.6, 128.9, 126.8, 126.6, 125.84, 125.80, 124.5, 122.3, 106.9, 60.9,



Page 38 of 58

90.7, 55.9, 49.0, 48.2, 46.1, 27.9, 26.0. TOF-HRMS calcd for C26H26O3Na (M+Na+) 409.1774, found 409.1775.

7-(2,4-Dimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(23f).

Following

the

general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as colorless sticky residue (19.9 mg, 0.056 mmol, 78%). IR (UATR): max 2928, 1611, 1586, 1503, 1455, 1290, 1206, 1155, 1036, 833 cm-1. 1H NMR (400 MHz, CDCl3):  7.44 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 6.8 Hz, 1H), 7.24–7.06 (m, 6H), 6.66 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.35 (dd, J = 8.4, 2.8 Hz, 1H), 4.51 (d, J = 4.0 Hz, 1H), 4.38 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 2.85–2.76 (m, 2H), 2.73–2.66 (m, 1H), 2.01–1.94 (m, 1H), 1.74–1.65 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  159.2,

158.4, 146.4, 145.1, 137.4, 137.1, 129.7, 128.8, 128.2, 126.7, 126.4, 125.79, 125.70, 125.2, 124.5, 103.7, 98.4, 55.4, 55.3, 48.4, 47.6, 46.0, 28.1, 26.0. TOF-HRMS calcd for C25H25O2 (M+H+) 357.1849, found 357.1855.

7-(3,4-Dimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(23g).

Following

the

general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as brown sticky residue as a 2:1 mixture of isomers (18.4 mg, 0.054 mmol, 75%). IR (UATR): max 3420, 2924, 1712, 1602, 1509, 1451, 1264, 1123, 808, 735 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.47–7.42 (m, 4H), 7.22–7.11 (m, 10H), 7.03– 7.01 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H, major), 6.79 (d, J = 8.0 Hz, 1H, minor), 6.76 (d, J = 2.0 Hz, 1H, minor), 6.67–6.65 (m, 3H), 5.57 (s, 1H, minor), 5.51 (s, 1H, major), 4.46 (d, J = 7.2 Hz, 2H), 4.11 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H, minor), 3.83 (s, 3H, major), 2.89–2.73 (m, 6H), 2.00–


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1.93 (m, 2H), 1.81–1.72 (m, 2H).

13

C{1H} NMR (100 MHz, CDCl3 ):  146.5 (minor), 145.8

(major), 145.6 (major), 145.5(minor), 145.4 (major), 145.1 (minor), 144.1 (major), 137.7 (minor), 137.2 (major), 136.0 (minor), 129.3 (minor), 129.2 (major), 128.8 (major), 126.94 (major), 126.90 (minor), 126.7 (major), 125.99 (major), 125.94 (minor), 125.89 (major), 125.86 (minor), 125.6 (minor), 125.5 (major), 124.89 (major), 124.81 (minor), 121.0 (major), 119.4 (minor), 114.2 (minor), 114.1 (major), 110.5 (minor), 110.4 (major), 55.98 (minor), 55.93 (major), 55.0 (major), 54.8 (minor), 49.0 (major), 48.8 (minor), 46.2 (major), 27.6 (minor), 27.5 (major), 25.5 (minor), 25.3 (major). TOF-HRMS calcd for C24H21O2 ([M-H2]+H+) 341.1536, found 341.1545.

4-(6,6a,7,11b-Tetrahydro-5H-benzo[c]fluoren-7-yl)benzene-1,3-diol

(23h).

Following

the

general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as dark brown sticky residue (12.8 mg, 0.039 mmol, 54%). IR (UATR): max 3369, 2921, 1611, 1510, 1448, 1226, 1171, 907, 802, 737 cm-1. 1H NMR (400 MHz, CDCl3):  7.43 (d, J = 7.6 Hz, 2H), 7.24–7.08 (m, 6H), 6.69 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 6.30 (d, J = 8.0 Hz, 1H), 4.81 (br s, 1H), 4.78 (br s, 1H), 4.42 (d, J = 7.6 Hz, 1H), 4.36 (d, J = 5.6 Hz, 1H), 2.89–2.71 (m, 3H), 2.01–1.93 (m, 1H), 1.79–1.71 (m, 1H).

13

C{1H} NMR

(100 MHz, CDCl3):  155.1, 154.7, 146.3, 144.0, 137.3, 137.0, 130.1, 129.4, 128.9, 127.17, 127.14, 125.9, 125.5, 125.1, 122.2, 107.6, 103.3, 49.4, 47.0, 46.1, 27.6, 25.5. TOF-HRMS calcd for C23H19O2 (M-H)- 327.1390, found 327.1397.

4-(6,6a,7,11b-Tetrahydro-5H-benzo[c]fluoren-7-yl)phenol

(23i).

Following

the

general

procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the



product was obtained as yellow sticky residue (14.8 mg, 0.048 mmol, 66%). IR (UATR): max 3362, 2921, 1611, 1510, 1347, 1225, 1171, 802, 770, 737 cm-1. 1H NMR (400 MHz, CDCl3):  7.44 (d, J = 7.2 Hz, 2H), 7.23–7.09 (m, 6H), 7.02 (t, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.79 (br s, 1H), 4.45 (d, J = 7.2 Hz, 1H), 4.13 (d, J = 6.0 Hz, 1H), 2.89–2.72 (m, 3H), 1.99–1.91 (m, 1H), 1.79–1.64 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3):  154.1, 145.9, 145.6, 137.2,

136.5, 129.3, 129.2, 128.9, 126.9, 126.7, 126.0, 125.9, 125.6, 124.9, 115.3, 54.6, 49.0, 46.2, 27.6, 25.4. TOF-HRMS calcd for C23H19O (M-H)- 311.1441, found 311.1435.

2-(6,6a,7,11b-Tetrahydro-5H-benzo[c]fluoren-7-yl)naphthalen-1-ol (23j). Following the general procedure and purification by column chromatography on silica gel (20% EtOAc/hexane), the product was obtained as black sticky residue (18.7 mg, 0.052 mmol, 72%). IR (UATR): max 3491, 2923, 1622, 1514, 1436, 1255, 1197, 964, 905, 726 cm-1. 1H NMR (400 MHz, CDCl3 ):  8.27 (d, J = 8.4 Hz, 1H), 8.11 (br d, J = 6.4 Hz, 1H), 7.61–7.52 (m, 2H), 7.44–7.37 (m, 2H), 7.25–7.10 (m, 6H), 6.64 (s, 2H), 5.20 (br s, 1H), 4.82 (s, 1H), 4.40 (d, J = 6.0 Hz, 1H), 2.83–2.80 (m, 3H), 2.21–2.17 (m, 1H), 1.83–1.76 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  150.2,

146.4, 144.4, 137.1, 136.5, 133.1, 132.4, 130.0, 128.9, 126.9, 126.8, 126.6, 126.2, 126.0, 125.7, 124.96, 124.90, 124.5, 123.7, 122.4, 107.9, 52.3, 47.6, 46.0, 28.7, 26.5. TOF-HRMS calcd for C27H21O (M-H)- 361.1597, found 361.1594.

7-Mesityl-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (23k). Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as yellow sticky residue (14.3 mg, 0.043 mmol, 59%). IR (UATR): max 2922, 1610, 1479, 1378, 1154, 1025, 850, 808, 772, 740 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.44 (d, J = 7.6


Page 40 of 58

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Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 5.4 Hz, 1H), 7.12–6.97 (m, 4H), 6.84 (s, 1H), 6.72 (d, J = 9.6 Hz, 2H), 4.79 (d, J = 8.8 Hz, 1H), 4.58 (d, J = 9.2 Hz, 1H), 3.24–3.18 (m, 1H), 2.90– 2.83 (m, 1H), 2.65–2.59 (m, 1H), 2.38 (s, 3H), 2.20 (s, 3H), 1.84–1.71 (m, 2H), 1.74 (s, 3H). 13

C{1H} NMR (100 MHz, CDCl3):  146.4, 145.4, 138.6, 137.9, 137.4, 137.3, 136.9, 135.6,

131.3, 128.8, 128.57, 128.51, 127.0, 126.3, 126.2, 125.6, 125.2, 123.9, 49.3, 47.1, 44.1, 26.5, 26.4, 21.8, 20.7, 20.6. TOF-HRMS calcd for C26H26 (M+) 338.2029, found 338.2023.

For compounds 25a-f, 25i, 25l, 25o-x, similar procedures were employed. The corresponding nucleophile (1.2 equiv; triethylsilane or 1,3-dimethoxybenzene or 1,2,4-trimethoxybenzene) was added to the reaction mixture before boron trifluoride diethyl etherate (1.2 equiv) was added. The resulting mixture was stirred until the starting material was consumed as monitored by TLC.

3-Methoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (25a). Following the general procedure and purification by column chromatography on silica gel (5% EtOAc/hexane), the product was obtained as pale brown sticky residue (7.8 mg, 0.031 mmol, 48%). IR (UATR): max 2922, 2833, 1606, 1488, 1258, 1240, 1032, 854, 813, 757 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.36 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 7.6 Hz, 2H), 7.12 (br d, J = 2.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.65 (br s, 1H), 4.26 (d, J = 6.4 Hz, 1H), 3.79 (s, 3H), 3.20 (dd, J = 15.6, 6.8 Hz, 1H), 2.76–2.63 (m, 4H), 1.76–1.71 (m, 1H), 1.58–1.54 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  157.7, 145.8, 142.2, 138.4, 130.8, 129.2, 126.2, 126.0, 125.0, 124.2, 113.6, 111.9, 55.2, 47.3, 38.8, 38.5, 28.9, 26.0. TOF-HRMS calcd for C18H17O ([M-H2]+H+) 249.1273, found 249.1266.



7-(2,4-Dimethoxyphenyl)-3-methoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

Page 42 of 58

(25b).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (15.5 mg, 0.040 mmol, 62%). IR (UATR): max 2927, 1609, 1583, 1500, 1256, 1237, 1116, 1037, 874, 799, 751 cm-1 . 1H NMR (400 MHz, CDCl3):  7.37–7.34 (m, 2H), 7.20–7.13 (m, 2H), 7.07 (d, J = 7.2 Hz, 1H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 6.66–6.64 (m, 2H), 6.51 (d, J = 1.6 Hz, 1H), 6.34 (dd, J = 8.6, 1.8 Hz, 1H), 4.49 (d, J = 4.0 Hz, 1H), 4.32 (d, J = 6.8 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 6H), 2.83–2.74 (m, 2H), 2.69–2.64 (m, 1H), 2.00–1.92 (m, 1H), 1.72–1.63 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  159.2, 158.4, 157.6, 146.8, 145.0, 138.6, 130.6, 129.3, 128.2, 126.6, 126.5, 125.8, 125.3, 124.4, 113.5, 112.0, 103.7, 98.5, 55.5, 55.3, 55.2, 48.3, 47.8, 45.3, 28.5, 25.9. TOFHRMS calcd for C26H27O3 (M+H+) 387.1954, found 387.1946.

3-Methoxy-7-(2,4,5-trimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(25c).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexanes), the product was obtained as pale brown sticky (19.1 mg, 0.046 mmol, 71%). IR (UATR): max 2929, 1607, 1500, 1462, 1395, 1255, 1200, 1175, 1030, 852 cm-1 . 1H NMR (400 MHz, CDCl3):  7.39 (t, J = 7.8 Hz, 2H), 7.21–7.12 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.65 (br s, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 4.57 (d, J = 5.6 Hz, 1H), 4.37 (d, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H), 3.65 (s, 3H), 2.89–2.84 (m, 1H), 2.77–2.70 (m, 2H), 1.98–1.93 (m, 1H), 1.74–1.70 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3 ):  157.5,

152.0, 148.0, 146.7, 145.1, 143.0, 138.6, 130.3, 129.4, 126.7, 126.5, 125.5, 124.6, 124.4, 113.5, 112.7, 112.0, 97.8, 56.7, 56.6, 56.2, 55.1, 48.1, 47.7, 45.5. TOF-HRMS calcd for C27H28O4Na (M+Na+) 439.1879, found 439.1886.


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2-Methoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (25d). Following the general procedure and purification by column chromatography on silica gel (5% EtOAc/hexane), the product was obtained as pale brown sticky residue (5.8 mg, 0.024 mmol, 36%). IR (UATR): max 2922, 1606, 1488, 1258, 1240, 1192, 1032, 939, 812, 777 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.29 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 7.15–7.11 (m, 2H), 7.03–6.98 (m, 2H), 6.74 (dd, J = 8.0, 2.8 Hz, 1H), 4.28 (d, J = 6.4Hz, 1H), 3.85 (s, 3H), 3.21 (dd, J = 15.4, 6.8 Hz, 1H), 2.83–2.75 (m, 1H), 2.73–2.59 (m, 3H), 1.77–1.71 (m, 1H), 1.59–1.49 (m, 1H).

13

C{1H} NMR (100 MHz,

CDCl3 ):  157.5, 145.2, 142.3, 138.0, 129.7, 129.4, 126.3, 126.0, 125.0, 124.2, 115.1, 111.7, 55.3, 48.3, 38.6, 38.5, 27.6, 26.4. TOF-HRMS calcd for C18H17O ([M-H2]+H+) 249.1273, found 249.1278.


(25e).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (11.3 mg, 0.029 mmol, 45%). IR (UATR): max 2925, 1516, 1493, 1392, 1205, 1182, 1031, 816, 752, 739 cm-1. 1H NMR (400 MHz, CDCl3):  7.40 (d, J = 6.8 Hz, 1H), 7.21–7.14 (m, 2H), 7.07 (d, J = 6.8 Hz, 1H), 7.03–6.99 (m, 2H), 6.71 (dd, J = 8.2, 2.6 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 6.35 (dd, J = 8.4, 2.4 Hz, 1H), 4.50 (d, J = 4.0 Hz, 1H), 4.34 (d, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.80–2.64 (m, 3H), 1.99–1.92 (m, 1H), 1.72–1.63 (m, 1H). 13

C{1H} NMR (100 MHz, CDCl3):  159.2, 158.4, 157.5, 146.2, 145.1, 138.1, 129.6, 128.2,

126.7, 126.5, 125.8, 125.2, 124.4, 114.9, 111.6, 103.7, 98.4, 55.4, 55.3, 55.2, 48.3, 47.6, 46.3, 27.2, 26.2. TOF-HRMS calcd for C26H27O3 (M+H+) 387.1954, found 387.1944.




Page 44 of 58

(25f).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (21.3 mg, 0.052 mmol, 79%). IR (UATR): max 2928, 1609, 1501, 1455, 1283, 1207, 1116, 1037, 838, 751 cm-1. 1H NMR (400 MHz, CDCl3):  7.45 (d, J = 7.2 Hz, 1H), 7.21–7.13 (m, 2H), 7.03 (d, J = 7.2 Hz, 3H), 6.71 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 4.58 (d, J = 5.6 Hz, 1H), 4.37 (d, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.66 (s, 3H), 2.86–2.79 (m, 1H), 2.77–2.65 (m, 2H), 1.97–1.92 (m, 1H), 1.76–1.68 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  157.6, 152.0, 148.0, 146.1, 145.4, 143.0, 138.2, 129.65, 129.60, 126.8, 126.5, 125.5, 124.6, 124.3, 114.6, 112.7, 111.6, 97.7, 56.7, 56.6, 56.2, 55.2, 48.0, 47.7, 46.5, 26.8, 25.7. TOF-HRMS calcd for C27H28O4Na (M+Na+) 439.1879, found 439.1877.


(25i).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (11.1 mg, 0.027 mmol, 41%). IR (UATR): max 2926, 1516, 1494, 1393, 1206, 1182, 1031, 915, 885, 752 cm-1. 1H NMR (400 MHz, CDCl3):  7.45 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.22–7.18 (m, 1H), 7.14–7.09 (m, 2H), 6.74 (dd, J = 8.4, 2.4 Hz, 1H), 6.59 (s, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.44 (s, 1H), 4.56 (d, J = 5.6 Hz, 1H), 4.36 (d, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H), 2.92–2.85 (m, 1H), 2.79–2.71 (m, 2H), 1.99–1.91 (m, 1H), 1.78–1.70 (m, 1H). 13

C{1H} NMR (100 MHz, CDCl3):  159.0, 152.0, 148.0, 146.9, 143.0, 138.5, 137.6, 137.3,


Page 45 of 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


129.3, 128.8, 125.8, 125.7, 125.2, 124.1, 112.7, 110.5, 97.7, 56.8, 56.6, 56.2, 55.3, 48.4, 47.8, 45.4, 27.7, 25.6. TOF-HRMS calcd for C27H28O4Na (M+Na+) 439.1879, found 439.1880.

3,9-Dimethoxy-7-(2,4,5-trimethoxyphenyl)-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(25l).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (12.9 mg, 0.029 mmol, 49%). IR (UATR): max 2926, 1608, 1506, 1466, 1333, 1246, 1205, 1031, 885, 740 cm-1. 1H NMR (400 MHz, CDCl3):  7.36 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 14.8, 8.4 Hz, 2H), 6.64 (s, 1H), 6.58 (d, J = 8.4 Hz, 2H), 6.43 (s, 1H), 4.54 (d, J = 5.2 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H), 2.89–2.83 (m, 1H), 2.76–2.71 (m, 2H), 1.96–1.91 (m, 1H), 1.74–1.68 (m, 1H).

13

C{1H} NMR (100 MHz,

CDCl3 ):  158.9, 157.5, 152.0, 148.0, 146.7, 143.0, 138.9, 138.5, 130.2, 129.8, 125.1, 124.2, 113.5, 112.7, 112.0, 110.6, 97.7, 56.8, 56.6, 56.2, 55.3, 55.1, 48.6, 47.7, 44.7, 28.0, 25.5. TOFHRMS calcd for C28H30O5Na (M+Na+) 469.1985, found 469.1968.


(25o).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (11.6 mg, 0.026 mmol, 44%). IR (UATR): max 2926, 1446, 1393, 1317, 1205, 1172, 1031, 875, 740, 718 cm-1. 1H NMR (400 MHz, CDCl3):  7.35 (d, J = 8.4 Hz, 1H), 7.03–6.99 (m, 2H), 6.75 (dd, J = 8.4, 2.2 Hz, 1H), 6.70 (dd, J = 8.4, 2.6 Hz, 1H), 6.59 (s, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.43 (s, 1H), 4.55 (d, J = 5.6 Hz, 1H), 4.32 (d, J = 7.6 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 3.68 (s, 3H), 2.86–2.77 (m, 1H), 2.75–2.64 (m, 2H), 1.96–1.89 (m, 1H), 1.76–1.67 (m, 1H). 13C{1H}



Page 46 of 58

NMR (100 MHz, CDCl3):  159.1, 157.6, 152.0, 148.1, 147.0, 143.1, 138.7, 138.4, 129.6, 129.5, 125.2, 124.1, 114.5, 112.8, 112.7, 111.5, 110.6, 97.8, 56.8, 56.6, 56.2, 55.3, 55.2, 48.4, 47.7, 45.7, 26.8, 25.8. TOF-HRMS calcd for C28H30O5Na (M+Na+) 469.1985, found 469.1977.

10-Methoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene (25p). Following the general procedure and purification by column chromatography on silica gel (5% EtOAc/hexane), the product was obtained as pale brown sticky residue (12.0 mg, 0.048 mmol, 74%). IR (UATR): max 2833, 1583, 1488, 1463, 1258, 1240, 1105, 1032, 812, 757 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.41 (d, J = 7.2 Hz, 1H), 7.26–7.22 (m, 1H), 7.17–7.09 (m, 3H), 6.81–6.80 (m, 1H), 6.69–6.66 (m, 1H), 4.28 (d, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.16 (dd, J = 15.2, 6.8 Hz, 1H), 2.84–2.62 (m, 4H), 1.78–1.71 (m, 1H), 1.59–1.49 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  158.5, 147.0, 137.2, 136.7, 134.2, 129.8, 129.0, 125.9, 125.7, 125.4, 111.5, 110.6, 55.3, 48.1, 39.1, 37.8, 28.6, 26.2. TOF-HRMS calcd for C18H17O ([M-H2]+H+) 249.1273, found 249.1265.


(25q).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky (19.8 mg, 0.051 mmol, 79%). IR (UATR): max 2928, 1607, 1500, 1437, 1334, 1264, 1167, 1037, 1032, 745 cm-1 . 1H NMR (400 MHz, CDCl3):  7.41 (d, J = 7.6 Hz, 1H), 7.21 (td, J = 7.2, 2.0 Hz, 1H), 7.15–7.08 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.73–6.70 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.35 (dd, J = 8.4, 2.8 Hz, 1H), 4.42 (d, J = 3.6 Hz, 1H), 4.33 (d, J = 6.8 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 2.80–2.76 (m, 2H), 2.68–2.64 (m, 1H), 2.01–1.94 (m, 1H), 1.74–1.65 (m, 1H).

13

C{1H} NMR (100 MHz, CDCl3):  159.2, 158.8, 158.3, 148.0,


Page 47 of 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


137.5, 136.9, 136.8, 129.7, 128.9, 128.0, 126.3, 125.8, 125.7, 125.6, 112.0, 110.5, 103.6, 98.4, 55.4, 55.35, 55.31, 48.0, 47.9, 46.1, 28.3, 26.3. TOF-HRMS calcd for C26H27O3 (M+H+) 387.1954, found 387.1946.


(25r).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (22.4 mg, 0.054 mmol, 83%). IR (UATR): max 2926, 1516, 1392, 1206, 1182, 1031, 885, 853, 770, 740 cm-1 . 1H NMR (400 MHz, CDCl3 ):  7.44 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.14–7.09 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 6.39 (s, 1H), 4.49 (d, J = 4.8 Hz, 1H), 4.36 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.66 (s, 3H), 2.90–2.83 (m, 1H), 2.79–2.69 (m, 2H), 2.00–1.93 (m, 1H), 1.77–1.68 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  158.8, 151.8, 147.9, 147.8, 142.9, 137.1, 136.9, 129.4, 128.8, 126.1, 125.8, 125.7, 124.8, 112.6, 112.1, 110.6, 97.7, 56.7, 56.5, 56.2, 55.3, 48.4, 47.4, 46.3, 27.9, 25.9. TOF-HRMS calcd for C27H28O4Na (M+Na+) 439.1879, found 439.1878.

3,10-Dimethoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(25s).

Following

the

general

procedure and purification by column chromatography on silica gel (5% EtOAc/hexane), the product was obtained as pale sticky brown residue (15.9 mg, 0.057 mmol, 96%). IR (UATR):

max 2922, 2833, 1606, 1488, 1326, 1258, 1192, 1032, 812, 757 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.36 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 6.71–6.68 (m, 2H), 4.25 (d, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.17 (dd, J = 15.2, 6.8 Hz, 1H), 2.82–2.75 (m, 2H), 2.76–2.63 (m, 2H), 1.81–1.79 (m, 1H), 1.61–1.50 (m, 1H).



13

Page 48 of 58

C{1H} NMR (100 MHz, CDCl3):  158.5, 157.7, 147.4, 138.4, 134.1, 130.6, 129.0, 125.4,

113.6, 112.0, 111.4, 111.5, 55.3, 55.2, 47.4, 9.3, 37.7, 28.9, 26.0. TOF-HRMS calcd for C19H21O2 (M+H+) 281.1536, found 281.1532.

7-(2,4-Dimethoxyphenyl)-3,10-dimethoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(25t).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (19.7 mg, 0.048 mmol, 80%). IR (UATR): max 2836, 1609, 1583, 1500, 1455, 1207, 1153, 1035, 835, 751 cm-1. 1H NMR (400 MHz, CDCl3):  7.39 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.65–6.63 (m, 2H), 6.50 (s, 1H), 6.34 (d, J = 8.4 Hz, 1H), 4.41 (d, J = 2.4 Hz, 1H), 4.27 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.77 (s, 9H), 2.78–2.74 (m, 2H), 2.66–2.60 (m, 1H), 1.99–1.92 (m, 1H), 1.72–1.62 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3 ):  159.2, 158.8, 158.3, 157.6, 148.4, 138.6, 136.8, 130.5, 129.1, 128.0, 126.3, 125.6, 113.5, 112.01, 112.00, 110.4, 103.6, 98.4, 55.4, 55.34, 55.30, 55.1, 48.2, 47.8, 45.4, 28.7, 26.2. TOF-HRMS calcd for C27H28O4 (M+) 416.1982, found 416.1942.


(25u).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (23.7 mg, 0.053 mmol, 90%). IR (UATR): max 2926, 1506, 1466, 1438, 1317, 1205, 1171, 1031, 815, 740 cm-1. 1H NMR (400 MHz, CDCl3):  7.36 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.58 (s, 1H), 6.38 (s, 1H), 4.48 (d, J = 4.4 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.66


Page 49 of 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(s, 3H), 2.87–2.81 (m, 1H), 2.77–2.66 (m, 2H), 1.98–1.91 (m, 1H), 1.75–1.66 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  158.8, 157.5, 151.8, 148.2, 147.9, 142.9, 138.6, 137.0, 130.3, 129.1, 126.1, 124.4, 113.5, 112.6, 112.1, 112.0, 110.5, 97.6, 56.7, 56.5, 56.2, 55.3, 55.1, 48.5, 47.2, 45.5, 28.3, 25.8. TOF-HRMS calcd for C28H30O5Na (M+Na+) 469.1985, found 469.1972.

2,10-Dimethoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(25v). Following

the

general

procedure and purification by column chromatography on silica gel (5% EtOAc/hexane), the product was obtained as pale brown sticky residue (11.9 mg, 0.043 mmol, 72%). IR (UATR):

max 2922, 1606, 1463, 1326, 1258, 1240, 1153, 1032, 812, 777 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.13 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.85 (br d, J = 1.2 Hz, 1H), 6.74 (dd, J = 8.2, 2.6 Hz, 1H), 6.70–6.67 (m, 1H), 4.24 (d, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.14 (dd, J = 15.4, 7.0 Hz, 1H), 2.82–2.74 (m, 1H), 2.73–2.59 (m, 3H), 1.76–1.70 (m, 1H), 1.56–1.50 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  158.5, 157.6, 146.9, 137.8, 134.3, 129.7, 129.4, 125.4, 115.0, 111.8, 111.5, 110.7, 55.39, 55.35, 48.5, 39.1, 37.7, 27.7, 26.4. TOF-HRMS calcd for C19H21O2 (M+H+) 281.1536, found 281.1538.

7-(2,4-Dimethoxyphenyl)-2,10-dimethoxy-6,6a,7,11b-tetrahydro-5H-benzo[c]fluorene

(25w).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexanes), the product was obtained as pale brown sticky residue (19.4 mg, 0.047 mmol, 79%). IR (UATR): max 2836, 1500, 1457, 1334, 1246, 1203, 1167, 1023, 814, 745 cm-1. 1H NMR (400 MHz, CDCl3 ):  7.00 (t, J = 8.4 Hz, 2H), 6.97 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.73–6.70 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.34 (dd, J = 8.4, 2.4 Hz, 1H), 4.42 (d, J = 3.6 Hz, 1H), 4.29 (d, J = 6.8 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.78 (s,



3H), 2.77–2.61 (m, 3H), 1.98–1.92 (m, 1H), 1.72–1.64 (m, 1H).

Page 50 of 58

13

C{1H} NMR (100 MHz,

CDCl3 ):  159.2, 158.8, 158.3, 157.6, 147.8, 137.9, 137.0, 129.67, 126.65, 128.0, 126.3, 125.6, 114.8, 112.0, 111.7, 110.5, 103.6, 98.4, 55.4, 55.37, 55.32, 55.30, 48.0, 47.8, 46.4, 27.4, 26.5. TOF-HRMS calcd for C27H29O4 (M+H+) 417.2060, found 417.2072.


(25x).

Following the general procedure and purification by column chromatography on silica gel (10% EtOAc/hexane), the product was obtained as pale brown sticky residue (22.7 mg, 0.051 mmol, 86%). IR (UATR): max 2929, 1607, 1500, 1462, 1313, 1256, 1200, 1030, 852, 815 cm-1. 1H NMR (400 MHz, CDCl3):  7.03–6.95 (m, 4H), 6.73 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 6.58 (s, 1H), 6.38 (s, 1H), 4.49 (d, J = 4.8 Hz, 1H), 4.32 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 2.83–2.76 (m, 1H), 2.73–2.65 (m, 2H), 1.98–1.91 (m, 1H), 1.75–1.65 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  158.8, 157.6, 151.9, 147.9, 147.7, 142.9, 138.0, 137.2, 129.6, 126.2, 124.7, 114.6, 112.6, 112.1, 111.7, 110.6, 97.7, 56.7, 56.5, 56.2, 55.3, 55.2, 48.4, 47.3, 46.6, 27.0, 26.1. TOF-HRMS calcd for C28H30O5Na (M+Na+) 469.1985, found 469.1977.

Supporting Information: The Supporting Information is available free of charge on the ACS Publications website. 1H and

13

C{1H} NMR spectra for all products (PDF), listings of J values

(JH5-H6 as well as JH6-H7) of 23a-k and 25a-x and selected NOEs.

Acknowledgments


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Financial support from the Thailand Research Fund (TRF; BRG5980010 and DBG6080007 for P.P.) and Mahidol University is gratefully acknowledged.

References 1) Tedesco, R.; Youngman, M. K.; Wilson, S. R.; Katzenellenbogen, J. A. Synthesis and Evaluation of Hexahydrochrysene and Tetrahydrobenzofluorene Ligands for the Estrogen Receptor. Bioorg. Med. Chem. Lett. 2001, 11, 1281–1284. 2) (a) Bartubara, I.; Mitsunaga, T.; Ohashi, H. Brazilin from Caesalpinia sappan wood as an Antiacne Agent. J. Wood Sci. 2010, 56, 77–81. (b) Wu, S. Q.; Otero, M.; Unger, F. M.; Goldring, M. B.; Phrutivorapongkul, A.; Chiari, C.; Kolb, A. Viernstein, H.; Toegel, S. Anti-inflammatory Activity of an Ethanolic Caesalpinia sappan Extract in Human Chondrocytes and Macrophages. J. Ethnopharmacol. 2011, 138, 364–372. (c) Lee, D.-Y.; Lee, M.-K.; Kim, G.-S.; Noh, H.-J.; Lee, M.-H. Brazilin Inhibits Growth and Induces Apoptosis in Human Bioblastoma Cells. Molecules 2013, 18, 2449–2457. (d) Jung, E.-G.; Han, K.-I.; Hwang, S. G.; Kwon, H.-J.; Patnaik, B. B.; Kim, Y. H.; Han, M.-D. Brazilin Isolated from Caesalpinia sappan L. Inhibits Rheumatoid Arthritis Activity in a Type-II Collagen Induced Arthritis Mouse Model. BMC Complement Altern. Med. 2015, 15, 124. (e) Lee, H.; Kang, S. W.; Byun, H. S.; Jeon, J.; Park, K. A.; Kang, K.; Seo, W.; Won, M.; Seok, J. H.; Han, M.-D.; Shen, H.-M.; Hur, G. M. Brazilin Limits Inflammatory Responses through Induction of Prosurvival Autophagy in Rheumatoid Fibroblast-Like Synoviocytes. PloS One 2015, 10, e0136122. (f) Nirmal, N. P.; Rajput, M. S.; Prasad, R. G. S. V.; Ahmad, M. Brazilin from Caesalpinia sappan Heartwood and its



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Pharmacological Activities: A Review. Asian Pac. J. Trop. Med. 2015, 8, 421–430 and references cited therein. 3) For total synthesis of racemic and (+)- or (–)-brazilin, please see: (a) Davis, F. A.; Chem, B.-C. Enantioselective Synthesis of

(+)-O-Trimethylsappanone B and

(+)-O-

Trimethylbrazilin. J. Org. Chem. 1993, 58, 1751–1753. (b) Huang, Y.; Zhang, J.; Pettus, T. R. R. Synthesis of (±)-Brazilin Using IBX. Org. Lett. 2005, 7, 5841–5844. (c) Wang, X.; Zhang, H.; Yang, X.; Zhao, J.; Pan, C. Enantioselective Total Synthesis of (+)Brazilin, (–)-Brazilein and (+)-Brazilide A. Chem. Commun. 2013, 49, 5405–5407. (d) Li, L.-Q.; Li, M.-M.; Wang, K.; Qin, H.-B. Total Synthesis of (±)-Brazilin and Formal Synthesis of (±)-Brazilein, (±)-Brazilide A Using m-CPBA. Tetrahedron Lett. 2013, 54, 6029–6031. (e) Yadav, J. S.; Mishra, A. K.; Das, S. Formal Synthesis of (±)-Brazilin and Total Synthesis of (±)-Brazilane. Tetrahedron 2014, 70, 7560–7566. (f) Javed, U.; Karim, M.; Jahng, K. C.; Park, J.-G.; Jahng, Y. Enantioselective Syntheses of (+)- and (–)Brazilin. Tetrahedron: Asymmetry 2014, 25, 1270–1274. (g) Jung, Y.; Kim, I. Total Synthesis of Brazilin. J. Org. Chem. 2015, 80, 2001–2005. 4) (a) Ishii, H.; Koyama, H.; Hagiwara, K.; Miura, T.; Xue, G.; Hashimoto, Y.; Kitahara, G.; Aida, Y.; Suzuki, M. Synthesis and Biological Evaluation of Deoxy-hematoxylin Derivatives as a Novel Class of Anti-HIV-1 Agents. Bioorg. Med. Chem. Lett. 2012, 22, 1469–1474. (b) Reddy, B. V. S.; Raju, N. P.; Someswarao, B.; Reddy, B. J. M.; Sridhar, B.; Marumudi, K.; Kumwar, A. C. A Novel Domino Cyclization for the Stereoselective Synthesis of Indeno[2,1-c]pyran and Cyclopenta[c]pyran Derivatives. Org. Biomol. Chem. 2015, 13, 4733–4736.


Page 53 of 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5) For an example of a transannular cyclization across a nine-membered ring system, see: Iqbal, M.; Black, R. G. J.; Winn, J.; Reeder, A. T.; Blake, A. J.; Clarke, P. A. Studies on Transannulation Reactions across a Nine-Membered Ring: the Synthesis of Natural Product-Like Structures. Org. Biomol. Chem. 2011, 9, 5062–5078. 6) For acid-mediated intramolecular cyclization of a styrenyl/stilbenyl olefin onto the benzylic alcohol or its derivatives, see: (a) Lantaño, B.; Aguirre, J. M.; Ugliarolo, E. A.; Benegas, M. L.; Moltrasio, G. Y. Scope of the Formal [3+2] Cycloaddition for the Synthesis of Substituted 3-Arylindanes and Related Compounds. Tetrahedron 2008, 64, 4090–4102. (b) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L. Total Synthesis of Diverse Carbogenic Complexity within the Resveratrol Class from a Common Building Block. J. Am Chem. Soc. 2009, 131, 1753–1765. (c) Lantaño, B.; Aguirre, J. M.; Ugliarolo, E. A.; Torviso, R.; Pomilio, N.; Moltrasio, G. Y. Scope of the Formal [3+2] Cycloaddition for the Synthesis of Five-Membered Ring of Functionalized Indanes. Tetrahedron 2012, 68, 913–921. (d) Sarnpitak, P.; Trongchit, K.; Kostenko, Y.; Sathalalai, S.; Gleeson, M. P.; Ruchirawat, S.; Ploypradith, P. Synthesis of Substituted 2‑Arylindanes from E‑(2-Stilbenyl)methanols via Lewis Acid-Mediated Cyclization and Nucleophililc Transfer from Trialkylsilyl Reagents. J. Org. Chem. 2013, 78, 8281–8296. 7) (a) Yet, L. Metal-Mediated Synthesis of Medium-Sized Rings. Chem. Rev. 2000, 100, 2963–3007 and references cited therein. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Metathesis Reactions in Total Synthesis. Angew. Chem. Int. Ed. Engl. 2005, 44, 4490– 4527 and references cited therein. (c) Monfette, S.; Fogg, D. E. Ring-Closing Metathesis of Medium and Large Rings: Challenges and Implications for Sustainable Synthesis. In Green Metathesis Chemistry; Dragutan, V., Demonceau, A., Finkelshtein, E. S., Eds.,



Page 54 of 58

Springer: Dordrecht, Germany, 2010; pp 129–156 and references cited therein. (c) Tori, M.; Mizutani, R. Construction of Eight-Membered Carbocycles with Trisubstituted Double Bonds Using the Ring Closing Metathesis Reaction. Molecules 2010, 15, 4242– 4260 and references cited therein. (d) Tymoshenko, D. O. Nine-Membered Rings. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds., Elsevier: Amsterdam, 2008; Vol. 14, pp 547–611 and references cited therein. 8) For similar considerations, see: (a) Otani, T.; Ueki, K.; Cho, K.; Kanai, K.; Tateno, K.; Saito, T. Construction of Dibenzo-Fused Seven- to Nine-Membered Carbocycles via Brønsted Acid-Promoted Intramolecular Friedel–Crafts-type Alkenylation. Chem. Commun. 2015, 51, 7895–7898. (b) Li, L.; Li, Z.-L.; Wang, F.-L.; Guo, Z.; Cheng, Y.-F.; Wang, N.; Dong, X.-W.; Fang, C.; Liu, J.; Hou, C.; Tan, B.; Liu, X.-Y. Radical Aryl Migration Enables Diversity-Oriented Synthesis of Structurally Diverse Medium/Macroor Bridged-Rings. Nat. Commun. 2016, 7, 13852. 9) (a) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Ring Closing Metathesis for the Formation of Medium Ring Ethers: The Total Synthesis of (–)-Isolaurallene. Tetrahedron 2002, 58, 1817–1834. (b) Basavaiah, D.; Reddy, B. S.; Lingam, H. Synthesis of Fused Nine-Membered Rings: a Simple Protocol for Synthesis of [1,2,3]-Triazolo-[1,4]Benzoxazonine Frameworks from the Baylis–Hillman Acetates. Tetrahedron 2013, 69, 10060–10067. (c) Das, P.; Gondo, S.; Nagender, P.; Uno, H.; Tokunaga, E.; Shibata, N. Access

to

Benzo-Fused

Nine-Membered

Heterocyclic

Alkenes

with

a

Trifluoromethylcarbinol Moiety via a Double Decarboxylative Formal Ring-Expansion Process under Palladium Catalysis. Chem. Sci. 2018, 9, 3276–3281.


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10) For other approaches (not by RCM) to access nine-membered rings via 1) [6 + 3] cycloaddition with tropones, see: (a) Trost, B. M.; McDougall, P. J.; Hartmann, O.; Walthen, P. T. Asymmetric Synthesis of Bicyclo[4.3.1]-decadienes and Bicyclo[3.3.2]decadienes via [6 + 3] Trimethylenemethane Cycloaddition with Tropones. J. Am. Chem. Soc. 2008, 130, 14960–14961. (b) Liu, H.; Wu, Y.; Zhao, Y.; Li, Z.; Zhang, L.; Yang, W.; Jiang, H.; Jing, C.; Yu, J. H.; Wang, B.; Xiao, Y.; Guo, H. Metal-Catalyzed [6 + 3] Cycloaddition of Tropone with Azomethine Ylides: A Practical Access to PiperidineFused Bicyclic Heterocycles. J. Am. Chem. Soc. 2014, 136, 2625–2629. 2) palladium catalysis, see: (c) Shintani, R.; Murakami, M.; Tsuji, T.; Tanno, H.; Hayashi, T. Palladium-Catalyzed Decarboxylative [4 + 3] Cyclization of -Methylidene-valerolactones with 1,1-Dicyanocyclopropoanes. Org. Lett. 2009, 11, 5642–5645. (d) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Diversity Oriented Synthesis of Indole-Based PeriAnnulated Compounds via Allylic Alkylation Reactions. Chem. Sci. 2013, 4, 97–102. (e) Huang, L.; Dai, L.-X.; You, S.-L. Enantioselective Synthesis of Indole-Annulated Medium-Sized Rings. J. Am. Chem. Soc. 2016, 138, 5793–5796. (f) Rong, Z.-Q.; Yang, L.-C.; Liu, S.; Yu, Z.; Wang, Y.-N.; Tan, Z. Y.; Huang, R.-Z.; Lan, Y.; Zhao, Y. NineMembered Benzofuran-Fused Heterocycles: Enantioselective Synthesis by Pd-Catalysis and Rearrangement via Transannular Bond Formation. J. Am. Chem. Soc. 2017, 139, 15304–15307. (g) Yang, L.-C.; Rong, Z.-Q.; Wang, Y.-N.; Tan, Z. Y.; Wang, M.; Zhao, Y. Construction of Nine-Membered Heterocycles through Palladium-Catalyzed Formal [5 + 4] Cycloaddition. Angew. Chem. Int. Ed. Engl. 2017, 56, 2927–2931. 3) ring expansion, see: (h) Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Biomimetic Diversity-



Oriented Synthesis of Benzannulated Medium Rings via Ring Expansion. Nat. Chem. Biol. 2013, 9, 21–29. 11) Surprisingly, the reaction did not proceed at all with the use of CF3CO2H; 21a could be fully recovered. This is quite in sharp contrast to other previously reported reactions via acid-mediated cyclization/nucleophilic addition. See ref. 6 for comparison. 12) (a) Tangdenpaisal, K.; Phakhodee, W.; Ruchirawat, S.; Ploypradith, P. Facile Synthesis of Diarylmethanes via Quinone Methides. Tetrahedron 2013, 69, 933–941. (b) Tangdenpaisal, K.; Ruchirawat, S.; Ploypradith, P. Synthesis of the Thyroid Hormone Analog GC-1 via Bi(OTf)3-Catalyzed Benzylation. Tetrahedron 2014, 70, 6789–6795. 13) Unfortunately, the O-alkylated product was rather unstable; complete characterization could not be obtained. 14) See Supporting Information for the detailed NOE values for compounds 23c, 23d, 23f, 23k, 25b, 25c, 25f, 25i, 25l, 25o, 25q, 25t, 25u, and 25x. Consistently larger NOE values were observed between H5-H6 (1.6-3.6%) than H6-H7 (0.5-1.2%). More importantly, no NOEs were observed between H5-H7. Taken together, the NOE studies strongly indicated that H5 and H6 are on the same phase (5,6-cis) while H5-H7 (as well as H6-H7) are not (5,7-trans). It should be noted that while the coupling constants between H5-H6 for 23a-k and 25a-25x are consistent (6.4–7.6 Hz; except 23c (8.8 Hz) and 23k (9.2 Hz)) and in the same range as those found for the indane derivatives with cis H2-H3 (8.0–8.1 Hz; similar position to C5-C6 for 23a-k and 25a-25x), those between H6-H7 range from 2.0-8.8 Hz and may not be indicative of the relative stereochemistry. For comparison, indane derivatives with trans H1-H2 exhibit coupling constants of 7–8 Hz. For more detail of coupling constants and NOE values of the indane derivatives, see: Jongcharoenkamol, J.;


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Chuathong, P; Amako, Y.; Kono, M.; Poonswat, K.; Ruchirawat, S; Ploypradith, P. Selective Divergent Synthesis of Indanols, Indanones, and Indenes via Acid-Mediated Cyclization of (Z)- and (E)-(2-Stibenyl)methanols and its Application for the Synthesis of Paucifloral F Derivatives. J. Org. Chem. 2018, 83, 13184–13210. 15) A compound with similar relative stereochemistry at C5-C6-C7 on the same skeleton as our final products (but with different substituent at C7) was obtained by different chemistry and characterized spectroscopically. The assignment of such stereochemistry was based on the correlations with other compounds whose structures were established by X-ray crystallography. For more detail, see: Kinoshita, H.; Ingham, O. J.; Ong, W. W.; Beeler, A. B.; Porco, J. A. Jr. Tandem Processes Identified from Reaction Screening: Nucleophilic Addition to Aryl N-Phosphinylimines Employing La(III)-TFAA Activation. J. Am. Chem. Soc. 2010, 132, 6412–6418. 16) While the pentadienyl cation-like intermediates have been implicated in the Nazarov-type conrotatory 4-electrocyclization, it is very unlikely that this transannular cyclization would proceed through such mechanism. If the reaction were to proceed through the Nazarov-type mechanism, the 5,6-trans, instead of the observed 5,6-cis, ring junction would be expected. Thus, for our substrates, the stepwise mechanism involving the intermediacy of two carbocations were proposed. For additional discussions on the Nazarov reactions, see: (a) Vinogradov, M. G.; Turova, O. V.; Zlotin, S. G. Nazarov Reaction: Current Trends and Recent Advances in the Synthesis of Natural Compounds and Their Analogs. Org. Biomol. Chem. 2017, 15, 8245–8269 and references cited therein. (b) Vaidya, T.; Cheng, R.; Carlsen, P. N.; Frontier, A. J.; Eisenberg, R. Cationic Cyclizations and Rearrangements Promoted by a Heterogeneous Gold Catalyst. Org. Lett.



2014, 16, 800–803. (c) Sai, M.; Matsubara, S. Lithium(1+)-Catalyzed Nazarov-Type Cyclization of 1-Arylbuta-2,3-dien-1-ols: Synthesis of Benzofulvene Derivatives. Synlett 2014, 25, 2067–2071.


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Stereoselective Convergent Synthesis of Tetrahydro-5H-benzo[c

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