Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 10107−10119
1,6-Hydroolefination and Cascade Cyclization of p‑Quinone Methides with Styrenes: Total Synthesis of (±)-Isopaucifloral F Abhijeet S. Jadhav,‡ Yogesh A. Pankhade,‡ Raju Hazra, and Ramasamy Vijaya Anand* Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, Knowledge City, S. A. S. Nagar, Manauli (PO), Punjab − 140306, India
J. Org. Chem. 2018.83:10107-10119. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/08/18. For personal use only.
S Supporting Information *
ABSTRACT: A Lewis acid-catalyzed intermolecular 1,6hydroolefination of p-quinone methides with styrenes leading to vinyl diarylmethanes and indenes has been developed. This protocol was also elaborated to the total synthesis of (±)-isopaucifloral F. Besides, interestingly, the reaction between 2-alkynylated p-quinone methides and styrenes provided a straightforward access to dihydrobenzo[a]fluorene derivatives in one pot with 100% atom-economy.
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INTRODUCTION Hydroolefination or hydroalkenylation refers to the direct addition of olefins to electrophiles with the conservation of 100% atom-economy in the products. Principally, this process offers direct access to substituted olefins. Over the past decade, much effort has been made to effect this transformation in a regioselective manner using appropriate catalytic systems. Especially, the transition-metal-catalyzed 1,2-hydroolefination of alkenes and alkynes has been well documented in the literature.1 On the other hand, the 1,4-conjugate hydroolefination of enones with simple olefins still remains as an underexplored transformation,2 although there are several other non-atom-economical methods that have been developed to introduce a vinyl group into the enone systems using alkenyl organometallic reagents.3 Surprisingly, until date, no reports are available for the direct 1,6-hydroolefination of dienone systems with olefins. Nevertheless, a few alternative methods are available for the vinylogous alkenylation of dienones using alkenyl organometallic reagents.4 However, the poor regioselectivity outcome (1,6- vs 1,4-addition) and the requirement of stoichiometric quantities of moisture-sensitive organometallic reagents make these processes practically unattractive. Therefore, designing and developing a highly regioselective 1,6-hydroolefination of dienone systems with simple olefins is highly desired, as one can potentially achieve 100% atom-economy in the products through this process. In recent years, there has been a growing interest in the area of p-quinone methides (p-QMs) chemistry.5 While working in this particular research area,6 we envisioned that p-QM could serve as a perfect 1,6-acceptor for the 1,6-hydroolefination reaction with styrenes. In the meantime, Cui and co-workers reported the Fe-catalyzed reductive hydroalkylation of pquinone methides with substituted allyl alcohol derivatives using silane as a reducing agent.7 Recently, Li’s group © 2018 American Chemical Society
developed a Lewis acid-catalyzed desilylative vinylogous 1,6conjugate addition of 3-propenyl-2-silyloxyindoles to p-QMs to access functionalized oxindole derivatives.8 However, the direct 1,6-hydroolefination of p-QMs to access vinyl diarylmethane derivatives is not precedented so far, which triggered us to investigate this transformation in detail (Scheme 1).
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RESULTS AND DISCUSSION We commenced the optimization studies by employing pquinone methide 1a and 1,1-diphenylethylene 2a under various reaction conditions, and the results are summarized in Table 1. To our delight, our initial attempt itself, using Cu(OTf)2 as a catalyst in CH2Cl2, gave a positive result, as the desired product 3a was obtained in 86% yield in 6 h at room temperature (entry 1). Other metal triflates, such as Zn(OTf)2, Sc(OTf)3, and AgOTf, were also found to be very effective to drive this transformation and, in those cases, 3a was isolated in 81%, 96%, and 99% yields, respectively (entries 2−4). Unfortunately, Mg(OTf)2 failed to catalyze this transformation even after 24 h (entry 5). Pleasingly, when the reaction was performed using Bi(OTf)3 as a catalyst, 3a was obtained in 99% yield within 5 min (entry 6). Thus, further optimization experiments were performed using Bi(OTf)3 in other solvents, such as 1,2-dicholoethane, toluene, DMF, etc. (entries 7−11). However, none them were found to be superior to CH2Cl2. No reaction occurred in the absence of the catalyst, which clearly indicates the requirement of a Lewis acid catalyst for this transformation (entry 12). The reaction was also conducted on a gram scale (entry 13) using 1 g of 1a under standard conditions (entry 6), and the product 3a was obtained in 92% yield. Received: June 4, 2018 Published: July 25, 2018 10107
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry Scheme 1. 1,6-Hydroolefination of p-QMs with Olefins
Table 1. Optimization Studiesa
Scheme 2. Substrate Scopea
entry
catalyst
solvent
time
yield [%]
1 2 3 4 5 6 7 8 9 10 11 12 13b
Cu(OTf)2 Zn(OTf)2 Sc(OTf)3 AgOTf Mg(OTf)2 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 Bi(OTf)3 − Bi(OTf)3
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 DCE toluene MeCN THF DMF CH2Cl2 CH2Cl2
6h 12 h 16 h 3.5 h 24 h 5 min 5 min 25 min 25 min 16 h 24 h 24 h 10 min
86 81 96 99 NR 99 95 97 94 71 NR NR 92
a
Reaction conditions: All reactions were carried out with 0.062 mmol of 1a and 0.074 mmol of 2a in solvent (1.5 mL) at room temperature (30−33 °C). bThe reaction was performed on a 1.0 g scale of 1a. DCE = 1,2-dichloroethane. NR = no reaction. a
Reaction conditions: The reactions were performed on a 0.043−0.2 mmol scale of 1(b−p) in 1.5−2 mL of CH2Cl2. bThe E:Z ratios were calculated based on 2-D NMR (refer to SI for the spectra).
With the optimized reaction conditions in hand (entry 6, Table 1), we next surveyed the substrate scope of this methodology using various p-quinone methides (1b−p), and the results are summarized in Scheme 2. This protocol worked extremely well, irrespective of the electronic nature of the aryl group attached to the p-QMs, and the corresponding products were obtained in good to excellent yields within a very short span of time (1−10 min). Most of the p-QMs (1b−n) provided the corresponding products (3b−n) in excellent isolated yields. In the case of p-QM (1o), derived from 2,6dimethylphenol, the expected product 3o was obtained in 90% yield. Other olefins, including the cyclic ones, reacted efficiently under optimized conditions and produced the respective products 3p−t in the range of 85−99% yields. In fact, this method was also found to be effective when styrene was used as a nucleophile, and, in this case, the desired product 3u was obtained in 60% yield. Interestingly, in the case of pQM 1p9 (derived from salicylaldehyde), a dihydrobenzopyran derivative 3v was obtained in 60% yield. In this particular case, we believe that the reaction between 1p and 2a generates a carbocation intermediate 4, which gets trapped by the intramolecular attack of the hydroxyl group of phenol to give the product 3v. We then shifted our attention to examine the intramolecular hydroolefination reaction using 2-alkenylated p-quinone methides (Scheme 3). It is interesting that this type of reactions would generate arylated indene derivatives, and such cores are often found in many biologically significant molecules
Scheme 3. Intramolecular Hydroolefination of p-QMsa
a Reaction conditions: Reactions were carried out on a 0.043−0.06 mmol scale of 5(a−f) in 1.5−2 mL of CH2Cl2.
including the resveratrol-based natural products (7, 8, and 9, Scheme 3).10 Delightfully, when the 2-alkenylated p-quinone methides (5a−f) were subjected to cyclization reaction under the optimized conditions, the respective indene derivatives 10108
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry Scheme 4. Total Synthesis of (±)-Isopaucifloral F (7)
Next, we were interested to examine the reaction between 2alkynylated p-quinone methides and styrenes. We envisioned that, in this case, it is possible to access substituted naphthalene derivatives (20) through 1,6-conjugate addition of olefins to 2-alkynylated p-quinone methides followed by intramolecular electrophilic alkene−alkyne cyclization in a one-pot manner (Scheme 5). In this context, a readily available
(6a−f) were obtained in the range of 72−97% isolated yields (Scheme 3). To show the synthetic application of the intramolecular hydroolefination reaction, we directed our efforts to synthesize (±)-isopaucifloral F (7), which is one of the resveratrolderived natural products.10 There are several divergent approaches reported for the synthesis of 710 and related natural products.11,12 Here we thought of utilizing the intramolecular hydroolefination strategy to construct the fivemembered ring core of 7. Thus, we initiated the total synthesis of 7 using a readily available bromoaldehyde 10 (Scheme 4). The Pd-catalyzed Heck reaction between 10 and 11 provided the alkenylated aldehyde 12, which on subsequent treatment with 2,6-di-tert-butylphenol (13) in the presence of piperidine and acetic anhydride delivered the 2-alkenylated p-QM 14 at elevated temperature. The p-QM 14 was then subjected to intramolecular hydroolefination using Bi(OTf)3 as a catalyst in toluene to provide the indene derivative 15 in 75% yield. The reduction of 15 with 5% Pd/C and H2 in ethanol gave the reduced product 16 as a single diastereomer (cis-isomer) in 99% yield. Initially, 16 was subjected to benzylic oxidation with SeO2 under various conditions. However, unfortunately, only decomposition of 16 was observed. We believed that the formation of many unidentified products could be due to the free phenolic group present in 16. Consequently, we have decided to protect the phenolic group as a methoxy group. Subsequently, 16 was treated with dimethyl sulfate under basic conditions to get the protected derivative, which was directly subjected to benzylic oxidation with SeO2. However, in this case, overoxidation took place, and, as a result, the enone 17 was obtained 45% yield (two steps). Interestingly, the reduction of 17 with Pd−C and H2 in refluxing ethanol directly gave the trans-isomer 18 in 96% yield with excellent diastereoselectivity (dr = 96:4).13 Finally, the deprotection of methoxy groups of 18 followed by the removal tert-butyl groups were carried out sequentially using excess of BBr3 and AlCl3, respectively, to provide the target 7 in 65% yield (two steps).
Scheme 5. Cascade Cyclization of 19a
2-alkynylated p-quinone methide 19a14 was treated with 2a using Bi(OTf)3 as a catalyst. But, unfortunately, only the decomposition of 19a was observed. Similarly, silver catalysts such as AgNO3 and AgOTf failed to effect this transformation, as decomposition of 19a was observed in both the cases. However, when AgSbF6 was used as a catalyst in CH2Cl2, 19a was completely consumed within 15 min. Interestingly, the expected naphthalene derivative 20 was not formed; instead, the dihydrobenzo[a]fluorene 21a was obtained as a sole product in 95% yield [dr {anti:syn} = >20:1] (Scheme 5). The structure of 21a was unambiguously confirmed by X-ray analysis. Further optimization was carried out using AgSbF6 as a catalyst in other solvents such as toluene, MeCN, and THF. However, in all those cases, neither 21a nor 20 was obtained, and in fact the starting material 19a remained as such. Similarly, other Lewis acids such as Cu(OTf)2, PdCl2, and 10109
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry Scheme 6. Cascade Cyclization of 2-Alkynylated p-QMsa
a
Reactions were carried out on 0.063−0.20 mmol of 19(b−o). The diastereomeric ratios were calculated from the 1H NMR analysis of the crude mixture.
Sc(OTf)3 failed to effect this transformation. An experiment was carried out in large scale using 1.0 g of 19a and 5 mol % of AgSbF6 in 15 mL of CH2Cl2, and in this case the desired product 21a was obtained in 90% yield. Of course, there few reports available for the synthesis of dihydrobenzo[a]fluorenes and related derivatives through metal/Lewis acid-catalyzed intramolecular alkene−alkyne or diyne cyclizations.15 However, since the projected one-pot strategy involving 1,6hydroolefination of 2-alkynylated p-QMs followed by intramolecular cyclization is not yet reported for the synthesis of dihydrobenzo[a]fluorenes, we proceeded with evaluation of the substrate scope using a wide range of 2-alkynylated p-QMs and styrenes, and the results are summarized in Scheme 6. Most of the 2-alkenylated p-QMs (19b−k) underwent reaction with 2a and provided the corresponding products 21b−k in good to excellent yields (79−97%) and diastereoselectivity [dr {anti:syn} = 7:1 to >20:1] (Scheme 6). Other p-QMs (19l−o), derived from substituted benzaldehydes, also gave the respective dihydrobenzo[a]fluorenes (21l−o) in good yields and excellent diastereoselectivity [dr {anti:syn} = 10:1 to >20:1]. The substrate scope was also elaborated using different alkenes (2b and 2c), and in both the cases the products 21p and 21q were obtained in 68 and 90% yields [dr {anti:syn} = 10:3 to 10:1]. A plausible mechanism for this reaction has been proposed (Scheme 7). We believe that, initially, silver catalyst activates the carbonyl group of p-QM 19a and the subsequent 1,6addition of olefin 2a generates a reactive carbocation intermediate 24, which gets trapped by the intramolecular attack of alkyne to generate another carbocation intermediate
Scheme 7. Plausible Mechanism for the Formation of 21a
25. Then the carbocation intermediate 25 undergoes intramolecular Friedel−Crafts type cyclization to give yet another carbocation intermediate 26, which further undergoes aromatization to generate the final product 21a (Scheme 7). We believe that the SbF6 anion plays a very important role in stabilizing the carbocation intermediates wherever involved. This could be the reason why this particular transformation 10110
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry
(m, 6H), 7.28−7.24 (m, 3H), 7.00 (s, 2H), 6.62 (d, J = 10.6 Hz, 1H), 5.12 (s, 1H), 4.79 (d, J = 10.6 Hz, 1H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 143.9, 142.5, 141.13, 141.11, 140.0, 139.0, 135.9, 134.8, 132.0, 130.1, 128.9, 128.87 (2C), 128.4, 128.3, 127.6, 127.4, 127.3, 127.2, 127.1, 125.1, 50.1, 34.6, 30.5; FT-IR (neat): 3635 cm−1; HRMS (ESI): m/z calcd for C41H41O [M − H]−: 549.3157; found: 549.3132. 2,6-Di-tert-butyl-4-(1-(4-ethylphenyl)-3,3-diphenylallyl)phenol (3d). The reaction was performed on 0.2 mmol of 1d; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (99.5 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.42−7.34 (m, 3H), 7.33−7.27 (m, 4H), 7.26−7.22 (m, 3H), 7.17−7.12 (m, 4H), 6.96 (s, 2H), 6.57 (d, J = 10.6 Hz, 1H), 5.08 (s, 1H), 4.7 (d, J = 10.7 Hz, 1H), 2.65 (d, J = 7.6 Hz, 2H), 1.41 (s, 18H), 1.25 (d, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.2, 142.7, 142.0, 141.8, 140.7, 140.1, 135.7, 135.0, 132.4, 130.2, 128.4, 128.3, 128.2, 128.0, 127.6, 127.3, 127.1, 125.1, 50.0, 34.5, 30.5, 28.6, 15.8; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C37H41O [M − H]−: 501.3157; found: 501.3143. 2,6-Di-tert-butyl-4-(1-(4-(tert-butyl)phenyl)-3,3-diphenylallyl)phenol (3e). The reaction was performed on 0.2 mmol of 1e; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (103 mg, 97% yield); 1 H NMR (400 MHz, CDCl3) δ 7.43−7.38 (m, 2H), 7.37−7.31 (m, 3H), 7.31−7.26 (m, 4H), 7.25−7.21 (m, 3H), 7.15 (d, J = 8.2 Hz, 2H), 6.96 (s, 2H), 6.59 (d, J = 10.7 Hz, 1H), 5.08 (s, 1H), 4.70 (d, J = 10.7 Hz, 1H), 1.41 (s, 18H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.2, 148.9, 142.7, 141.5, 140.8, 140.1, 135.7, 134.8, 132.3, 130.2, 128.3, 128.2, 128.0, 127.6, 127.3, 127.1, 125.4, 125.1, 49.9, 34.5 (2C), 31.5, 30.5; FT-IR (neat): 3638 cm−1; HRMS (ESI): m/z calcd for C39H45O [M − H]−: 529.3470; found: 529.3445. 2,6-Di-tert-butyl-4-(3,3-diphenyl-1-(4-(phenylthio)phenyl)allyl)phenol (3f). The reaction was performed on 0.049 mmol of 1f; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (28.6 mg, 99% yield); mp = 137−139 °C; 1H NMR (400 MHz, CDCl3) δ 7.42−7.33 (m, 5H), 7.31−7.27 (m, 8H), 7.25−7.20 (m, 4H), 7.19−7.17 (m, 2H), 6.92 (s, 2H), 6.53 (d, J = 10.6 Hz, 1H), 5.10 (s, 1H), 4.72 (d, J = 10.6 Hz, 1H), 1.40 (s, 18H), 13C NMR (100 MHz, CDCl3) δ 152.3, 144.3, 142.4, 141.4, 139.9, 136.9, 135.9, 134.5, 132.5, 132.2, 131.6, 130.2, 130.1, 129.5, 129.2, 128.4, 128.3, 127.5, 127.4, 127.3, 126.7, 125.0, 50.0, 34.5, 30.4; FT-IR (neat): 3635 cm−1; HRMS (ESI): m/z calcd for C41H41OS [M − H]−: 581.2878; found: 581.2852. 2,6-Di-tert-butyl-4-(1-(2-fluorophenyl)-3,3-diphenylallyl)phenol (3g). The reaction was performed on 0.064 mmol of 1g; Rf = 0.4 (5% EtOAc in hexane); colorless gummy solid (30.3 mg, 96% yield); 1H NMR (400 MHz, CDCl3) δ 7.41−7.33 (m, 3H), 7.33−7.28 (m, 5H), 7.27−7.21 (m, 2H), 7.20−7.17 (m, 2H), 7.12 (td, J = 7.5, 1.2 Hz, 1H), 7.06−7.01 (m, 1H), 6.96 (s, 2H), 6.63 (dd, J = 10.5, 1.6 Hz, 1H), 5.09 (s, 1H), 5.01 (d, J = 10.5 Hz, 1H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 160.8 (d, JC−F = 245.1 Hz), 152.2, 142.6, 142, 139.8, 135.7, 133.8, 131.4 (d, JC−F = 14.4 Hz), 130.54, 130.53, 130.1 (d, JC−F = 4.7 Hz), 130.0, 128.4, 128.3, 128.2 (d, JC−F = 8.3 Hz), 127.6, 127.3 (d, JC−F = 6.6 Hz), 124.5, 124.3 (d, JC−F = 3.4 Hz), 115.8 (d, JC−F = 22.3 Hz), 44.4 (d, JC−F = 1.5 Hz), 34.5, 30.4; 19F NMR (376 MHz, CDCl3) δ −62.45 FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C35H38FO [M + H]+: 493.2907; found: 493.2899. 4-(1-(4-Bromophenyl)-3,3-diphenylallyl)-2,6-di-tert-butylphenol (3h). The reaction was performed on 0.053 mmol of 1h; Rf = 0.4 (5% EtOAc in hexane); white solid (28.3 mg, 96% yield); mp = 144−146 °C; 1H NMR (400 MHz, CDCl3) δ 7.44−7.40 (m, 3H), 7.38−7.31 (m, 2H), 7.29−7.22 (m, 5H), 7.21−7.19 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.91 (s, 2H), 6.49 (d, J = 10.6 Hz, 1H), 5.11 (s, 1H), 4.67 (d, J = 10.6 Hz, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 143.9, 142.3, 141.5, 139.9, 136.0, 134.3, 131.5, 131.3, 130.3, 130.0, 128.4, 128.3, 127.5, 127.4, 127.37, 124.9, 120.0, 49.9, 34.5, 30.5; FTIR (neat): 3636 cm−1; HRMS (ESI): m/z calcd for C35H38BrO [M + H]+: 553.2106; found: 553.2100. 2,6-Di-tert-butyl-4-(3,3-diphenyl-1-(3-(trifluoromethyl)phenyl)allyl)phenol (3i). The reaction was performed on 0.052 mmol of 1i; Rf = 0.4 (5% EtOAc in hexane); colorless gummy solid (21.2 mg, 74% yield); 1H NMR (400 MHz, CDCl3) δ 7.50−7.48 (m, 3H), 7.45−
worked only with AgSbF6 and that other Lewis acids, including other silver salts, failed to catalyze this transformation.
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CONCLUSION We have developed an efficient Lewis acid-catalyzed protocol for the synthesis of vinyl diarylmethane and indene derivatives. Short reaction time, excellent yields of the products, and 100% atom-economy are the salient features of this methodology. The intramolecular version of the hydroolefination reaction was elaborated to the total synthesis of (±)-isopaucifloral F (13% overall yield). Moreover, we have shown that the present method can also be extended to 2-alkynylated p-QMs to access substituted dihydrobenzo[a]fluorene derivatives in good yields and excellent diastereoselectivity.
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EXPERIMENTAL SECTION
General Information. All reactions were carried out under argon atmosphere by employing flame-dried glassware. Most of the reagents and starting materials were purchased from commercial sources and used as such. p-Quinone methides 1a−p6a and 19a−o14 were prepared by following literature procedures. Melting points were recorded on SMP20 melting point apparatus and are uncorrected. 1H, 13 C, and 19F spectra were recorded in CDCl3 (400, 100, and 376 MHz, respectively) on Bruker FT-NMR spectrometer. Chemical shift (δ) values are reported in parts per million (ppm) relative to TMS, and the coupling constants (J) are reported in hertz (Hz). High resolution mass spectra were recorded on a Waters Q-TOF PremierHAB213 spectrometer. FT-IR spectra were recorded on a PerkinElmer FT-IR spectrometer. Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates. Column chromatography was carried out through silica gel (100−200 mesh) using EtOAc/hexane as an eluent. General Procedure for the Synthesis of Vinyl Diarylmethane Derivatives (3a−v). Substituted alkene (1.2 equiv) was added to a solution of p-quinone methide (1 equiv) and Bi(OTf)3 (0.1 equiv) in CH2Cl2 (0.05 M), and the resultant mixture was stirred vigorously at room temperature until the p-quinone methide was completely consumed (monitored by TLC). After completion of the reaction, solvent was removed under reduced pressure and the residue was directly loaded on a silica gel column and eluted using EtOAc/ hexane mixture to obtain pure vinyl diarylmethane derivatives. 2,6-Di-tert-butyl-4-(1-(4-methoxyphenyl)-3,3-diphenylallyl)phenol (3a). The reaction was performed on 0.061 mmol of 1a; Rf = 0.3 (5% EtOAc in hexane); white solid (30.8 mg, 99% yield); mp = 145−147 °C; 1H NMR (400 MHz, CDCl3) δ 7.46−7.41 (m, 2H), 7.39 (dt, J = 6.1, 1.6 Hz, 1H), 7.37−7.30 (m, 4H), 7.30−7.25 (m, 3H), 7.21−7.17 (m, 2H), 7.00 (s, 2H), 6.93−6.89 (m, 2H), 6.59 (d, J = 10.6 Hz, 1H), 5.13 (s, 1H), 4.74 (d, J = 10.6 Hz, 1H), 3.85 (s, 3H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 158.0, 152.2, 142.6, 140.7, 140.1, 136.8, 135.7, 135.1, 132.4, 130.1, 129.5, 128.3, 128.2, 127.5, 127.3, 127.2, 125.0, 113.9, 55.4, 49.5, 34.5, 30.5; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C36H39O2 [M − H]−: 503.2950; found: 503.2928. 2,6-Di-tert-butyl-4-(1,3,3-triphenylallyl)phenol (3b). The reaction was performed on 0.2 mmol of 1b; Rf = 0.4 (5% EtOAc in hexane); colorless gummy solid (94 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.44−7.32 (m, 5H), 7.32−7.29 (m, 4H), 7.28−7.26 (m, 4H), 7.24−7.22 (m, 2H), 6.97 (s, 2H), 6.6 (d, J = 10.6 Hz, 1H), 5.11 (s, 1H), 4.76 (d, J = 10.6 Hz, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.2, 144.7, 142.6, 141.0, 140.0, 135.8, 134.9, 132.1, 130.1, 128.6, 128.5, 128.4, 128.3, 127.6, 127.3, 127.2, 126.2, 125.1, 50.4, 34.5, 30.5; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C35H37O [M − H]−: 473.2844; found: 473.2826. 4-(1-([1,1′-Biphenyl]-4-yl)-3,3-diphenylallyl)-2,6-di-tert-butylphenol (3c). The reaction was performed on 0.054 mmol of 1c; Rf = 0.4 (5% EtOAc in hexane); white solid (28.9 mg, 97% yield); mp = 174− 176 °C; 1H NMR (400 MHz, CDCl3) δ 7.65−7.63 (m, 2H), 7.59− 7.57 (m, 2H), 7.48−7.41 (m, 4H), 7.40−7.35 (m, 2H), 7.34−7.31 10111
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry
hexane); colorless gummy solid (67.2 mg, 90% yield); 1H NMR (400 MHz, CDCl3) δ 7.42−7.36 (m, 3H), 7.35−7.27 (m, 7H), 7.26−7.18 (m, 5H), 6.80 (s, 2H), 6.56 (d, J = 10.6 Hz, 1H), 4.73 (d, J = 10.6 Hz, 1H), 4.56 (s, 1H), 2.23 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.7, 145.2, 142.5, 141.1, 139.9, 136.2, 131.6, 130.0, 128.6, 128.5, 128.4 (2C), 128.2, 127.6, 127.3, 127.28, 126.2, 123.1, 49.9, 16.2; FTIR (neat): 3575 cm−1; HRMS (ESI): m/z calcd for C29H25O [M − H]−: 389.1905; found: 389.1891. 2,6-Di-tert-butyl-4-((3,4-dihydronaphthalen-2-yl)(phenyl)methyl)phenol (3p). The reaction was performed on 0.067 mmol of 1b; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (26.4 mg, 93% yield); 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 2H), 7.25−7.18 (m, 3H), 7.15−7.09 (m, 3H), 7.04 (s, 2H), 6.96−6.92 (m, 1H), 6.00 (d, J = 1.0 Hz, 1H), 5.12 (s, 1H), 4.82 (s, 1H), 2.82 (t, J = 8.0 Hz, 2H), 2.33−2.20 (m, 2H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 144.8, 143.0, 135.6, 135.0, 134.8, 132.6, 129.5, 128.3, 127.3, 126.5, 126.49, 126.3, 126.1, 125.9, 125.4, 58.6, 34.5, 30.5, 28.7, 27.9; FT-IR (neat): 3638 cm−1; HRMS (ESI): m/z calcd for C31H35O [M − H]−: 423.2688; found: 423.2671. (E)-4-(3-(6-Bromobenzo[d][1,3]dioxol-5-yl)-1-phenylallyl)-2,6-ditert-butylphenol (3q). The reaction was performed on 0.067 mmol of 1b; Rf = 0.2 (5% EtOAc in hexane); colorless gummy solid (17.4 mg, 50% yield); 1H NMR (400 MHz, CDCl3) δ 7.34−7.31 (m, 2H), 7.27−7.20 (m, 3H), 7.03 (s, 2H), 7.02 (s, 1H), 6.98 (s, 1H), 6.62 (dd, J = 15.6, 1.1 Hz, 1H), 6.43 (dd, J = 15.6, 7.6 Hz, 1H), 5.95 (s, 2H), 5.11 (s, 1H), 4.82 (d, J = 7.6 Hz, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 147.7, 147.6, 143.9, 135.8, 134.9, 133.6, 131.0, 129.8, 128.7, 128.5, 126.4, 125.3, 114.5, 112.7, 106.5, 101.8, 54.3, 34.5, 30.5; FT-IR (neat): 3633 cm−1; HRMS (ESI): m/z calcd for C30H34BrO3 [M + H]+: 521.1691; found: 521.1669. 2,6-Di-tert-butyl-4-(3-(4-methoxyphenyl)-1-phenylbut-2-en-1yl)phenol (3r). The reaction was performed on 0.067 mmol of 1b; Rf = 0.1 (5% EtOAc in hexane); colorless gummy solid (25.3 mg, 85% yield, E:Z = 4:1); major isomer: 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.6 Hz, 2H), 7.31−7.27 (m, 3H), 7.22−7.18 (m, 2H), 7.04 (s, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.18 (d, J = 9.5 Hz, 1H), 5.09 (s, 1H), 4.98 (d, J = 9.5 Hz, 1H), 3.82 (s, 3H), 2.13 (s, 3H), 1.41 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 158.7, 152.2, 145.3, 136.6, 135.7, 135.3, 134.3, 130.3, 128.5, 128.46, 127.1, 126.1, 125.0, 113.6, 55.4, 50.0, 34.5, 30.5, 16.5; FT-IR (neat): 3636 cm−1; HRMS (ESI): m/z calcd for C31H37O2 [M − H]−: 441.2794; found: 441.2778. 4-(3,3-Bis(4-chlorophenyl)-1-phenylallyl)-2,6-di-tert-butylphenol (3s). The reaction was performed on 0.1 mmol of 1b; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (54.0 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.39−7.36 (m, 2H), 7.34−7.30 (m, 2H), 7.27−7.23 (m, 3H), 7.21−7.17 (m, 4H), 7.15−7.12 (m, 2H), 6.91 (s, 2H), 6.56 (d, J = 10.6 Hz, 1H), 5.11 (s, 1H), 4.68 (d, J = 10.6 Hz, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 144.3, 140.6, 138.9, 138.0, 135.9, 134.4, 133.5, 133.3, 133.1, 131.4, 128.8, 128.76, 128.7, 128.5, 128.4, 126.4, 124.9, 50.5, 34.5, 30.4; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C35H35Cl2O [M − H]−: 541.2065; found: 541.2039. 2,6-Di-tert-butyl-4-(3-(4-methoxyphenyl)-1,3-diphenylallyl)phenol (3t). The reaction was performed on 0.1 mmol of 1b; Rf = 0.1 (5% EtOAc in hexane); colorless gummy solid (50.1 mg, 97% yield, E:Z = 5:1); major isomer: 1H NMR (400 MHz, CDCl3) δ 7.42−7.36 (m, 2H), 7.35−7.29 (m, 3H), 7.27−7.20 (m, 7H), 6.95 (s, 2H), 6.85−6.81 (m, 2H), 6.49 (d, J = 10.6 Hz, 1H), 5.09 (s, 1H), 4.71 (d, J = 10.6 Hz, 1H), 3.80 (s, 3H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 159.0, 152.2, 144.8, 140.5, 140.3, 135.7, 135.3, 135.1, 130.5, 130.1, 128.7, 128.6, 128.5, 128.3, 127.2, 126.2, 125.1, 113.6, 55.4, 50.3, 34.5, 30.5; FT-IR (neat): 3636 cm−1; HRMS (ESI): m/z calcd for C36H39O2 [M − H]−: 503.2950; found: 503.2926. (E)-2,6-Di-tert-butyl-4-(1,3-diphenylallyl)phenol (3u). The reaction was performed on 0.2 mmol of 1b; Rf = 0.5 (5% EtOAc in hexane); colorless gummy solid (49.3 mg, 60%); 1H NMR (400 MHz, CDCl3) 7.38 (d, J = 7.6 Hz, 2H), 7.32−7.28 (m, 4H), 7.27− 7.21 (m, 4H), 7.05 (s, 2H), 6.68 (dd, J = 15.8, 7.7 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 5.11 (s, 1H), 4.81 (d, J = 7.7 Hz, 1H), 1.15 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 152.4, 144.2, 137.7, 135.9, 134.0,
7.34 (m, 5H), 7.32−7.29 (m, 4H), 7.27−7.19 (m, 2H), 6.90 (s, 2H), 6.53 (d, J = 10.5 Hz, 1H), 5.13 (s, 1H), 4.77 (d, J = 10.5 Hz, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 145.7, 142.2, 141.9, 139.8, 136.0, 134.0, 132.0 (q, JC−F = 1 Hz), 131.0, 130.9, 130.6, 130.0, 128.9, 128.5, 128.3, 127.5, 127.47, 125.3 (q, JC−F = 3.8 Hz), 124.9, 124.5 (q, JC−F = 270.4 Hz), 123.1 (q, JC−F = 3.4 Hz), 50.2, 34.5, 30.4; 19F NMR (376 MHz, CDCl3) δ −115.82; FT-IR (neat): 3639 cm−1; HRMS (ESI): m/z calcd for C36H38F3O [M + H]+: 543.2875; found: 543.2864. 2,6-Di-tert-butyl-4-(1-(4-nitrophenyl)-3,3-diphenylallyl)phenol (3j). The reaction was performed on 0.2 mmol of 1j; Rf = 0.2 (5% EtOAc in hexane); colorless gummy solid (92.4 mg, 90% yield); 1H NMR (400 MHz, CDCl3) δ 8.19−8.15 (m, 2H), 7.43−7.36 (m, 5H), 7.32−7.24 (m, 5H), 7.19−7.17 (m, 2H), 6.89 (s, 2H), 6.51 (d, J = 10.5 Hz, 1H), 5.16 (s, 1H), 4.81 (d, J = 10.4 Hz, 1H), 1.40 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 152.8, 152.6, 146.5, 142.5, 141.9, 139.6, 136.2, 133.5, 130.1, 129.8, 129.3 (2C), 128.6, 128.4, 127.7, 127.5, 124.9, 123.8, 50.5, 34.5, 30.4; FT-IR (neat): 3633 cm−1; HRMS (ESI): m/z calcd for C35H36NO3 [M − H]−: 518.2695; found: 518.2678. 4-(1-(6-Bromobenzo[d][1,3]dioxol-5-yl)-3,3-diphenylallyl)-2,6-ditert-butylphenol (3k). The reaction was performed on 0.048 mmol of 1k; Rf = 0.2 (5% EtOAc in hexane); colorless gummy solid (24.7 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 7.36−7.30 (m, 3H), 7.28−7.23 (m, 5H), 7.13−7.11 (m, 2H), 6.99 (s, 1H), 6.95 (s, 2H), 6.85 (s, 1H), 6.46 (d, J = 10.1 Hz, 1H), 5.96 (s, 2H), 5.10 (d, J = 10.1 Hz, 1H), 5.07 (s, 1H), 1.39 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.2, 147.7, 146.7, 142.7, 142.6, 139.8, 137.5, 135.7, 134.1, 130.8, 130.0, 128.3, 128.27, 127.8, 127.4, 127.3, 124.6, 114.9, 112.8, 109.7, 101.8, 48.9, 34.5, 30.5; FT-IR (neat): 3635 cm−1; HRMS (ESI): m/z calcd for C36H36BrO3 [M − H]−: 595.1848; found: 595.1823. 2,6-Di-tert-butyl-4-(1-(naphthalen-1-yl)-3,3-diphenylallyl)phenol (3l). The reaction was performed on 0.2 mmol of 1l; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (104 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 1H), 7.77 (dd, J = 7.4, 1.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.51−7.42 (m, 3H), 7.36−7.30 (m, 4H), 7.29−7.22 (m, 5H), 7.21−7.16 (m, 2H), 6.96 (s, 2H), 6.69 (d, J = 10.3 Hz, 1H), 5.49 (d, J = 10.3 Hz, 1H), 5.07 (s, 1H), 1.36 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.1, 142.8, 141.1, 140.9, 140.0, 135.7, 135.0, 134.2, 132.4, 131.8, 130.2, 128.7, 128.3, 128.2, 127.8, 127.4, 127.2, 127.1, 126.0, 125.7, 125.6, 125.4, 125.1, 124.6, 46.6, 34.5, 30.5; FT-IR (neat): 3634 cm−1; HRMS (ESI): m/z calcd for C39H39O [M − H]−: 523.3001; found: 523.3026. 4-(1-(9H-Fluoren-2-yl)-3,3-diphenylallyl)-2,6-di-tert-butylphenol (3m). The reaction was performed on 0.052 mmol of 1m; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (21.5 mg, 73% yield); 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.44−7.35 (m, 5H), 7.34−7.31 (m, 3H), 7.29−7.22 (m, 6H), 6.99 (s, 2H), 6.63 (d, J = 10.6 Hz, 1H), 5.10 (s, 1H), 4.81 (d, J = 10.6 Hz, 1H), 3.88 (s, 2H), 1.40 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 152.2, 143.7, 143.5, 143.46, 142.6, 141.9, 140.9, 140.1, 139.9, 135.8, 135.2, 132.2, 130.1, 128.4, 128.3, 127.6, 127.32, 127.30, 127.2, 126.8, 126.5, 125.2, 125.1, 125.0, 119.9, 119.8, 50.5, 37.1, 34.5, 30.5; FT-IR (neat): 3635 cm−1; HRMS (ESI): m/z calcd for C42H41O [M − H]−: 561.3157; found: 561.3135. 2,6-Di-tert-butyl-4-(3,3-diphenyl-1-(pyren-1-yl)allyl)phenol (3n). The reaction was performed on 0.047 mmol of 1n; Rf = 0.3 (5% EtOAc in hexane); pale yellow solid (28.5 mg, 99% yield); mp = 196−198 °C; 1H NMR (400 MHz, CDCl3) δ 8.21−8.14 (m, 3H), 8.10−8.05 (m, 3H), 8.00 (t, J = 7.6 Hz, 1H), 7.96−7.91 (m, 2H), 7.41−7.34 (m, 3H), 7.32−7.24 (m, 5H), 7.23−7.19 (m, 2H), 7.05 (s, 2H), 6.85 (d, J = 10.2 Hz, 1H), 5.85 (d, J = 10.2 Hz, 1H), 5.10 (s, 1H), 1.35 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.2, 142.7, 141.5, 140.0, 138.8, 135.8, 135.4, 132.4, 131.6, 131.0, 130.2, 130.0, 128.8, 128.4, 128.3, 127.8, 127.7, 127.5, 127.3, 127.1, 127.0, 126.7, 125.9, 125.3, 125.2, 125.1 (2C), 125.0, 124.8, 124.0, 46.5, 34.5, 30.4; FT-IR (neat): 3632 cm−1; HRMS (ESI): m/z calcd for C45H41O [M − H]−: 597.3157; found: 597.3132. 2,6-Dimethyl-4-(1,3,3-triphenylallyl)phenol (3o). The reaction was performed on 0.19 mmol of 1o; Rf = 0.3 (10% EtOAc in 10112
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry
139.4 (d, JC−F = 1.9 Hz), 137.1, 135.8 (d, JC−F = 7.7 Hz), 134.5, 133.8 (d, JC−F = 3.2 Hz), 133.5, 132.1 (d, JC−F = 1.8 Hz), 128.9, 128.4 (d, JC−F = 8.3 Hz), 128.3 127.8, 126.9, 125.4, 117.8 (d, JC−F = 22.2 Hz), 116.5 (d, JC−F = 21.4 Hz), 35.6, 35.3, 29.7, 29.6; 19F NMR (376 MHz, CDCl3) δ −114.24; FT-IR (neat): 2955, 1614 cm−1; HRMS (ESI): m/z calcd for C29H32FO [M + H]+: 415.2437; found: 415.2424. (E)-2,6-Di-tert-butyl-4-(2-(4-methoxystyryl)benzylidene)cyclohexa-2,5-dienone (5e). Rf = 0.3 (5% EtOAc in hexane); orange solid (420 mg, 68% yield); mp = 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.43− 7.38 (m, 2H), 7.36 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 4.0 Hz, 2H), 7.14−7.08 (m, 2H), 7.00 (d, J = 16.1 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H), 1.36 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 159.8, 149.3, 147.9, 141.7, 138.0, 134.9, 133.9, 132.6, 131.9, 131.6, 130.0, 129.4, 128.5, 128.2, 127.0, 126.5, 124.2, 114.3, 55.5, 35.5, 35.2, 29.7, 29.6; FT-IR (neat): 2956, 1612 cm−1; HRMS (ESI): m/z calcd for C30H35O2 [M + H]+: 427.2637; found: 427.2641. (E)-2,6-Di-tert-butyl-4-((6-styrylbenzo[d][1,3]dioxol-5-yl)methylene)cyclohexa-2,5-dienone (5f). Rf = 0.3 (5% EtOAc in hexane); orange solid (450 mg, 71% yield); mp = 188−190 °C; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.6 Hz, 2H), 7.38−7.27 (m, 5H), 7.21−7.17 (m, 2H), 7.05 (s, 1H), 6.92 (d, J = 16.0 Hz, 1H), 6.83 (s, 1H), 6.06 (s, 2H), 1.35 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.6, 149.3, 149.1, 147.8, 147.5, 141.1, 137.2, 134.9, 132.9, 132.2, 131.0, 128.9, 128.4, 128.2, 128.1, 126.8, 126.1, 110.9, 106.3, 101.8, 35.6, 35.2, 29.7, 29.6; FT-IR (neat): 2956, 1598 cm−1; HRMS (ESI): m/z calcd for C30H33O3 [M + H]+: 441.2430; found: 441.2443. General Procedure for the Synthesis of Indene Derivatives (6a−f). Bi(OTf)3 (0.1 equiv) was added to a solution of alkenylated p-quinone methide (1 equiv) in CH2Cl2 (0.05 M) at room temperature, and the resultant mixture was stirred vigorously until the p-quinone methide was completely consumed (progress was monitored by TLC). After completion of the reaction, solvent was removed under reduced pressure and the residue was directly loaded on a silica gel column and eluted using EtOAc/hexane mixture to obtain pure indene derivatives. 2,6-Di-tert-butyl-4-(2-phenyl-1H-inden-1-yl)phenol (6a). The reaction was performed on 0.049 mmol of 5a; Rf = 0.4 (5% EtOAc in hexane); white solid (16.4 mg, 82% yield); mp = 170−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.49−7.47 (m, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.30−7.23 (m, 5H), 7.20−7.16 (m, 1H), 7.12 (td, J = 7.4, 1.1 Hz, 1H), 6.90 (s, 2H), 4.98 (s, 1H), 4.91 (s, 1H), 1.32 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 150.5, 149.5, 143.3, 135.9, 135.8, 130.1, 128.4, 127.9, 127.2, 127.0, 126.8, 125.3, 124.6, 123.9, 121.1, 56.3, 34.4, 30.5; FT-IR (neat): 3636 cm−1; HRMS (ESI): m/z calcd for C29H31O [M − H]−: 395.2375; found: 395.2361. 2,6-Di-tert-butyl-4-(5,6-dimethoxy-2-phenyl-1H-inden-1-yl)phenol (6b). The reaction was performed on 0.043 mmol of 5b; Rf = 0.1 (5% EtOAc in hexane); colorless gummy solid (17.5 mg, 87% yield); 1H NMR (400 MHz, CDCl3) δ 7.4 (d, J = 7.4 Hz, 2H), 7.26− 7.23 (m, 2H), 7.18−7.13 (m, 2H), 6.97 (s, 1H), 6.89 (s, 2H), 6.87 (s, 1H), 4.99 (s, 1H), 4.83 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 1.33 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 149.7, 148.5, 147.5, 142.3, 136.02, 136.0, 135.9, 130.4, 128.3, 127.5, 126.8, 126.7, 124.7, 108.2, 104.5, 56.34, 56.25, 56.22, 34.4, 30.5; FT-IR (neat): 3638 cm−1; HRMS (ESI): m/z calcd for C31H35O3 [M − H]−: 455.2586; found: 455.2571. 2,6-Di-tert-butyl-4-(5-methyl-2-phenyl-1H-inden-1-yl)phenol (6c). The reaction was performed on 0.048 mmol of 5c; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (18.0 mg, 90% yield); mp = 169−171 °C; 1H NMR (400 MHz, CDCl3) δ 7.5 (d, J = 7.9 Hz, 1H), 7.27−7.21 (m, 5H), 7.17 (t, J = 7.7 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.89 (s, 2H), 4.96 (s, 1H), 4.87 (s, 1H), 2.38 (s, 3H), 1.32 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 152.4, 150.6, 146.7, 143.5, 136.4, 135.9, 135.87, 130.4, 128.4, 127.9, 127.1, 127.0, 126.1, 124.6, 123.5, 121.8, 55.9, 34.4, 30.5, 21.6; FT-IR (neat): 3642 cm−1; HRMS (ESI): m/z calcd for C30H35O [M + H]+: 411.2688; found: 411.2663.
133.6, 130.9, 128.8, 128.6, 128.5, 127.3, 126.4, 126.3, 125.3, 54.4, 34.5, 30.5; FT-IR (neat): 3632 cm−1; HRMS (ESI): m/z calcd for C29H33O [M − H]−: 397.2531; found: 397.2546. 2,6-Di-tert-butyl-4-(2,2-diphenylchroman-4-yl)phenol (3v). The reaction was performed on 0.1 mmol of 1q;9 Rf = 0.2 (5% EtOAc in hexane); colorless gummy solid (28.5 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ 7.58−7.53 (m, 4H), 7.37−7.31 (m, 4H), 7.27−7.22 (m, 2H), 7.19−7.14 (m, 2H), 6.96 (s, 2H), 6.78−6.74 (m, 1H), 6.69−6.67 (m, 1H), 5.14 (s, 1H), 3.80 (dd, J = 12.5, 5.1 Hz, 1H), 3.16 (dd, J = 13.8, 5.2 Hz, 1H), 2.65 (dd, J = 13.6, 12.8 Hz, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.1, 152.6, 146.1, 144.1, 136.1, 134.7, 129.8, 128.7, 128.4, 127.7, 127.4, 127.1, 126.4, 126.2, 125.8, 125.4, 120.4, 117.2, 82.0, 41.9, 40.0, 34.5, 30.5; FT-IR (neat): 3636 cm−1; HRMS (ESI): m/z calcd for C35H37O2 [M − H]−: 489.2794; found: 489.2815. General Procedure for the Synthesis of 2-Alkenylated pQuinone Methides (5a−f). In a Dean−Stark apparatus, a mixture of 2-alkenyl benzaldehyde (1.44 mmol, 1 equiv) and 2,6-di-tertbutylphenol (1.44 mmol, 1 equiv) in toluene (15 mL) was heated at 100 °C for 30 min. Piperidine (2.88 mmol, 2 equiv) was then added to this reaction mixture at 100 °C in a dropwise manner, and the resultant mixture was stirred at 150 °C for 12 h. The reaction mixture was cooled to 100 °C, acetic anhydride (2.88 mmol, 2 equiv) was added, and the resulting solution was stirred for additional 1 h at the same temperature. The reaction mixture was then cooled to room temperature, poured in to ice cold water (50 mL), and extracted with dichloromethane (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using mixture of ethyl acetate/hexane to obtain a pure 2-alkenylated p-quinone methides. (E)-2,6-Di-tert-butyl-4-(2-styrylbenzylidene)cyclohexa-2,5-dienone (5a). Rf = 0.4 (5% EtOAc in hexane); yellow solid (380 mg, 66% yield); mp = 168−170 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.44−7.34 (m, 7H), 7.32− 7.23 (m, 2H), 7.09−7.03 (m, 2H), 1.36 (s, 9H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 149.4, 148.0, 141.4, 137.7, 137.2, 134.8, 134.2, 132.8, 132.3, 131.7, 129.4, 128.9, 128.5, 128.3, 127.5, 126.9, 126.8, 126.5, 35.5, 35.2, 29.7, 29.6; FT-IR (neat): 2957, 1614 cm−1; HRMS (ESI): m/z calcd for C29H33O [M + H]+: 397.2531; found: 397.2520. (E)-2,6-Di-tert-butyl-4-(4,5-dimethoxy-2-styrylbenzylidene)cyclohexa-2,5-dienone (5b). Rf = 0.1 (5% EtOAc in hexane); orange solid (541 mg, 82% yield); mp = 164−166 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H), 7.44 (s, 1H), 7.38−7.35 (m, 3H), 7.29−7.22 (m, 2H), 7.17 (s, 1H), 7.08 (s, 1H), 6.94 (d, J = 16.0 Hz, 1H), 6.88 (s, 1H), 4.01 (s, 3H), 3.91 (s, 3H), 1.35 (s, 9H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.5, 150.2, 149.2, 148.5, 147.7, 141.4, 137.3, 135.0, 131.9, 131.4, 131.0, 128.9, 128.5, 128.1, 127.1, 126.7, 126.2, 114.2, 109.1, 56.2, 56.1, 35.6, 35.2, 29.7, 29.66; FT-IR (neat): 2957, 1613 cm−1; HRMS (ESI): m/z calcd for C31H37O3 [M + H]+: 457.2743; found: 457.2727. (E)-2,6-Di-tert-butyl-4-(4-methyl-2-styrylbenzylidene)cyclohexa2,5-dienone (5c). Rf = 0.4 (5% EtOAc in hexane); yellow solid (423 mg, 71% yield); mp = 181−183 °C; 1H NMR (400 MHz, CDCl3) δ 7.51−7.50 (m, 3H), 7.39−7.35 (m, 4H), 7.30 (d, J = 7.0 Hz, 1H), 7.26−7.22 (m, 2H)), 7.17 (d, J = 7.8 Hz, 1H), 7.07 s, 1H), 7.03 (d, J = 16.2 Hz, 1H), 2.44 (s, 3H), 1.35 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 149.2, 147.8, 141.7, 139.6, 137.6, 137.3, 135.0, 132.4, 132.2, 131.7, 131.6, 128.9, 128.6, 128.5, 128.2, 127.4, 126.9, 126.5, 35.5, 35.2, 29.7, 29.6, 21.6; FT-IR (neat): 2921, 1614 cm−1; HRMS (ESI): m/z calcd for C30H35O [M + H]+: 411.2688; found: 411.2671. (E)-2,6-Di-tert-butyl-4-(5-fluoro-2-styrylbenzylidene)cyclohexa2,5-dienone (5d). Rf = 0.4 (5% EtOAc in hexane); yellow solid (360 mg, 60% yield); mp = 151−153 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.8, 5.6 Hz, 1H), 7.48 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.31−7.26 (m, 3H), 7.19−7.10 (m, 2H), 7.06−7.03 (m, 2H), 6.98 (d, J = 16.1 Hz, 1H), 1.35 (s, 9H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.6, 161.9 (d, JC−F = 246.8 Hz), 149.9, 148.5, 10113
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry 2,6-Di-tert-butyl-4-(6-fluoro-2-phenyl-1H-inden-1-yl)phenol (6d). The reaction was performed on 0.06 mmol of 5d; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (18.1 mg, 72% yield); mp = 190−192 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.5 Hz, 2H), 7.32−7.24 (m, 4H), 7.18 (t, J = 7.3 Hz, 1H), 6.98−6.92 (m, 2H), 6.88 (s, 2H), 5.03 (s, 1H), 4.88 (s, 1H), 1.33 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 161.7 (d, JC−F = 242 Hz), 152.7, 151.7 (d, JC−F = 8 Hz), 150.3 (d, JC−F = 3.8 Hz), 139.2, 136.1, 135.5, 129.6, 128.4, 127.3, 126.9 (d, JC−F = 0.8 Hz), 126.8, 124.5, 121.6 (d, JC−F = 8.5 Hz), 113.7 (d, JC−F = 22.8 Hz), 111.8 (d, JC−F = 23.2 Hz), 56.4 (d, JC−F = 2.2 Hz), 34.4, 30.4; 19F NMR (376 MHz, CDCl3) δ −117.34; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C29H32FO [M + H]+: 415.2437; found: 415.2432. 2,6-Di-tert-butyl-4-(2-(4-methoxyphenyl)-1H-inden-1-yl)phenol (6e). The reaction was performed on 0.047 mmol of 5e; Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (14.9 mg, 74% yield); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 7.24−7.18 (m, 3H), 7.09 (t, J = 7.4 Hz, 1H), 6.90 (s, 2H), 6.81(d, J = 8.5 Hz, 2H), 4.99 (s, 1H), 4.85 (s, 1H), 3.79 (s, 3H), 1.33 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 158.9, 152.4, 150.0, 149.3, 143.6, 135.9, 130.4, 128.6, 128.2, 126.8, 126.1, 124.8, 124.6, 123.8, 120.7, 113.8, 56.3, 55.4, 34.4, 30.5; FT-IR (neat): 3638 cm−1; HRMS (ESI): m/z calcd for C30H35O2 [M + H]+: 427.2637; found: 427.2619. 2,6-Di-tert-butyl-4-(6-phenyl-5H-indeno[5,6-d][1,3]dioxol-5-yl)phenol (6f). The reaction was performed on 0.049 mmol of 5f; Rf = 0.3 (5% EtOAc in hexane); pale yellow solid (21.2 mg, 97% yield); mp = 198−200 °C; 1H NMR (400 MHz, CDCl3) δ 7.43−7.41 (m, 2H), 7.24 (t, J = 7.5 Hz, 2H), 7.18−7.12 (m, 2H), 6.88−6.87 (m, 3H), 6.76 (s, 1H), 5.92 (dd, J = 7, 1.2 Hz, 2H), 4.99 (s, 1H), 4.78 (s, 1H), 1.33 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 149.6, 146.8, 146.0, 143.9, 136.9, 136.0, 135.8, 130.2, 128.4, 127.6, 126.8, 126.6, 124.5, 105.6, 101.9, 101.0, 56.0, 34.4, 30.5; FT-IR (neat): 3631 cm−1; HRMS (ESI): m/z calcd for C30H33O3 [M + H]+: 441.2430; found: 441.2443. Total Synthesis of (±)-Isopaucifloral F (7). (E)-2-(3,5Dimethoxystyryl)-4,6-dimethoxybenzaldehyde (12). A mixture of aryl halide 10 (2.30 g, 9.38 mmol), styrene 11 (3.1 g, 18.76 mmol), Pd(OAc)2 (0.12 g, 0.56 mmol), and K3PO4 (2.39 g, 11.3 mmol) in N,N-dimethylacetamide (DMA, 8 mL) was added to a vial under nitrogen atmosphere and heated at 130 °C for 6 h. Reaction was monitored by TLC. After the completion of reaction, water was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified through a silica gel column using 20% EtOAc/ hexane mixture to obtain pure (E)-2-(3,5-dimethoxystyryl)-4,6dimethoxybenzaldehyde 12 (2.3 g, 75% yield) as a pale yellow solid. Rf = 0.3 (20% EtOAc in hexane); mp = 122−124 °C; 1H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H), 8.12 (d, J = 16.1 Hz, 1H), 6.96 (d, J = 16.1 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.72 (d, J = 2.2 Hz, 2H), 6.42−6.40 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.83 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 190.7, 165.1, 164.7, 161.0, 142.9, 139.3, 132.6, 128.6, 116.4, 105.1, 104.0, 100.7, 97.5, 56.0, 55.7, 55.5; FT-IR (neat): 2941, 1669 cm−1; HRMS (ESI): m/z calcd for C19H21O5 [M + H]+: 329.1389; found: 329.1373. (E)-2,6-Di-tert-butyl-4-(2-(3,5-dimethoxystyryl)-4,6dimethoxybenzylidene)cyclohexa-2,5-dienone (14). A mixture of 12 (1.70 g, 5.17 mmol) and 2,6-di-tert-butylphenol 13 (1.07 g, 5.17 mmol) in toluene (20 mL) was heated at 100 °C in a Dean−Stark apparatus for 30 min. Piperidine (1.02 mL, 10.34 mmol) was then added to this reaction mixture at the same temperature in a dropwise manner, and the resultant mixture was stirred at 150 °C for 12 h. The reaction mixture was cooled to 100 °C, and acetic anhydride (0.98 mL, 10.34 mmol) was added to it and stirred for additional 1 h at the same temperature. The reaction mixture was then cooled to room temperature and poured in to ice cold water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography using a CH2Cl2:hexane (60:40) mixture as eluent to obtain a pure (E)-2,6-di-tert-butyl-4-(2-(3,5-dimethoxystyryl)-4,6dimethoxybenzylidene)cyclohexa-2,5-dienone (2.3 g, 86% yield) as an orange solid. Rf = 0.5 (60% DCM in hexane); mp = 201−203 °C; 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 16.2 Hz, 1H), 6.96−6.91 (m, 2H), 6.89 (d, J = 1.7 Hz, 1H), 6.46−6.45 (m, 3H), 6.33 (brs, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.70 (s, 6H), 1.33 (s, 9H), 1.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 161.6, 161.0, 159.6, 148.1, 147.1, 139.2, 138.4, 138.2, 135.0, 133.4, 130.1, 129.8, 128.4, 117.4, 104.4, 101.7, 101.0, 97.9, 55.9, 55.7, 55.4, 35.3, 35.1, 29.6, 29.4; FT-IR (neat): 2955, 1597 cm−1; HRMS (ESI): m/z calcd for C33H41O5 [M + H]+: 517.2954; found: 517.2934. 2,6-Di-tert-butyl-4-(2-(3,5-dimethoxyphenyl)-5,7-dimethoxy-1Hinden-1-yl)phenol (15). Bi(OTf)3 (0.06 g, 0.096 mmol) was added to a solution of p-quinone methide 14 (0.5 g, 0.96 mmol) in toluene at room temperature, and the resultant mixture was stirred vigorously until the p-quinone methide was completely consumed (progress was monitored by TLC). After completion of the reaction, solvent was removed under reduced pressure and the residue was directly loaded on a silica gel column and eluted using 5% EtOAc/hexane mixture to provide pure 2,6-di-tert-butyl-4-(2-(3,5-dimethoxyphenyl)-5,7-dimethoxy-1H-inden-1-yl)phenol 15 (375 mg, 75% yield) as a pale yellow solid. Rf = 0.26 (10% EtOAc in hexane); mp = 199−201 °C; 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 0.7 Hz, 1H), 6.96 (s, 2H), 6.62−6.60 (m, 3H), 6.30 (t, J = 2.2 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 4.94 (s, 1H), 4.90 (s, 1H), 3.84 (s, 3H), 3.68 (s, 6H), 3.64 (s, 3H), 1.32 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 160.9, 160.5, 155.9, 152.3, 152.0, 145.4, 137.7, 135.3, 129.3, 129.1, 127.9, 125.2, 105.0, 100.1, 98.9, 97.0, 55.7 (2C), 55.3, 54.6, 34.4, 30.5; FT-IR (neat): 3634 cm−1; HRMS (ESI): m/z calcd for C33H41O5 [M + H]+: 517.2954; found: 517.2939. 2,6-Di-tert-butyl-4-(2-(3,5-dimethoxyphenyl)-5,7-dimethoxy-2,3dihydro-1H-inden-1-yl)phenol (16). A suspension of 15 (0.39 g, 0.75 mmol) and 5% Pd/C (0.008 g, 0.075 mmol) in ethanol (8 mL) was stirred under hydrogen (1 atm) for 24 h at room temperature. After completion of the reaction, the reaction mixture was filtered through Celite pad and washed with ethyl acetate. The solvent was removed under reduced pressure, and the residue was directly loaded on a silica gel column and purified using 5−10% ethyl acetate/hexane mixture as eluent to get pure 2,6-di-tert-butyl-4-(2-(3,5-dimethoxyphenyl)-5,7dimethoxy-2,3-dihydro-1H-inden-1-yl)phenol 16 (390 mg, 99% yield) as a white solid (single cis-diastereomer). Rf = 0.3 (10% EtOAc in hexane); mp = 133−135 °C; 1H NMR (400 MHz, CDCl3) δ 6.54 (d, J = 1.6 Hz, 1H), 6.36 (d, J = 1.7 Hz, 1H), 6.29 (s, 2H), 6.20 (t, J = 2.3 Hz, 1H), 5.89 (d, J = 2.2 Hz, 2H), 4.90 (s, 1H), 4.46 (d, J = 7.7 Hz, 1H), 3.89−3.82 (m, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 3.56 (s, 6H), 3.16 (dd, J = 15.3, 11.8 Hz, 1H), 2.95 (dd, J = 15.4, 7.3 Hz, 1H), 1.21 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 160.8, 160.0, 156.8, 152.0, 146.1, 143.7, 134.7, 130.6, 125.2, 124.9, 106.5, 100.6, 99.0, 97.1, 55.7, 55.5, 55.1, 53.3, 52.6, 36.6, 34.1, 30.3; FT-IR (neat): 3626 cm−1; HRMS (ESI): m/z calcd for C33H41O5 [M − H]−: 517.2954; found: 517.2930. 3-(3,5-Di-tert-butyl-4-methoxyphenyl)-2-(3,5-dimethoxyphenyl)4,6-dimethoxy-1H-inden-1-one (17). Potassium tert-butoxide (0.14 g, 1.26 mmol) was added in a portionwise manner to a stirred solution of 16 (0.33 g, 0.63 mmol) in anhydrous DMSO (8 mL) at ambient temperature, and the resulting mixture was stirred for 30 min at 45 °C. The reaction mixture was then cooled to room temperature, and CH3I (0.12 g, 1.26 mmol) was added to it. The resultant mixture was stirred at 45 °C for 4 h. It was then cooled to room temperature and poured in to ice-cold water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was filtered through a short pack of silica gel and concentrated under reduced pressure. The resultant white solid was dissolved in 1,4-dioxane (6 mL), SeO2 (0.08 g, 0.76 mmol) was added to it, and the resultant solution was heated at 110 °C for 36 h. Upon completion (as judged by TLC), the reaction mixture was cooled to room temperature, poured into H2O (5 mL), and extracted with 10114
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry EtOAc (3 × 15 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain pure 3-(3,5-di-tert-butyl-4-methoxyphenyl)-2-(3,5dimethoxyphenyl)-4,6-dimethoxy-1H-inden-1-one 17 (0.155 g, 45% yield) as a dark purple solid. Rf = 0.15 (10% EtOAc in hexane); mp = 197−199 °C; 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 2H), 6.88 (d, J = 2.1 Hz, 1H), 6.46 (d, J = 2.1 Hz, 1H), 6.27 (t, J = 2.3 Hz, 1H), 6.24 (d, J = 2.3 Hz, 2H), 3.87 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H), 3.58 (s, 6H), 1.31 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 195.8, 162.9, 160.2, 160.16, 160.1, 155.0, 142.6, 134.9, 133.6, 130.9, 128.4, 128.2, 121.8, 107.9, 103.7, 102.7, 100.1, 64.4, 56.0, 55.7, 55.1, 35.8, 32.1; FTIR (neat): 1704 cm−1; HRMS (ESI): m/z calcd for C34H41O6 [M + H]+: 545.2903; found: 545.2889 3-(3,5-Di-tert-butyl-4-methoxyphenyl)-2-(3,5-dimethoxyphenyl)4,6-dimethoxy-2,3-dihydro-1H-inden-1-one (18). A suspension of 17 (0.065 g, 0.12 mmol) and 5% Pd/C (0.0013 g, 0.01 mmol) in ethanol (5 mL) was stirred under an atmosphere of hydrogen at high pressure (5 bar) at 78 °C for 36 h. The pressure was released, and the reaction mixture was filtered through Celite pad and washed with ethyl acetate. The solvent was removed under reduced pressure, and the residue was directly loaded on a silica gel column and purified by using 5−10% ethyl acetate/hexane mixture as eluent to obtain pure 3(3,5-di-tert-butyl-4-methoxyphenyl)-2-(3,5-dimethoxyphenyl)-4,6-dimethoxy-2,3-dihydro-1H-inden-1-one 18 (0.063 g, 96% yield) as a colorless gummy solid. Diastereomeric ratio (trans:cis = 96:4). Rf = 0.19 (10% EtOAc in hexane); major diastereomer (trans): 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 2.1 Hz, 1H), 6.86 (s, 2H), 6.70 (d, J = 2.1 Hz, 1H), 6.36 (t, J = 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 2H), 4.51 (d, J = 2.5 Hz, 1H), 3.88 (s, 3H), 3.74 (s, 6H), 3.68−3.67 (m, 4H), 3.66 (s, 3H), 1.34 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 205.9, 161.9, 161.1, 157.91, 157.9, 143.2, 142.1, 138.7, 138.6, 136.5, 125.4, 106.5, 106.2, 99.1, 96.7, 65.0, 64.2, 55.9, 55.6, 55.4, 51.4, 35.8, 32.2; FT-IR (neat): 1714 cm−1; HRMS (ESI): m/z calcd for C34H43O6 [M + H]+: 547.3060; found: 547.3044. Isopaucifloral F (7). A solution of compound 18 (0.06 g, 0.11 mmol) in CH2Cl2 (2 mL) was added slowly to a solution of boron tribromide (0.15 mL, 1.64 mmol) dissolved in 5 mL of anhydrous CH2Cl2 at −78 °C. The reaction mixture was then slowly warmed to room temperature and stirred for 24 h. Ice−water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous toluene (3 mL), AlCl3 (0.22 g, 1.64 mmol) in CH3NO2 (1 mL) was added to it at room temperature, and the resultant mixture was heated to 60 °C for 1 h. Then the mixture was cooled and transferred to a separatory funnel containing 1:1 ice/1 N HCl and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with sat. aq NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was purified by column chromatography by using CH2Cl2/MeOH (90:10) mixture as eluent to give pure isopaucifloral F 7 (0.026 g, 65% yield) as a colorless gummy solid. Rf = 0.1 (10% MeOH in CH2Cl2); 1H NMR (400 MHz, acetone-d6) δ 8.93 (s, 1H), 8.68 (s, 1H), 8.31 (s, 3H), 6.91−6.88 (m, 2H), 6.77− 6.73 (m, 3H), 6.72 (d, J = 2.1 Hz, 1H), 6.25 (t, J = 2.2 Hz, 1H), 6.11 (d, J = 2.2 Hz, 2H), 4.48 (d, J = 2.4 Hz, 1H), 3.42 (d, J = 2.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 205.2, 160.1, 159.5, 156.7, 156.6, 143.2, 139.9, 135.5, 135.4, 128.8, 116.0, 110.2, 106.8, 101.9, 100.4, 66.2, 51.3; FT-IR (neat): 3323, 1693 cm−1; HRMS (ESI): m/z calcd for C21H15O6 [M − H]−: 363.0869; found: 363.0858. General Procedure for the Synthesis of Dihydrobenzo[a]fluorene Derivatives (21a−q). Substituted alkene (1.2 equiv) was added to a solution of 2-alkynylated p-quinone methide (1 equiv) and AgSbF6 (0.1 equiv) in CH2Cl2 (0.05 M), and the resultant mixture was stirred vigorously at room temperature until the 2-alkynylated pquinone methide was completely consumed (monitored by TLC). After completion of the reaction, solvent was removed under reduced pressure, and the residue was directly loaded on a silica gel column
and eluted using EtOAc/hexane mixture to obtain pure dihydrobenzo[a]fluorene derivatives. 2,6-Di-tert-butyl-4-(6a,11-diphenyl-6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21a). The reaction was performed on a 0.25 mmol scale of 19a; Rf = 0.5 (5% EtOAc in hexane); white solid (137 mg, 95% yield, dr {anti:syn} = >20:1); mp = 272−274 °C; 1H NMR (400 MHz, CDCl3) δ 7.55−7.52 (m, 6H), 7.48−7.44 (m, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.28−7.24 (m, 2H), 7.22−7.17 (m, 4H), 7.15− 7.11 (m, 1H), 6.97−6.94 (m, 3H), 6.90 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 5.09 (s, 1H), 4.01 (dd, J = 12.0, 5.4 Hz, 1H), 3.47 (dd, J = 13.6, 5.4 Hz, 1H), 2.13 (t, J = 12.3 Hz, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.4, 146.1, 144.6, 141.3, 141.0, 137.3, 136.8, 135.9, 135.7, 132.2, 130.1, 129.7 (2C), 129.0, 128.9, 127.7, 127.3, 127.0, 126.7, 126.5, 125.7, 125.5, 125.4, 122.8, 120.9, 58.9, 44.3, 43.3, 34.5, 30.5; FT-IR (neat): 3641 cm−1; HRMS (ESI): m/z calcd for C43H43O [M + H]+: 575.3314; found: 575.3291. 4-(11-([1,1′-Biphenyl]-4-yl)-6a-phenyl-6,6a-dihydro-5H-benzo[a]fluoren-5-yl)-2,6-di-tert-butylphenol (21b). The reaction was performed on a 0.2 mmol scale of 19b; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (120.1 mg, 92% yield, dr {anti:syn} = >20:1); mp = 272−274 °C; 1H NMR (400 MHz, CDCl3) δ 7.79− 7.74 (m, 4H), 7.61 (d, J = 7.6 Hz, 2H), 7.57−7.50 (m, 4H), 7.43− 7.39 (m, 2H), 7.32−7.26 (m, 4H), 7.23−7.13 (m, 3H), 6.99−6.91 (m, 4H), 6.77 (d, J = 7.4 Hz, 1H), 5.10 (s, 1H), 4.03 (dd, J = 11.8, 5.3 Hz, 1H), 3.49 (dd, J = 13.7, 5.4 Hz, 1H), 2.15 (t, J = 12.9 Hz, 1H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.5, 146.3, 144.5, 141.3, 141.1, 140.9, 140.3, 137.4, 136.4, 136.0, 134.7, 132.2, 130.2, 130.1, 129.0, 128.9, 127.6, 127.5, 127.4, 127.2 (2C), 127.1, 126.7, 126.5, 125.7, 125.6, 125.5, 122.8, 120.9, 59.0, 44.3, 43.4, 34.5, 30.5; FT-IR (neat): 3635 cm−1; HRMS (ESI): m/z calcd for C49H45O [M − H]−: 649.3470 found: 649.3475. 2,6-Di-tert-butyl-4-(6a-phenyl-11-(p-tolyl)-6,6a-dihydro-5Hbenzo[a]fluoren-5-yl)phenol (21c). The reaction was performed on a 0.098 mmol scale of 21c; Rf = 0.5 (10% EtOAc in hexane); pale yellow solid (55 mg, 96% yield, dr {anti:syn} = >20:1); mp = 263− 265 °C; 1H NMR (400 MHz, CDCl3) δ 7.58−7.56 (m, 2H), 7.45− 7.42 (m, 3H), 7.39−7.33 (m, 2H), 7.30−7.26 (m, 3H), 7.23−7.18 (m, 3H), 7.17−7.09 (m, 2H), 6.98−6.95 (m, 3H), 6.78−6.76 (m, 1H), 5.12 (s, 1H), 4.04 (dd, J = 11.9, 5.4 Hz, 1H), 3.49 (dd, J = 12.6, 5.5 Hz, 1H), 2.51 (s, 3H), 2.15 (dd, J = 13.5, 12.6 Hz, 1H), 1.44 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.4, 145.8, 144.7, 141.3, 140.9, 137.4, 137.3, 136.8, 135.9, 132.6, 132.4, 130.1, 129.7, 129.5, 128.9, 127.4, 127.3, 127.0, 126.6, 126.5, 125.6, 125.5, 125.4, 122.7, 120.9, 58.8, 44.3, 43.3, 34.5, 30.5, 21.6; FT-IR (neat): 3641 cm−1; HRMS (ESI): m/z calcd for C44H43O [M − H]−: 587.3314; found: 587.3297. 2,6-Di-tert-butyl-4-(11-(4-(tert-butyl)phenyl)-6a-phenyl-6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21d). The reaction was performed on a 0.2 mmol scale of 19d; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (110.8 mg, 87% yield, dr {anti:syn} = >20:1); mp = 178−180 °C; 1H NMR (400 MHz, CDCl3) δ 7.55− 7.53 (m, 4H), 7.46 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.28−7.23 (m, 4H), 7.19 (t, J = 7.9 Hz, 2H), 7.14−7.10 (m, 1H), 6.97−6.90 (m, 4H), 6.75 (d, J = 7.3 Hz, 1H), 5.09 (s, 1H), 4.02 (dd, J = 11.9, 5.4 Hz, 1H), 3.46 (dd, J = 13.6, 5.5 Hz, 1H), 2.14−2.08 (m, 1H), 1.43 (s, 9H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.4, 150.5, 145.8, 144.7, 141.4, 140.9, 137.5, 136.8, 135.9, 132.5, 132.4, 130.1, 129.2, 128.9, 127.4, 127.2, 127.0, 126.6, 126.5, 125.8, 125.5, 125.4 (2C), 122.7, 121.1, 58.9, 44.3, 43.4, 34.9, 34.5, 31.6, 30.5; FT-IR (neat): 3644 cm−1; HRMS (ESI): m/z calcd for C47H49O [M − H]−: 629.3783; found: 629.3804. 2,6-Di-tert-butyl-4-(11-(4-methoxyphenyl)-6a-phenyl-6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21e). The reaction was performed on a 0.070 mmol scale of 19e; Rf = 0.4 (5% EtOAc in hexane); white solid (39 mg, 92% yield, dr {anti:syn} = >20:1); mp = 261−263 °C; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.4 Hz, 1H), 7.28−7.24 (m, 3H), 7.21−7.11 (m, 4H), 7.07 (d, J = 8.5 Hz, 2H), 6.97−6.91 (m, 4H), 6.75 (d, J = 6.9 Hz, 1H), 5.09 (s, 1H), 4.00 (dd, J = 11.8, 5.2 Hz, 1H), 3.92 (s, 3H), 3.46 (dd, J = 13.6, 5.4 Hz, 1H), 2.11 (t, J = 12.9 10115
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry Hz, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 159.1 152.3, 151.4, 145.7, 144.8, 141.4, 141.0, 137.4, 136.4, 135.9, 132.4, 130.8, 130.1, 128.9, 127.8, 127.3, 127.2, 127.0, 126.6, 126.5, 125.6, 125.5, 125.4, 122.7, 120.9, 114.5, 58.8, 55.4, 44.3, 43.3, 34.5, 30.5; FT-IR (neat): 3634 cm−1; HRMS (ESI): m/z calcd for C44H43O2 [M − H]−: 603.3263; found: 603.3281. 2,6-Di-tert-butyl-4-(11-(4-phenoxyphenyl)-6a-phenyl-6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21f). The reaction was performed on a 0.2 mmol scale of 19f; Rf = 0.5 (5% EtOAc in hexane); orange gummy solid (114.9 mg, 85% yield, dr {anti:syn} = >20:1); 1H NMR (400 MHz, CDCl3) δ 7.55−7.49 (m, 4H), 7.45−7.40 (m, 3H), 7.30−7.23 (m, 4H), 7.22−7.12 (m, 8H), 7.00−6.95 (m, 2H), 6.94 (s, 2H), 6.79−6.75 (m, 1H), 5.10 (s, 1H), 4.02 (dd, J = 11.9, 5.3 Hz, 1H), 3.47 (dd, J = 13.6, 5.5 Hz, 1H), 2.11 (dd, J = 13.6, 12.2 Hz, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 157.2, 156.9, 152.3, 151.5, 146.2, 144.5, 141.2, 141.1, 137.3, 136.2, 136.0, 132.2, 131.1, 130.5, 130.2, 130.0, 128.9, 127.4, 127.3, 127.0, 126.7, 126.5, 125.7, 125.5, 125.4, 123.6, 122.8, 120.8, 119.3, 119.2, 58.9, 44.3, 43.4, 34.5, 30.5; FT-IR (neat): 3417 cm−1; HRMS (ESI): m/z calcd for C49H45O2 [M − H]−: 665.3420; found: 665.3444. 2,6-Di-tert-butyl-4-(11-(3-fluorophenyl)-6a-phenyl-6,6a-dihydro5H-benzo[a]fluoren-5-yl)phenol (21g). The reaction was performed on a 0.072 mmol scale of 19g; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (36 mg, 84% yield, dr {anti:syn} = >10:1); mp = 264− 266 °C; 1H NMR (400 MHz, CDCl3) δ 7.54−7.48 (m, 3H), 7.42 (d, J = 7.3 Hz, 1H), 7.32−7.26 (m, 3H), 7.23−7.14 (m, 7H), 7.00−6.92 (m, 4H), 6.77 (d, J = 7.5 Hz, 1H), 5.11 (s, 1H), 4.03 (dd, J = 11.9, 5.3 Hz, 1H), 3.48 (dd, J = 13.7, 5.4 Hz, 1H), 2.15−2.07 (m, 1H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 163.3 (d, JC−F = 244.9 Hz), 152.4, 151.4, 146.9, 144.0, 141.1, 141.0, 138.0 (d, JC−F = 31.3 Hz), 137.2, 136.0, 135.5 (d, JC−F = 2.0 Hz), 131.8, 130.6 (d, JC−F = 33.4 Hz), 130.2, 128.9, 127.7, 127.3, 127.1, 126.8, 126.4, 125.9, 125.7, 125.5 (d, JC−F = 2.8 Hz), 125.4, 122.9, 120.7, 116.3 (d, JC−F = 21.2 Hz), 114.7 (d, JC−F = 20.8 Hz), 59.0, 44.3, 43.4, 34.5, 30.5; 19F NMR (376 MHz, CDCl3) δ −112.54; FT-IR (neat): 3630 cm−1; HRMS (ESI): m/z calcd for C43H40FO [M − H]−: 591.3063; found: 591.3083. 2,6-Di-tert-butyl-4-(6a-phenyl-11-(thiophen-3-yl)-6,6a-dihydro5H-benzo[a]fluoren-5-yl)phenol (21h). The reaction was performed on a 0.075 mmol scale of 19h; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (36 mg, 82% yield, dr {anti:syn} = >20:1); mp = 203− 205 °C; 1H NMR (400 MHz, CDCl3) δ 7.53−7.48 (m, 4H), 7.40 (d, J = 7.3 Hz, 1H), 7.37−7.33 (m, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.28− 7.24 (m, 2H), 7.22−7.10 (m, 4H), 7.00−6.96 (m, 2H), 6.93 (s, 2H), 6.78−6.74 (m, 1H), 5.09 (s, 1H), 4.01 (dd, J = 12.0, 5.4 Hz, 1H), 3.45 (dd, J = 13.6, 5.5 Hz, 1H), 2.10 (dd, J = 13.4, 12.2 Hz, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.3 146.8, 144.2, 141.2, 141.0, 137.3 135.9, 135.5, 132.3, 131.7, 130.1, 128.9, 128.8, 127.5, 127.2, 127.1, 126.7, 126.5, 126.0, 125.7, 125.6, 125.4, 124.0, 122.8, 120.9, 58.9, 44.3, 43.4, 34.5, 30.5; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C41H41OS [M + H]+: 581.2878; found: 581.2863. 2,6-Di-tert-butyl-4-(11-(cyclohexylmethyl)-6a-phenyl-6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21i). The reaction was performed on a 0.072 mmol scale of 19i; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (34 mg, 79% yield, dr {anti:syn} = >20:1); mp = 173−175 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.25−7.21 (m, 4H), 7.15−7.08 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.87 (s, 2H), 6.76 (d, J = 7.7 Hz, 1H), 5.06 (s, 1H), 3.95 (dd, J = 12.2, 5.2 Hz, 1H), 3.35 (dd, J = 13.6, 5.4 Hz, 1H), 2.98 (dd, J = 13.6, 8.5 Hz, 1H), 2.87 (dd, J = 13.7, 5.7 Hz, 1H), 1.98−1.87 (m, 3H), 1.79−1.77 (m, 2H), 1.66−1.65 (m, 2H), 1.37 (s, 18H), 1.21− 1.16 (m, 3H), 1.08−0.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.8, 145.6, 144.8, 141.6, 140.6, 137.3, 136.1, 135.9, 133.6, 130.2, 128.8, 126.9, 126.8, 126.7, 126.53, 126.5, 125.9, 125.5, 125.3, 122.6, 120.7, 59.0, 44.5, 44.1, 38.5, 34.5, 34.4, 33.8, 33.7, 30.5, 26.7, 26.6, 26.57; FT-IR (neat): 3641 cm−1; HRMS (ESI): m/z calcd for C44H51O [M + H]+: 595.3940; found: 595.3967.
2,6-Di-tert-butyl-4-(11-(6-methoxynaphthalen-2-yl)-6a-phenyl6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21j). The reaction was performed on a 0.063 mmol scale of 19j; Rf = 0.4 (5% EtOAc in hexane); white solid (40 mg, 97% yield, dr {anti:syn} = >7:1); mp = 236−238 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.59−7.56 (m, 3H), 7.44 (d, J = 7.1 Hz, 1H), 7.31−7.23 (m, 6H), 7.22−7.13 (m, 3H), 6.98−6.93 (m, 3H), 6.84 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.11 (s, 1H), 4.06 (dd, J = 11.9, 5.4 Hz, 1H), 4.00 (s, 3H), 3.51 (dd, J = 13.6, 5.5 Hz, 1H), 2.18 (t, J = 13.2 Hz, 1H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 158.0, 152.3, 151.5, 146.2, 144.7, 141.3, 141.0, 137.4, 136.7, 135.9, 134.1, 132.3, 130.9, 130.1, 129.7, 129.4, 128.9, 128.4, 128.36, 127.5, 127.4, 127.3, 127.0, 126.7, 126.5, 125.7, 125.6, 125.5, 122.8, 120.9, 119.1, 106.0, 58.9, 55.5, 44.3, 43.3, 34.5, 30.5; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C48H45O2 [M − H]−: 653.3420; found: 653.3424. 2,6-Di-tert-butyl-4-(6a,11-diphenyl-6,6a-dihydro-5H-indeno[2′,1’:5,6]naphtho[2,3-d][1,3]dioxol-5-yl)phenol (21k). The reaction was performed on a 0.068 mmol scale of 19k; Rf = 0.3 (5% EtOAc in hexane); pale orange (40 mg, 94% yield, dr {anti:syn} = >20:1); mp = 230−232 °C; 1H NMR (400 MHz, CDCl3) δ 7.55−7.49 (m, 6H), 7.46−7.42 (m, 1H), 7.36 (d, J = 7.3 Hz, 1H), 7.29−7.25 (m, 2H), 7.19−7.13 (m, 3H), 7.10 (td, J = 7.2, 2 Hz, 1H), 6.90 (s, 2H), 6.63 (s, 1H), 6.20 (s, 1H), 5.81 (d, J = 1.3 Hz, 1H), 5.75 (d, J = 1.3 Hz, 1H), 5.08 (s, 1H), 3.87 (dd, J = 11.8, 5.4 Hz, 1H), 3.41 (dd, J = 13.6, 5.5 Hz, 1H), 2.06 (dd, J = 13.4, 12.1 Hz, 1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 150.9, 147.1, 145.9, 145.4, 144.7, 141.4, 137.2, 136.0, 135.64, 135.6, 129.7, 129.1, 128.9, 127.8, 127.0, 126.7, 126.5 (2C), 125.9, 125.5, 125.3, 122.7, 120.6, 110.0, 106.7, 100.8, 58.8, 44.6, 43.0, 34.5, 30.5; FT-IR (neat): 3634 cm−1; HRMS (ESI): m/z calcd for C44H41O3 [M − H]−: 617.3056; found: 617.3051. 2,6-Di-tert-butyl-4-(2-methyl-6a,11-diphenyl-6,6a-dihydro-5Hbenzo[a]fluoren-5-yl)phenol (21l). The reaction was performed on a 0.2 mmol scale of 19l; Rf = 0.5 (5% EtOAc in hexane); white solid (99 mg, 84% yield, dr {anti:syn} = >10:1); mp = 97−99 °C; 1H NMR (400 MHz, CDCl3) δ 7.58−7.52 (m, 6H), 7.50−7.46 (m, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.23−7.13 (m, 4H), 7.02 (s, 1H), 6.97 (s, 2H), 6.79 (dd, J = 8.0, 1.4 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.11 (s, 1H), 3.99 (dd, J = 12.0, 5.2 Hz, 1H), 3.49 (dd, J = 13.6, 5.4 Hz, 1H), 2.15 (dd, J = 13.4, 12.3 Hz, 1H), 2.08 (s, 3H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.5, 146.3, 144.6, 141.4, 138.0, 137.4, 136.7, 135.9, 135.8, 134.6, 131.9, 129.8, 129.7, 128.9, 128.4, 127.9, 127.6, 127.0, 126.6, 126.5, 125.6, 125.4, 122.7, 120.8, 58.9, 44.0, 43.4, 34.5, 30.5, 21.2; FT-IR (neat): 3638 cm−1; HRMS (ESI): m/z calcd for C44H45O [M + H]+: 589.3470; found: 589.3447. 2,6-Di-tert-butyl-4-(3-methoxy-6a,11-diphenyl-6,6a-dihydro-5Hbenzo[a]fluoren-5-yl)phenol (21m). The reaction was performed on a 0.2 mmol scale of 19m; Rf = 0.4 (5% EtOAc in hexane); Pale yellow (99.6 mg, 82% yield, dr {anti:syn} = >20:1); mp = 226−228 °C; 1H NMR (400 MHz, CDCl3) δ 7.55−7.53 (m, 6H), 7.47−7.43 (m, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.29−7.25 (m, 2H), 7.19−7.09 (m, 5H), 6.94 (s, 2H), 6.50 (dd, J = 8.6, 2.2 Hz, 1H), 6.28 (s, 1H), 5.09 (s, 1H), 3.96 (dd, J = 12.0, 5.1 Hz, 1H), 3.57 (s, 3H), 3.44 (dd, J = 13.6, 5.2 Hz, 1H), 2.16 (t, J = 12.9 Hz, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 158.7, 152.4, 151.1, 145.9, 144.8, 142.8, 141.5, 136.8, 136.0, 135.96, 135.3, 129.7, 129.0, 128.9, 128.6, 127.6, 127.0, 126.6, 126.5, 125.4, 125.3, 125.29, 122.7, 120.5, 115.2, 111.6, 58.7, 55.0, 44.6, 42.8, 34.5, 30.5; FT-IR (neat): 3644 cm−1; HRMS (ESI): m/z calcd for C44H45O2 [M + H]+: 605.3419; found: 605.3393. 2,6-Di-tert-butyl-4-(2,4-dimethoxy-6a,11-diphenyl-6,6a-dihydro5H-benzo[a]fluoren-5-yl)phenol (21n). The reaction was performed on a 0.088 mmol scale of 19n; Rf = 0.3 (5% EtOAc in hexane); white solid (35 mg, 62% yield, dr {anti:syn} = >20:1); mp = 261−263 °C; 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.3 Hz, 2H), 7.52 (t, J = 7.4 Hz, 2H), 7.46−7.42 (m, 3H), 7.32 (d, J = 7.3 Hz, 1H), 7.27−7.21 (m, 3H), 7.19−7.08 (m, 3H), 6.90 (s, 2H), 6.29 (d, J = 2.3 Hz, 1H), 6.12 (d, J = 2.3 Hz, 1H), 4.93 (s, 1H), 4.08 (dd, J = 10.7, 7.0 Hz, 1H), 3.56 (dd, J = 14.1, 6.9 Hz, 1H), 3.42 (s, 3H), 3.19 (s, 3H), 1.85 (dd, J = 14.1, 10.8 Hz, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 10116
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry Notes
158.9, 158.2, 152.0, 151.3, 147.3, 144.1, 140.8, 139.7, 136.7, 135.6, 135.3, 134.0, 129.8, 128.9, 128.7, 127.7, 126.9, 126.5 (2C), 125.7, 123.8, 123.1, 123.0, 120.9, 103.1, 100.2, 58.9, 55.5, 54.9, 43.1, 40.0, 34.4, 30.6; FT-IR (neat): 3634 cm−1; HRMS (ESI): m/z calcd for C45H47O3 [M + H]+: 635.3525; found: 635.3552. 2,6-Di-tert-butyl-4-(3-fluoro-6a,11-diphenyl-6,6a-dihydro-5Hbenzo[a]fluoren-5-yl)phenol (21o). The reaction was performed on a 0.048 mmol scale of 19o; Rf = 0.5 (5% EtOAc in hexane); colorless gummy solid (17 mg, 60% yield, dr {anti:syn} = >10:1); mp = 190− 192 °C; 1H NMR (400 MHz, CDCl3) δ 7.55−7.43 (m, 7H), 7.40 (d, J = 7.3 Hz, 1H), 7.29−7.25 (m, 2H), 7.21−7.11 (m, 5H), 6.91 (s, 2H), 6.61 (td, J = 8.4, 2.3 Hz, 1H), 6.46−6.42 (m, 1H), 5.12 (s, 1H), 3.96 (dd, J = 12.0, 5.4 Hz, 1H), 3.45 (dd, J = 13.7, 5.5 Hz, 1H), 2.11 (dd, J = 13.6, 12.1 Hz, 1H), 1.42 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 162.0 (d, JC−F = 244.8 Hz), 152.6, 151.2, 145.0, 144.5, 143.7 (d, JC−F = 7.0 Hz), 141.1, 136 (d, JC−F = 1.3 Hz), 136.5, 136.2, 135.5, 129.6, 129.1, 129.0, 128.97, 128.4 (d, JC−F = 2.9 Hz), 127.8, 127.1, 126.8, 126.4, 125.7, 125.3, 122.8, 120.9, 116.5 (d, JC−F = 21.4 Hz), 113.2 (d, JC−F = 21.7 Hz), 58.8, 44.6, 42.9, 34.5, 30.5; 19F NMR (376 MHz, CDCl3) δ −113.84; FT-IR (neat): 3639 cm−1; HRMS (ESI): m/z calcd for C43H41FNaO [M + Na]+: 615.3039; found: 615.3014. 2,6-Di-tert-butyl-4-(6a-methyl-11-phenyl-6,6a-dihydro-5Hbenzo[a]fluoren-5-yl)phenol (21p). The reaction was performed on a 0.12 mmol scale of 19a; Rf = 0.4 (5% EtOAc in hexane); white solid (42 mg, 68% yield, dr {anti:syn} = >10:3); major isomer: mp = 87− 89 °C; 1H NMR (400 MHz, CDCl3) δ 7.49−7.44 (m, 5H), 7.28− 7.23 (m, 3H), 7.16−7.05 (m, 3H), 7.01−6.92 (m, 4H), 5.09 (s, 1H), 4.34 (dd, J = 11.8, 6.1 Hz, 1H), 2.72 (dd, J = 13.2, 6.1 Hz, 1H), 1.79− 1.73 (m, 1H), 1.47 (s, 3H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 152.2, 147.6, 145.0, 140.9, 137.8, 136.0, 135.9, 134.0, 131.6, 130.4, 129.7, 128.9, 127.5, 127.4, 127.3, 127.0, 125.5, 125.4, 125.2, 121.6, 120.7, 50.6, 44.1, 34.5 (2C), 30.5, 21.1; FT-IR (neat): 3638 cm−1; HRMS (ESI): m/z calcd for C38H39O [M − H]−: 511.3000; found: 511.3022. 2,6-Di-tert-butyl-4-(9-chloro-6a-(4-chlorophenyl)-11-phenyl6,6a-dihydro-5H-benzo[a]fluoren-5-yl)phenol (21q). The reaction was performed on a 0.2 mmol scale of 19a; Rf = 0.1 (5% EtOAc in hexane); white solid (116.7 mg, 90% yield, dr {anti:syn} = >10:1); mp = 102−104 °C; 1H NMR (400 MHz, CDCl3) δ 7.57−7.53 (m, 2H), 7.51−7.48 (m, 3H), 7.44−7.42 (m, 2H), 7.27−7.23 (m, 3H), 7.19 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.0, 1.9 Hz, 1H), 7.00 (td, J = 7.5, 1.3 Hz, 1H), 6.95−6.90 (m, 3H), 6.78 (d, J = 7.7 Hz, 1H), 5.13 (s, 1H), 3.98 (dd, J = 11.9, 5.4 Hz, 1H), 3.40 (dd, J = 13.8, 5.6 Hz, 1H), 2.10 (dd, J = 13.5, 12.4 Hz, 1H), 1.43 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 149.2, 147.3, 146.3, 140.9, 139.3, 137.0, 136.1, 136.06, 134.8, 133.3, 132.7, 131.5, 130.2, 129.5, 129.24, 129.2, 128.1, 128.0, 127.8, 127.4, 125.8, 125.6, 125.4, 123.6, 121.2, 58.1, 44.2, 43.1, 34.5, 30.5; FT-IR (neat): 3637 cm−1; HRMS (ESI): m/z calcd for C43H39Cl2O [M − H]−: 641.2378; found: 641.2408.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge DST-SERB (EMR/2015/ 001759) for the financial support and IISER Mohali for the infrastructure. A.S.J. and Y.A.P. thank IISER Mohali for the research fellowship. The NMR, HRMS, and XtaLabmini single crystal X-ray facilities at IISER Mohali are gratefully acknowledged. We thank Mr. Mayank Joshi (IISER Mohali) for his help in solving the crystal structure. We also thank Dr. Sugumar Venkatramani (IISER Mohali) for useful discussions.
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(1) For selected examples: (a) RajanBabu, T. V. Asymmetric Hydrovinylation Reaction. Chem. Rev. 2003, 103, 2845−2860. (b) RajanBabu, T. V. In Pursuit of an Ideal Carbon-Carbon BondForming Reaction: Development and Applications of the Hydrovinylation of Olefins. Synlett 2009, 2009, 853−885. (c) Hilt, G. Hydrovinylation Reactions − Atom-Economic Transformations with Steadily Increasing Synthetic Potential. Eur. J. Org. Chem. 2012, 2012, 4441−4451. (d) Greenhalgh, M. D.; Jones, A. S.; Thomas, S. P. IronCatalysed Hydrofunctionalisation of Alkenes and Alkynes. ChemCatChem 2015, 7, 190−222. (e) Ho, C.-Y.; Chan, C.-W.; He, L. Catalytic Asymmetric Hydroalkenylation of Vinylarenes: Electronic Effects of Substrates and Chiral N-Heterocyclic Carbene Ligands. Angew. Chem., Int. Ed. 2015, 54, 4512−4516. (f) Wu, J.; Yoshikai, N. Cobalt-Catalyzed Alkenylzincation of Unfunctionalized Alkynes. Angew. Chem., Int. Ed. 2016, 55, 336−340. (g) Liu, M.; Zhang, J.; Zhou, H.; Yang, H.; Xia, C.; Jiang, G. Efficient Hydroarylation and Hydroalkenylation of Vinylarenes by Brønsted Acid Catalysis. RSC Adv. 2016, 6, 76780−76784. (h) Watabe, Y.; Kanazawa, K.; Fujita, T.; Ichikawa, J. Nickel-Catalyzed Hydroalkenylation of Alkynes through C−F Bond Activation: Synthesis of 2-Fluoro-1,3-dienes. Synthesis 2017, 49, 3569−3575. (2) For selected references: (a) Ho, C.-Y.; Ohmiya, H.; Jamison, T. F. α-Olefins as Alkenylmetal Equivalents in Catalytic Conjugate Addition Reactions. Angew. Chem., Int. Ed. 2008, 47, 1893−1895. (b) Ogoshi, S.; Haba, T.; Ohashi, M. Nickel-Catalyzed Direct Conjugate Addition of Simple Alkenes to Enones. J. Am. Chem. Soc. 2009, 131, 10350−10351. (c) Zhao, C.; Toste, F. D.; Bergman, R. G. Direct Michael Addition of Alkenes via a Cobalt-Dinitrosyl Mediated Vinylic C−H Functionalization Reaction. J. Am. Chem. Soc. 2011, 133, 10787−10789. (d) Okamoto, K.; Tamura, E.; Ohe, K. Direct Michael Addition of Alkenes via a Cobalt-Dinitrosyl Mediated Vinylic C−H Functionalization Reaction. Angew. Chem., Int. Ed. 2013, 52, 10639. (e) Li, K.; Wan, Q.; Kang, Q. Chiral-at-Metal Rh(III) Complex Catalyzed Asymmetric Conjugate Addition of Unactivated Alkenes with α,β-Unsaturated 2-Acyl Imidazoles. Org. Lett. 2017, 19, 3299− 3302. (3) For selected examples: (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; et al. Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryl- and Alkenylboronic Acids to Enones. J. Am. Chem. Soc. 1998, 120, 5579− 5580. (b) Oi, S.; Taira, A.; Honma, Y.; Inoue, Y. Asymmetric 1,4Addition of Organosiloxanes to α,β-Unsaturated Carbonyl Compounds Catalyzed by a Chiral Rhodium Complex. Org. Lett. 2003, 5, 97−99. (c) Duursma, A.; Boiteau, J.-G.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. Highly Enantioselective Conjugate Additions of Potassium Organotrifluoroborates to Enones by Use of Monodentate Phosphoramidite Ligands. J. Org. Chem. 2004, 69, 8045−8052. (d) Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R. A Catalytic Asymmetric ThreeComponent 1,4-Addition/Aldol Reaction: Enantioselective Synthesis of the Spirocyclic System of Vannusal A. Angew. Chem., Int. Ed. 2005, 44, 3874−3879. (e) Mahoney, S. J.; Dumas, A. M.; Fillion, E. Asymmetric Addition of Alkenylstannanes to Alkylidene Meldrum’s Acids. Org. Lett. 2009, 11, 5346−5349. (f) Müller, D.; Alexakis, A.
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01401. 1
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REFERENCES
H, 13C, and 19F spectra of all new compounds (PDF) X-ray crystallographic data for compound 21a (CIF)
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[email protected]. ORCID
Ramasamy Vijaya Anand: 0000-0001-9490-4569 Author Contributions ‡
These authors contributed equally. 10117
DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
Article
The Journal of Organic Chemistry
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DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
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DOI: 10.1021/acs.joc.8b01401 J. Org. Chem. 2018, 83, 10107−10119
