Synthesis of Cyclohepta[b]indoles - ACS Publications - American

Note Cite This: J. Org. Chem. 2018, 83, 8615−8626

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Exploring Gold Catalysis in a 1,6-Conjugate Addition/Domino Electrophilic Cyclization Cascade: Synthesis of Cyclohepta[b]indoles Abhijeet S. Jadhav, Yogesh A. Pankhade, and Ramasamy Vijaya Anand* Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, S. A. S. Nagar, Manauli (PO), Punjab 140306, India

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ABSTRACT: An effective method for the construction of the structurally complex fused cyclohepta[b]indole core has been developed through an intermolecular 1,6-conjugate addition of indoles to 2-alkynyl p-quinone methides followed by an intramolecular electrophilic cyclization under oxophilic and alkynophilic gold catalysis.

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metal-catalyzed three-component or two-component [4+3]cycloaddition reactions,3 dearomative indole [5+2]-cycloaddition reactions,4 [3,3]-sigmatropic rearrangements,5 iodine-mediated6 or Au-catalyzed electrophilic cyclizations,7 metal-catalyzed intramolecular cyclizations,8 and multicatalytic orthogonal tandem catalysis approach.9 In addition, a few enantioselective protocols have been developed to access enantiomerically pure cyclohepta[b]indole derivatives.10 However, although all of the above-mentioned processes are elegant, most of them involve a multistep approach. Therefore, developing a one-pot domino process to access the cyclohepta[b]indole core is indeed highly desirable. While exploring p-quinone methides (p-QMs)11 as electrophiles in the 1,6-conjugate addition of a variety of nucleophiles to access unsymmetrical diarylmethanes and triarylmethanes,12 we envisaged that by using an appropriately modified p-QM having another electrophilic center at the o-position of the aryl moiety, it could be possible to access the cyclohepta[b]indole core through the 1,6-conjugate addition of an indole to the p-QM followed by intramolecular cyclization. In this context, we thought that the presence of an alkyne moiety at the o-position of the aryl ring of p-QM (7) would serve as the secondary electrophile, which can be easily activated by electrophilic metal catalysts (Scheme 1). In line with this concept, we sought to develop a domino process to synthesize cyclohepta[b]indole derivatives using a suitable catalytic system. Since this process involves two steps, i.e., the 1,6-conjugate addition of indole to p-QM followed by intramolecular cyclization, selecting the most suitable catalytic system

ing-fused indole is deliberated as one of the privileged structural motifs in the area of drug discovery.1 Particularly, the cyclohepta[b]indole core (a seven-membered ring fused with an indole at the 2- and 3-positions) attracted the synthetic community due to its prevalent occurrence in many biologically significant natural products (1−3, Figure 1).2 Moreover, many

Figure 1. Some biologically active cyclohepta[b]indoles.

unnatural/synthetic cyclohepta[b]indole derivatives, such as 4, 5, and 6 (Figure 1), have shown noteworthy therapeutic deeds.2 The combination of unmatched medicinal properties as well as the structural complexity made the cyclohepta[b]indole motif a valuable and also a synthetically challenging target. As a result, many well-designed approaches have been established for the construction of the cyclohepta[b]indole core,2 mostly through © 2018 American Chemical Society

Received: March 7, 2018 Published: May 30, 2018 8615

DOI: 10.1021/acs.joc.8b00607 J. Org. Chem. 2018, 83, 8615−8626

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The Journal of Organic Chemistry Scheme 1. Proposed Domino Process to Access Cyclohepta[b]indoles

Table 1. Optimization Studiesa

entry

catalyst

solvent

time [h]

yield [%]

1 2 3b 4b 5b 6b 7c 8b 9b 10b 11 12 13 14 15b,d

PPh3AuCl (5 mol %) AgOTf (5 mol %) AgOTf/PPh3AuCl AgOTf/PPh3AuCl AgOTf/PPh3AuCl AgOTf/PPh3AuCl AgOTf/PPh3AuCl AgSbF6/PPh3AuCl AgNTf2/PPh3AuCl AgOTf/AuCl t Bu3PAuNTf2 (5 mol %) PPh3AuNTf2 (5 mol %) Cu(OTf)2 (5 mol %) PdCl2 (5 mol %) AgOTf/PPh3AuCl

DCE DCE DCE MeCN PhMe THF THF THF THF THF THF THF THF THF THF

24 24 2.5 24 24 2.5 14 3 5 3 2.5 4 24 24 2.5

nd nd 88 20 92 96 88 94 76 90 88 85 nd nd 90

a All reactions were carried out with 0.075 mmol of 7a and 0.068 mmol of 8a in a solvent (1.5 mL) at room temperature. b5 mol % each of Ag and Au catalysts were used. c2.5 mol % each of Ag and Au catalysts were used. dReaction was carried out with 1.4 mmol of 7a and 1.28 mmol of 8a. DCE = 1,2-dichloroethane; nd = not detected.

relatively longer for completion (entry 7). The optimization studies were then extended using the combination of different silver and gold catalysts in THF at room temperature (entries 8−10). However, in all of those cases, although the reaction was taking place efficiently, the yield of 10a was a bit inferior when compared to entry 6. Interestingly, when the reaction was carried with more reactive cationic gold(I) complexes, such as tBu3PAuNTf2 or Ph3PAuNTf2, 10a was obtained in 88 and 85% isolated yields, respectively (entries 11 and 12). These experiments clearly indicate that the cationic gold catalyst is responsible for driving the 1,6-conjugate addition as well as the electrophilic cyclization. Moreover, these experiments also confirm the oxophilic nature of the gold catalysts. In fact, the oxophilic gold catalysis14 is relatively an underexplored area until now. In the present case, we believe that the gold catalyst acts as an oxophilic catalyst by activating the carbonyl group of 7a and facilitates the 1,6-conjugate addition of 8a to 7a. Even in the case of entry 6, the cationic gold species Ph3PAuOTf (generated in situ by the reaction of AgOTf and Ph3PAuCl) is actually involved in the catalytic process. Other metal catalysts, such as Cu(OTf)2 and PdCl2, failed to catalyze this transformation (entries 13 and 14). A relatively large scale reaction was performed using 7a (0.56 g, 1.4 mmol scale)

is a challenging task as both of the steps require catalytic activation. Keeping all of the above-mentioned aspects in mind, we started the optimization studies using an alkynylated p-QM 7a and indole 8a under various catalytic systems and conditions (Table 1). Our initial attempt using either PPh3AuCl or AgOTf as a catalyst in DCE at room temperature was not encouraging as the expected product 10a was not observed under the reaction conditions (entries 1 and 2). Since the combination of Ag and Au has been proven to be one of the best catalytic systems in many domino organic transformations leading to complex systems,13 we thought of exploring this combination in our optimization studies. To our delight, when a reaction was performed with the combination of AgOTf (5 mol %) and PPh3AuCl (5 mol %) as catalysts in DCE, the expected product 10a was isolated in 88% yield (entry 3). The structure of 10a was unambiguously confirmed by X-ray crystallography. Further elaboration of the optimization studies (entries 4−6) in other solvents revealed that THF was the most suitable solvent for this transformation, and in that case, 10a was obtained in 96% isolated yield within 2.5 h (entry 6). When the catalyst loading was reduced to 2.5 mol % each, 10a was obtained in 88% yield; however, the reaction took 8616


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The Journal of Organic Chemistry Scheme 2. Substrate Scope

Remarkably, electron-poor indole 8m also provided the corresponding product 11m in 93% yield. Aryl- and vinyl-substituted indoles (8n, 8o, 8q, and 8r) furnished the corresponding cyclohepta[b]indole derivatives (11n, 11o, 11q, and 11r) in 65− 99% yields. This methodology was also found to be suitable for N-alkylated indoles (8s−u), and in those case, the desired products 11s−u were obtained in 57−73% yields. To identify the possible intermediate in this transformation, a few control experiments were performed (Scheme 4). We believed that the reaction was proceeding through the intermolecular 1,6-conjugate addition of indole to the 2-alkynyl p-QM followed by an intramolecular electrophilic cyclization. In this context, a few experiments were performed using p-QM 7q [without the alkyne substituent] and indole 8a (Scheme 4). When 7q was treated with indole using 5 mol % AgOTf in THF at rt, the 1,6-adduct 9a was obtained in 65% yield. However, the reaction took a very long time to complete (36 h). When the same reaction was performed using the combination of Ag and Au catalysts, 9a was obtained in 80% yield within 5 min. These experiments evidently indicate that the 1,6-adduct is the most probable intermediate in this transformation. Then, we thought of performing additional experiments with the isolated intermediate 9 (which was conveniently prepared in 90% yield by treating 7a with 8a in the presence of 5 mol % Bi(OTf)3 in DCE at rt). When 9 was subjected to ring-closure in the presence of AgOTf or PPh3AuCl, in neither case, 10a was observed. Interestingly, when the combination of both of the catalysts was employed, 10a was obtained in 80% yield (Scheme 4). From these experiments, one can confidently confirm that the cationic gold(I) species (generated by the reaction of AgOTf with PPh3AuCl) is responsible for driving the 1,6-conjugate addition as well as electrophilic cyclization steps by acting as an oxophilic and alkynophilic catalyst, respectively.

and indole 8a (1.28 mmol) under the best conditions (entry 6), and in this case, 10a was isolated in 90% yield (entry 15). After finding an optimal condition for this transformation (Table 1, entry 6), the substrate scope was investigated using a wide range of alkynylated p-QMs (7b−p) and the results are summarized in Scheme 2. Most of the alkynylated p-QMs (7b−h and 7k), bearing electron-rich aryl substituents at the alkyne part, underwent a smooth transformation to their respective cyclohepta[b]indole derivatives (10b−h and 10k) in moderate to excellent yields. Interestingly, other p-QMs (7i and 7j), substituted with electron-poor aryl groups at the alkyne part, also reacted with indole and provided the corresponding products 10i and 10j in 91 and 96% yields, respectively. In the case of 7l, where the alkyne is substituted with an aliphatic group, the expected cyclohepta[b]indole derivative 10l was obtained in 60% isolated yield. Other p-QMs, 7m and 7n (substituted at the benzene ring), also provided the expected products 10m and 10n in 88 and 65% yields, respectively. To examine the reactivity of terminal alkynes in this methodology, an experiment was conducted with the p-QM-containing terminal alkyne 7o (R2 = H) under standard conditions. Interestingly, in this case, the expected cyclohepta[b]indole was not obtained. Instead, a carbazole derivative, 10o, was obtained in 41% isolated yield. This protocol was also elaborated for another p-QM 7p, derived from 2,6-dimethylphenol, and the expected product, 10p, was obtained in 86% yield. The scope of this transformation was also extended by treating 7a with a variety of substituted indoles under the optimized reaction conditions, and results are summarized in Scheme 3. In general, alkyl-, alkoxy-, and halo-substituted indoles (8b−l and 8p) reacted smoothly and provided the corresponding products 11b−l and 11p in moderate to excellent yields (63−99%). 8617


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The Journal of Organic Chemistry Scheme 3. Substrate Scope with Different Indoles

Scheme 4. Control Experiments

Scheme 5. Plausible Mechanism

Moreover, these experiments also clearly confirm that the reaction is actually proceeding through the intermediate 9. Based on the above-mentioned control experiments, a plausible mechanism has been proposed (Scheme 5). Initially, the cationic gold(I) species are generated by the anion metathesis reaction of AgOTf with PPh3AuCl.15 This active cationic gold complex acts as an oxophilic catalyst and activates the carbonyl of 7a, which facilitates the addition of indole to form 1,6-adduct 9. Now, there are two possible ways in which the electrophilic cyclization can occur. One possibility is that intermediate 12 undergoes 6-endo-dig cyclization through the activation of the alkyne moiety by the Au catalyst to give a spirocyclic intermediate 13 (Path A in Scheme 5),7b which on ring expansion provides the carbocation 14.16 Elimination of a proton from 14 followed by protonation generates the product 10a with the regeneration of the active Au catalyst. Another possibility is that intermediate 12 undergoes 7-endo-dig cyclization to give intermediate 15,17 which on aromatization followed by protonation produces product 10a with the elimination of the active Au catalyst (Path B in Scheme 5).

To improve the substrate scope of this transformation further, we performed a de-tert-butylation reaction of 10a with an excess of AlCl3 in benzene, and the de-tert-butylated product 16 was obtained in 80% yield within an hour (Scheme 6). In conclusion, we have developed an effective method for the synthesis of cyclohepta[b]indole derivatives through the goldcatalyzed intermolecular 1,6-conjugate addition of indoles to 2-alkynyl p-quinone methides followed by an intramolecular electrophilic cyclization. We have also shown the oxophilic nature of the cationic gold species in activating the p-quinone methide through control experiments. 8618


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The Journal of Organic Chemistry

C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.2, 139.1, 137.6, 135.1, 132.9, 132.7, 131.6, 130.7, 129.3, 129, 128.4, 128.1, 124.5, 119.9, 96, 87.1, 35.6, 35.2, 29.7, 29.6, 21.7; FT-IR (neat) 2957, 2217, 1614, 1566, 1510, 1361, 1254, 1090, 815, 757, cm−1; HRMS (ESI) m/z calcd for C30H33O [M + H]+ 409.2531, found 409.2513 2,6-Di-tert-butyl-4-(2-((4-(tert-butyl)phenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7d): Rf = 0.6 (5% EtOAc in hexane); orange solid (292 mg, 67% yield); mp = 85−87 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7 Hz, 1H), 7.53 (s, 1H), 7.46−7.44 (m, 4H), 7.40− 7.38 (m, 4H), 7.09 (s, 1H), 1.36 (s, 9H), 1.33 (s, 9H), 1.27 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 186.8, 152.3, 149.4, 148.1, 141.2, 137.6, 135.1, 132.9, 132.7, 131.5, 130.8, 129, 128.3, 128.2, 125.6, 124.6, 120, 96, 87.1, 35.6, 35.2, 35, 31.3, 29.7, 29.65; IR (neat) 2958, 2217, 1615, 1361, 1458, 1256, 834, 757 cm−1; HRMS (ESI) m/z calcd for C33H39O [M + H]+ 451.3001, found 451.3018. 2,6-Di-tert-butyl-4-(2-((4-pentylphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7e): Rf = 0.6 (5% EtOAc in hexane); orange gummy solid (281 mg, 75% yield); 1H NMR (400 MHz, CDCl3) δ 7.64−7.62 (m, 1H), 7.54 (s, 1H), 7.47−7.43 (m, 3H), 7.41−7.36 (m, 3H), 7.18 (d, J = 8.1 Hz, 2H), 7.1 (d, J = 2 Hz, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.66−1.58 (m, 2H), 1.37 (s, 9H), 1.34−1.30 (m, 4H), 1.28 (s, 9H), 0.9 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.3, 148.1, 144.2, 141.3, 137.6, 135.1, 132.9, 132.7, 131.6, 130.7, 129, 128.7, 128.4, 128.1, 124.5, 120.1, 96.1, 87.1, 36, 35.5, 35.2, 31.6, 31.1, 29.7, 29.6, 22.7, 14.2; IR (neat) 2958, 2929, 2861, 2215, 1614, 1567, 1362, 1179, 949, 758 cm−1; HRMS (ESI) m/z calcd for C34H41O [M + H]+ 465.3157, found 465.3141. 2,6-Di-tert-butyl-4-(2-((4-methoxyphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7f): Rf = 0.5 (5% EtOAc in hexane); orange solid (240 mg, 70% yield); mp = 139−141 °C; 1H NMR (400 MHz, CDCl3) δ 7.64−7.59 (m, 1H), 7.53 (s, 1H), 7.46−7.42 (m, 4H), 7.41− 7.35 (m, 2H), 7.09 (d, J = 2.2 Hz, 1H), 6.90−6.87 (m, 2H), 3.84 (s, 3H), 1.36 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 160.1, 149.4, 148.1, 141.3, 137.5, 135.1, 133.2, 132.8, 132.7, 130.7, 129, 128.4, 128, 124.7, 115.1, 114.2, 95.9, 86.5, 55.5, 35.6, 35.2, 29.7, 29.6; IR (neat) 2957, 2212, 1614, 1566, 1511, 1361, 1288, 1251, 1091, 1031, 831, 757 cm−1; HRMS (ESI) m/z calcd for C30H33O2 [M + H]+ 425.2481, found 425.2474. 2,6-Di-tert-butyl-4-(2-((4-phenoxyphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7g): Rf = 0.5 (5% EtOAc in hexane); orange gummy solid (259 mg, 67% yield); 1H NMR (400 MHz, CDCl3) δ 7.64−7.62 (m, 1H), 7.52 (s, 1H), 7.48−7.43 (m, 4H), 7.41−7.35 (m, 4H), 7.16 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 7.7 Hz, 2H), 7−6.96 (m, 2H), 1.35 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 158.2, 156.4, 149.4, 148.1, 141.1, 137.6, 135, 133.4, 132.9, 132.8, 130.8, 130.1, 129, 128.4, 128.2, 124.4, 124.2, 119.7, 118.5, 117.4, 95.4, 87.1, 35.6, 35.2, 29.7, 29.6; IR (neat) 2957, 2214, 1614, 1587, 1566, 1505, 1488, 1361, 1241, 1167, 1023 cm−1; HRMS (ESI) m/z calcd for C35H35O2 [M + H]+ 487.2637, found 487.2650. 2,6-Di-tert-butyl-4-(2-((2-chlorophenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7h): Rf = 0.6 (5% EtOAc in hexane); orange solid (232 mg, 66% yield); mp = 130−132 °C; 1H NMR (400 MHz, CDCl3) δ 7.71−7.67 (m, 2H), 7.57−7.55 (m, 1H), 7.52−7.50 (m, 1H), 7.46−7.38 (m, 4H), 7.31−7.24 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 1.35 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.6, 148.1, 141.2, 138, 136.1, 135.3, 133.4, 132.9, 132.6, 130.5, 129.8, 129.6, 128.9, 128.7, 128.1, 126.8, 124, 123, 92.7, 92.6, 35.6, 35.2, 29.7; IR (neat) 2956, 1614, 1566, 1482, 1361, 1254, 1023, 820, 754 cm−1; HRMS (ESI) m/z calcd for C29H30ClO [M + H]+ 429.1985, found 429.1967. 2,6-Di-tert-butyl-4-(2-((3-fluorophenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7i): Rf = 0.6 (5% EtOAc in hexane); yellow solid (211 mg, 63% yield); mp = 128−130 °C; 1H NMR (400 MHz, CDCl3) δ 7.65−7.63 (m, 1H), 7.49−7.46 (m, 2H), 7.44−7.38 (m, 3H), 7.35−7.28 (m, 2H), 7.21−7.18 (m, 1H), 7.09−7.04 (m, 2H), 1.36 (s, 9H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 162.5 (d, JC−F = 245.4 Hz), 149.5, 148.3, 140.6, 137.9, 134.9, 133.04, 133.0, 130.8, 130.2 (d, JC−F = 8.6 Hz), 129.0, 128.7, 128.2, 127.6 (d, JC−F = 3.0 Hz), 124.8 (d, JC−F = 9.5 Hz), 123.7, 118.5 (d, JC−F = 22.7 Hz), 116.2 (d, JC−F = 21.1 Hz), 94.2 (d, JC−F = 3.4 Hz), 88.6, 35.6, 35.2, 29.7, 29.6; 19F NMR (376 MHz, CDCl3) δ −112.58; IR (neat) 2957, 1614, 1580, 1361, 1254, 13

Scheme 6. De-tert-butylation of 10a

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EXPERIMENTAL SECTION

General Information. All reactions were carried out under an argon atmosphere employing flame-dried glassware. Most of the reagents and starting materials were purchased from commercial sources and used as such. 4-(2-Bromobenzylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (p-Quinone methide) and 4-(2-bromobenzyl)-2,6-dimethylphenol were prepared by following a literature procedure.12a,18 Melting points were recorded on a SMP20 melting point apparatus and are uncorrected. 1H, 13C, and 19F spectra were recorded in CDCl3 (400, 100, and 376 MHz, respectively) on a 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 Perkin− Elmer 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 2-Alkynylated p-Quinone Methides (7a−n, 7p, and 17). Terminal acetylene (1.22 mmol) was added to a stirred solution of PdCl2(PPh3)2 (0.04 mmol), CuI (0.04 mmol), and 4-(2-bromobenzylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (0.8 mmol) in triethylamine (5 mL) at room temperature, and the reaction mixture was heated to 70 °C under an inert atmosphere. After completion of the reaction (by TLC), triethylamine was removed under reduced pressure and the reaction mixture was then diluted with dichloromethane (30 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (20 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography using hexane/EtOAc to obtain pure alkynylated p-quinone methide derivatives. 2,6-Di-tert-butyl-4-(2-(phenylethynyl)benzylidene)cyclohexa-2,5dienone (7a): Rf = 0.6 (5% EtOAc in hexane); yellow solid (290 mg, 91% yield); mp = 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.1 Hz, 1H), 7.53−7.47 (m, 3H), 7.45−7.39 (m, 4H), 7.37−7.36 (m, 3H), 7.09 (s, 1H), 1.36 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.1, 137.7, 135.1, 133.0, 132.8, 131.7, 131.7, 130.8, 129.0, 128.9, 128.6, 128.3, 124.3, 123, 95.7, 87.7, 35.6, 35.2, 29.7, 29.6; FT-IR (neat) 2957, 2217, 1614, 1566, 1492, 1361, 1254, 1091, 820, 755 cm−1; HRMS (ESI) m/z calcd for C29H31O [M + H]+ 395.2375, found 395.2358. 4-(2-([1,1′-Biphenyl]-4-ylethynyl)benzylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (7b): Rf = 0.5 (5% EtOAc in hexane); orange solid (258 mg, 69% yield); mp = 127−129 °C; 1H NMR (400 MHz, CDCl3) δ 7.69−7.67 (m, 1H), 7.63−7.61 (m, 4H), 7.60−7.57 (m, 3H), 7.50− 7.44 (m, 5H), 7.43−7.37 (m, 2H), 7.14 (s, 1H), 1.40 (s, 9H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.4, 148.1, 141.6, 141.1, 140.3, 137.7, 135.0, 132.9, 132.8, 132.1, 130.7, 129, 128.97, 128.3, 127.9, 127.2, 127.1, 127.1, 124.3, 121.8, 95.7, 88.4, 35.6, 35.2, 29.7, 29.6; FT-IR (neat) 2957, 2214, 1614, 1566, 1456, 1486, 1361, 1254, 1091 cm−1; HRMS (ESI) m/z calcd for C35H35O [M + H]+ 471.2688, found 471.2708. 2,6-Di-tert-butyl-4-(2-(p-tolylethynyl)benzylidene)cyclohexa-2,5dienone (7c): Rf = 0.6 (5% EtOAc in hexane); orange solid (254 mg, 77% yield); mp = 148−150 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7 Hz, 1H), 7.54 (s, 1H), 7.47−7.44 (m, 2H), 7.41−7.36 (m, 4H), 7.17 (d, J = 7.7 Hz, 2H), 7.1 (s, 1H), 2.38 (s, 3H), 1.36 (s, 9H), 1.27 (s, 9H); 8619


Note

The Journal of Organic Chemistry 1214, 870, 783, 757, 680 cm−1; HRMS (ESI) m/z calcd for C29H30FO [M + H]+ 413.2281, found 413.2263 Methyl 4-((2-((3,5-Di-tert-butyl-4-oxocyclohexa-2,5-dien-1ylidene)methyl)phenyl)ethynyl)benzoate (7j): Rf = 0.3 (5% EtOAc in hexane); yellow solid (200 mg, 55% yield); mp = 159−161 °C; 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.49−7.45 (m, 3H), 7.40−7.38 (m, 2H), 7.09 (s, 1H), 3.93 (s, 3H), 1.36 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 166.6, 149.5, 148.3, 140.6, 137.9, 134.9, 133.1, 133, 131.6, 130.8, 130, 129.7, 129, 128.8, 128.2, 127.6, 123.6, 94.7, 90.6, 52.5, 35.6, 35.2, 29.7, 29.6; IR (neat) 2956, 2213, 1726, 1614, 1307, 1276, 1361, 1107, 1018, 916, 768 cm−1; HRMS (ESI) m/z calcd for C31H33O3 [M + H]+ 453.2430, found 453.2413. 2,6-Di-tert-butyl-4-(2-((4-methoxy-2-methylphenyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (7k): Rf = 0.4 (5% EtOAc in hexane); orange solid (288 mg, 81% yield); mp = 166−168 °C; 1 H NMR (400 MHz, CDCl3) δ 7.64−7.61 (m, 1H), 7.58 (s, 1H), 7.48− 7.44 (m, 3H), 7.42−7.38 (m, 2H), 7.08−7.07 (m, 1H), 6.79−6.78 (m, 1H), 6.75−6.72 (m, 1H), 3.82 (s, 3H), 2.49 (s, 3H), 1.35 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 160.1, 149.4, 148.1, 142.1, 141.5, 137.2, 135.1, 133.5, 132.6, 132.4, 130.5, 129, 128.2, 127.9, 125, 115.3, 115.1, 111.6, 95.2, 90.3, 55.4, 35.6, 35.2, 29.7, 29.7, 21.3; IR (neat) 2956, 2204, 1613, 1556, 1500, 1239, 1163, 1040, 816, 757 cm−1; HRMS (ESI) m/z calcd for C31H35O2 [M + H]+ 439.2637, found 439.2619. 2,6-Di-tert-butyl-4-(2-(3-cyclohexylprop-1-yn-1-yl)benzylidene)cyclohexa-2,5-dienone (7l): Rf = 0.7 (5% EtOAc in hexane); orange solid (217 mg, 66% yield); mp = 87−89 °C; 1H NMR (400 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.42−7.40 (m, 2H), 7.36−7.30 (m, 2H), 7.05 (d, J = 2 Hz, 1H), 2.37 (d, J = 6.5 Hz, 2H), 1.87 (d, J = 11.7 Hz, 2H), 1.77−1.73 (m, 2H), 1.70−1.53 (m, 3H), 1.34 (s, 9H), 1.28 (s, 9H), 1.21−1.14 (m, 2H), 1.12−1.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.3, 147.9, 141.9, 137.5, 135.2, 132.8, 132.2, 130.6, 128.9, 128.3, 127.5, 125.3, 96.4, 79.9, 37.6, 35.6, 35.1, 32.9, 29.7, 29.6, 27.6, 26.4, 26.3; IR (neat) 2924, 2853, 2225, 1615, 1566, 1449, 1361, 1254, 888, 757 cm−1; HRMS (ESI) m/z calcd for C30H39O [M + H]+ 415.3001, found 415.3018. 2,6-Di-tert-butyl-4-(4-methyl-2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7m): Rf = 0.6 (5% EtOAc in hexane); orange gummy solid (290 mg, 88% yield); 1H NMR (400 MHz, CDCl3) δ 7.53−7.50 (m, 3H), 7.49−7.46 (m, 2H), 7.39−7.35 (m, 4H), 7.23 (d, J = 7.92 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 2.41 (s, 3H), 1.36 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.2, 147.9, 141.3, 139.4, 135.2, 134.9, 133.5, 132.3, 131.7, 130.7, 129.4, 128.8, 128.6, 128.4, 124.2, 123, 95.3, 87.8, 35.5, 35.2, 29.7, 29.6, 21.3; FT-IR (neat) 2956, 2211, 1613, 1567, 1455, 1360, 1255, 1023, 889, 754, cm−1; HRMS (ESI) m/z calcd for C30H33O [M + H]+ 409.2531, found 409.2521. 2,6-Di-tert-butyl-4-(5-methoxy-2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7n): Rf = 0.5 (5% EtOAc in hexane); brown solid (282 mg, 82% yield); mp = 153−155 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.5 Hz, 1H), 7.50−7.47 (m, 4 H), 7.37−7.33 (m, 3H), 7.09 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 6.0 2.5 Hz, 1H), 3.87 (s, 1H), 1.35 (s, 9H), 1.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.7, 159.4, 149.4, 148.2, 140.9, 139, 135, 134.2, 132.9, 131.6, 128.54, 128.51, 128.3, 123.3, 116.6, 115.6, 115.5, 94.2, 87.7, 55.6, 35.6, 35.2, 29.69, 29.67; IR (neat) 2956, 2922, 2218, 1614, 1457, 1361, 1260, 835, 751 cm−1; HRMS (ESI) m/z calcd for C30H33O2 [M + H]+ 425.2481, found 425.2465. 2,6-Di-tert-butyl-4-(2-((trimethylsilyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (17): Rf = 0.6 (5% EtOAc in hexane); yellow gummy liquid (235 mg, 75% yield); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.46−7.38 (m, 4H), 7.33 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 1.3 Hz, 1H), 1.34 (s, 9H), 1.28 (s, 9H), 0.26 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.5, 148.2, 141.2, 138.1, 135.2, 133.0, 132.6, 130.4, 128.8, 128.5, 128.1, 124.2, 103.1, 101.5, 35.6, 35.1, 29.7, 29.6, 0.04; FT-IR (neat) 2955, 2155, 1617 cm−1; HRMS (ESI) m/z calcd for C26H35OSi [M + H]+ 391.2457, found 391.2465. 2,6-Di-tert-butyl-4-(2-ethynylbenzylidene)cyclohexa-2,5-dienone (7o). To a solution of 2,6-di-tert-butyl-4-(2-((trimethylsilyl)ethynyl)benzylidene)cyclohexa-2,5-dienone (17) (205 mg, 0.64 mmol) in DMF

(5 mL) was added potassium fluoride (52 mg, 0.89 mmol). The resulting mixture was stirred at room temperature for 4 h. The mixture was poured into water and then extracted with dichloromethane (15 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude mixture was purified through silica gel column chromatography to afford pure 2,6-ditert-butyl-4-(2-ethynylbenzylidene)cyclohexa-2,5-dienone (7o) (184 mg, 90% yield) as a yellow solid: Rf = 0.6 (5% EtOAc in hexane); mp = 148− 150 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.6 Hz, 1H), 7.47− 7.41 (m, 3H), 7.38−7.34 (m, 2H), 7.07 (s, 1H), 3.42 (s, 1H), 1.34 (s, 9H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 186.8, 149.6, 148.2, 140.5, 138.3, 135.1, 133.6, 132.9, 130.8, 129.0, 128.9, 128.0, 123.1, 83.6, 81.7, 35.6, 35.2, 29.7; FT-IR (neat) 3299, 2956, 2101 cm−1; HRMS (ESI) m/z calcd for C23H27O [M + H]+ 319.2062, found 319.2053. 4-(2-Bromobenzylidene)-2,6-dimethylcyclohexa-2,5-dienone (18). A mixture of potassium ferricyanide (1.04 g, 3.17 mmol) and potassium hydroxide (0.19 g, 3.3 mmol, 4.2 equiv) in water (5 mL) was added to a solution of 4-(2-bromobenzyl)-2,6-dimethylphenol18 (0.23 g, 0.79 mmol) in hexanes (25 mL) under an inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. The aqueous layer was separated and extracted with hexanes (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude mixture was filtered through a short plug of a silica gel column to afford pure 4-(2-bromobenzylidene)2,6-dimethylcyclohexa-2,5-dienone (18) (0.21 g, 92% yield) as a yellow solid: Rf = 0.4 (10% EtOAc in hexane); mp = 108−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.43−7.39 (m, 2H), 7.30−7.25 (m, 2H), 7.22 (s, 1H), 7.13 (s, 1H), 2.07 (s, 3H), 7.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.5, 141.1, 138.4, 138.1, 136.4, 135.7, 133.3, 132.5, 132.47, 131.3, 130.5, 127.5, 125.1, 17.0, 16.4; FT-IR (neat) 2922, 1619 cm−1; HRMS (ESI) m/z calcd for C15H14BrO [M + H]+ 289.0228, found 289.0220. 2,6-Dimethyl-4-(2-(phenylethynyl)benzylidene)cyclohexa-2,5-dienone (7p). The reaction was performed in a 0.55 mmol scale of 18. Compound 7p: Rf = 0.4 (10% EtOAc in hexane); orange gummy solid (40 mg, 24% yield); 1H NMR (400 MHz, CDCl3) δ 7.65−7.63 (m, 2H), 7.54−7.48 (m, 4H), 7.45−7.36 (m, 6H), 7.14 (s, 1H), 2.09 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.6, 141.3, 138.8, 137.9, 137.4, 136.2, 132.9, 132.5, 131.7 (2C), 131.0, 129.2, 128.9, 128.6, 128.4, 124.4, 122.9, 96.0, 87.4, 17.0, 16.4; FT-IR (neat) 2922, 2214, 1617 cm−1; HRMS (ESI) m/z calcd for C23H19O [M + H]+ 311.1436, found 311.1449. General Procedure for the Synthesis of Cyclohepta[b]indole Derivatives (10a−p and 11b−o). A mixture of indole (0.1 mmol), 2-alkynylated p-quinone methide (0.11 mmol), AgOTf (0.005 mmol), and PPh3AuCl (0.005 mmol) in dry THF (2 mL) was stirred under an inert atmosphere, and the progress was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure and the residue was directly loaded on a silica gel column and eluted using an EtOAc/hexane mixture to obtain pure cyclohepta[b]indol derivatives. 2,6-Di-tert-butyl-4-(6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10a). The reaction was performed in a 0.042 mmol scale of 8a. Compound 10a: Rf = 0.3 (5% EtOAc in hexane); white solid (20.7 mg, 86% yield); mp = 223−225 °C ; 1H NMR (400 MHz, CDCl3) δ 7.91−7.89 (m, 2H), 7.56−7.54 (m, 3H), 7.49− 7.41 (m, 5H), 7.32−7.27 (m, 2H), 7.23−7.17 (m, 2H), 6.95 (s, 1H), 6.85 (s, 2H), 5.81 (s, 1H), 4.93 (s, 1H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.2, 140.7, 136.9, 135, 134.8, 134.1, 133.3, 131.7, 131.5, 130.7, 130.5, 129, 128.8, 128.3, 127.9, 126.1, 125.1, 124, 122.9, 119.8, 118.8, 118.4, 110.9, 46.9, 34.3, 30.4; FT-IR (neat) 3633, 3430, 1599, 1321, 1372, 1230, 1157, 766, 740, 699 cm−1; HRMS (ESI) m/z calcd for C37H38NO [M + H]+ 512.2935, found 512.2935. 4-(6-([1,1′-Biphenyl]-4-yl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2b]indol-12-yl)-2,6-di-tert-butylphenol (10b). The reaction was performed in an 0.085 mmol scale of 8a. Compound 10b: Rf = 0.1 (5% EtOAc in hexane); white solid (25 mg, 50% yield); mp = 223−225 °C; 1 H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.7−7.66 (m, 4H), 7.63−7.61 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.52− 7.48 (m, 3H), 7.45−7.39 (m, 2H), 7.34−7.3 (m, 2H), 7.25−7.18 (m, 2H), 7.01 (s, 1H), 6.86 (s, 2H), 5.83 (s, 1H), 4.93 (s, 1H), 1.26 (s, 18H); 8620


Note

The Journal of Organic Chemistry C NMR (100 MHz, CDCl3) δ 151.9, 141.3, 141.2, 140.6, 139.6, 136.9, 135, 134.8, 134.1, 132.9, 131.6, 131.5, 130.6, 130.5, 129.4, 129.1, 129, 127.9, 127.7, 127.5, 127.2, 126.1, 124, 123, 119.8, 118.9, 118.4, 111, 46.9, 34.3, 30.4; FT-IR (neat) 3445, 3234, 2957, 1614, 1566, 1486, 1254, 1091, 1023 cm−1; HRMS (ESI) m/z calcd for C43H42NO [M + H]+ 588.3266, found 588.3246. 2,6-Di-tert-butyl-4-(6-(p-tolyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10c). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10c: Rf = 0.3 (5% EtOAc in hexane); white solid (35.6 mg, 99% yield); mp = 222−224 °C; 1 H NMR (400 MHz, CDCl3) δ 7.94−7.92 (m, 2H), 7.58 (d, J = 7.5 Hz, 1H), 7.51−7.43 (m, 4H), 7.35−7.29 (m, 4H), 7.25−7.20 (m, 2H), 6.97 (s, 1H), 6.89 (s, 2H), 5.84 (s, 1H), 4.96 (s, 1H), 2.47 (s, 3H), 1.29 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.2, 138.2, 137.8, 136.8, 135.1, 134.8, 134.1, 133.2, 131.9, 131.4, 130.4, 130.2, 129.5, 128.9, 128.87, 127.9, 126, 124, 122.8, 119.7, 118.6, 118.4, 110.9, 46.9, 34.3, 30.4, 21.4; FT-IR (neat) 3637, 3460, 2958, 2872, 1600, 1152, 814, 805, 741 cm−1; HRMS (ESI) m/z calcd for C38H40NO [M + H]+ 526.3110, found 526.3091. 2,6-Di-tert-butyl-4-(6-(4-(tert-butyl)phenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10d). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10d: Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (34.7 mg, 90% yield); mp = 220− 222 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.47−7.46 (m, 5H), 7.40 (t, J = 7.2 Hz, 1H), 7.31−7.27 (m, 2H), 7.22−7.15 (m, 2H), 6.92 (s, 1H), 6.80 (s, 2H), 5.79 (s, 1H), 4.90 (s, 1H), 1.39 (s, 9H), 1.23 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 151.4, 141.1, 137.7, 136.8, 135.1, 134.7, 134.2, 133.1, 131.9, 131.4, 130.5, 130.4, 128.8, 128.7, 128, 126, 125.7, 124, 122.8, 119.7, 118.5, 118.4, 110.9, 46.8, 34.9, 34.3, 31.5, 30.4; FT-IR (neat) 3647, 3319, 2961, 1656, 1364, 1317, 1267, 1154, 828, 744 cm−1; HRMS (ESI) m/z calcd for C41H46NO [M + H]+ 568.3579, found 568.3553. 2,6-Di-tert-butyl-4-(6-(4-pentylphenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10e). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10e: Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (34 mg, 86% yield); mp = 90−92 °C; 1 H NMR (400 MHz, CDCl3) δ 7.90−7.86 (m, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.46−7.38 (m, 4H), 7.30−7.24 (m, 4H), 7.22−7.15 (m, 2H), 6.91 (s, 1H), 6.81 (s, 2H), 5.78 (s, 1H), 4.90 (s, 1H), 2.66 (t, J = 7.5 Hz, 2H), 1.69−1.66 (m, 2H), 1.42−1.38 (m, 4H), 1.23 (s, 18H), 0.94−0.92 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9, 143.3, 141.2, 137.9, 136.8, 135.1, 134.7, 134.1, 133.3, 131.9, 131.4, 130.4, 130.3, 128.9, 128.84, 128.81, 127.9, 126, 124, 122.8, 119.7, 118.5, 118.4, 110.9, 46.8, 35.9, 34.3, 31.8, 31.4, 30.4, 22.7, 14.2; FT-IR (neat) 3639, 3394, 2957, 2929, 2858, 1655, 1603, 1263, 1153, 1021, 743 cm−1; HRMS (ESI) m/z calcd for C42H48NO [M + H]+ 582.3736, found 582.3712. 2,6-Di-tert-butyl-4-(6-(4-methoxyphenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10f). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10f: Rf = 0.1 (5% EtOAc in hexane); white solid (36.4 mg, 99% yield); mp = 88−90 °C; 1 H NMR (400 MHz, CDCl3) δ 7.88−7.87 (m, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.47−7.44 (m, 3H), 7.39 (d, J = 7.4 Hz, 1H), 7.30−7.26 (m, 2H), 7.22−7.15 (m, 2H), 6.97 (d, J = 7.8 Hz, 2H), 6.89 (s, 1H), 6.84 (s, 2H), 5.78 (s, 1H), 4.91 (s, 1H), 3.87 (s, 3H), 1.24 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 159.8, 151.9, 141.2, 136.8, 135.1, 134.8, 134.1, 133.1, 132.9, 132, 131.3, 130.4, 130.2, 129.9, 128.8, 127.9, 126, 124, 122.8, 119.7, 118.5, 118.4, 114.2, 110.9, 55.6, 46.9, 34.3, 30.4; FT-IR (neat) 3632, 3391, 2958, 1652, 1606, 1510, 1248, 1175, 1032, 828, 744 cm−1; HRMS (ESI) m/z calcd for C38H38NO2 [M − H]+ 540.2903, found 540.2924. 2,6-Di-tert-butyl-4-(6-(4-phenoxyphenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10g). The reaction was performed in an 0.085 mmol scale of 8a. Compound 10g: Rf = 0.1 (5% EtOAc in hexane); white solid (48.4 mg, 94% yield); mp = 116− 118 °C; 1H NMR (400 MHz, CDCl3) δ 7.92−7.90 (m, 2H), 7.57−7.46 (m, 4H), 7.45−7.40 (m, 3H), 7.32−7.29 (m, 2H), 7.25−7.17 (m, 3H), 7.14−7.08 (m, 4H), 6.95 (s, 1H), 6.86 (s, 2H), 5.82 (s, 1H), 4.95 (s, 1H), 1.26 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 157.7, 156.8, 151.9, 141.2, 136.8, 135.4, 135, 134.8, 134, 132.6, 131.7, 131.4, 130.5, 130.3, 13

130.3, 130, 128.9, 127.9, 126.1, 124, 123.9, 122.9, 119.8, 119.5, 119.5, 118.7, 118.4, 110.9, 46.8, 34.3, 30.4; FT-IR (neat) 3635, 3406, 2960, 1652, 1588, 1434, 1316, 1242, 1166 cm−1; HRMS (ESI) m/z calcd for C43H42NO2 [M + H]+ 604.3216, found 604.3243. 2,6-Di-tert-butyl-4-(6-(2-chlorophenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10h). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10h: Rf = 0.2 (5% EtOAc in hexane); white solid (33.6 mg, 91% yield); mp = 236−238 °C; 1 H NMR (400 MHz, CDCl3) δ 7.95−7.93 (m, 1H), 7.58 (s, 1H), 7.54− 7.43 (m, 4H), 7.37−7.33 (m, 4H), 7.26−7.24 (m, 1H), 7.21−7.19 (m, 2H), 6.85 (s, 1H), 6.71 (s, 2H), 5.85 (s, 1H), 4.92 (s, 1H), 1.22 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 151.8, 139.9, 139.4, 137, 135.2, 134.6, 134.6, 133.6, 132.2, 131.8, 131.6, 131.3, 131.0, 130.2, 129.6, 129.5, 128.3, 127.1, 126.3, 124.2, 124.2, 122.8, 120, 118.8, 118.3, 110.9, 46.4, 34.2, 30.3; FT-IR (neat) 3639, 3464, 2957, 1340, 1233, 1152, 764, 742 cm−1; HRMS (ESI) m/z calcd for C37H37ClNO [M + H]+ 546.2564, found 546.2540. 2,6-Di-tert-butyl-4-(6-(3-fluorophenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10i). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10i: Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (32.6 mg, 91% yield); mp = 102−104 °C; 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.47−7.38 (m, 3H), 7.32−7.30 (m, 3H), 7.24− 7.17 (m, 3H), 7.1 (td, J = 8.3, 1.7 Hz, 1H), 6.94 (s, 1H), 6.80 (s, 2H), 5.79 (s, 1H), 4.93 (s, 1H), 1.23 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 163.1 (d, JC−F = 245.1 Hz), 151.9, 142.9 (d, JC−F = 7.3 Hz), 141.4, 137, 134.9, 134.7, 133.9, 132.2 (d, JC−F = 2.0 Hz), 131.5, 131.2, 131.1, 130.5, 130.3 (d, JC−F = 8.2 Hz), 129.3, 127.8, 126.1, 124.6 (d, JC−F = 2.6 Hz), 123.9, 123.1, 119.9, 119.3, 118.5, 115.9 (d, JC−F = 21.6 Hz), 115.2 (d, JC−F = 21 Hz), 111, 46.8, 34.3, 30.3; 19F NMR (376 MHz, CDCl3) δ −112.62; FT-IR (neat) 3637, 3398, 2960, 1651, 1611, 1484, 1435, 1265, 1155, 877, 787, 742 cm−1; HRMS (ESI) m/z calcd for C37H37FNO [M + H]+ 530.2859, found 530.2841. Methyl 4-(12-(3,5-Di-tert-butyl-4-hydroxyphenyl)-5,12dihydrobenzo[4,5]cyclohepta[1,2-b]indol-6-yl)benzoate (10j). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10j: Rf = 0.4 (10% EtOAc in hexane); pale yellow solid (37.5 mg, 97% yield); mp = 111−113 °C; 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J = 7.6, 2H), 7.92−7.89 (m, 2H), 7.61 (d, J = 7.7, 2H), 7.55 (d, J = 7.7, 1H), 7.49 (d, J = 7.6, 1H), 7.44 (t, J = 7.4, 1H), 7.33−7.29 (m, 2H), 7.25−7.18 (m, 2H), 7 (s, 1H), 6.83 (s, 2H), 5.81 (s, 1H), 4.93 (s, 1H), 3.95 (s, 3H), 1.24 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 166.9, 151.9, 145.2, 141.5, 137, 134.9, 134.7, 133.9, 132.5, 131.6, 130.9, 130.5, 130.1, 129.8, 129.4, 128.9, 127.8, 126.1, 123.9, 123.9, 123.2, 120, 119.4, 118.5, 111, 52.4, 46.8, 34.3, 30.4; FT-IR (neat) 3635, 3361, 2956, 1714, 1651, 1608, 1363, 1282, 1117, 1019, 774, 743 cm−1; HRMS (ESI) m/z calcd for C39H38NO3 [M − H]+ 568.2852, found 568.2829. 2,6-Di-tert-butyl-4-(6-(4-methoxy-2-methylphenyl)-5,12dihydrobenzo[4,5]cyclohepta-[1,2-b]indol-12-yl)phenol (10k). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10k: Rf = 0.2 (5% EtOAc in hexane); white solid (30.1 mg, 80% yield); mp = 191−193 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.1 Hz, 1H), 7.54−7.49 (m, 3H), 7.43 (t, J = 7.2, 1H), 7.36−7.32 (m, 2H), 7.22−7.17 (m, 3H), 6.84−6.81 (m, 2H), 6.71−6.67 (m, 3H), 5.86 (s, 1H), 4.91 (s, 1H), 3.84 (s, 3H), 1.27 (s, 3H), 1.19 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 159.6, 151.7, 139.2, 139, 136.7, 135.9, 134.7, 133.3, 132.8, 132.7, 132.5, 131.1, 131, 130.9, 129.1, 128.3, 126.3, 124.2, 124.2, 122.6, 120, 118.5, 118.2, 116, 111.1, 110.9, 55.4, 46.2, 34.2, 30.2, 19.9; FT-IR (neat) 3640, 3370, 2963, 1604, 1502, 1239, 1163, 743 cm−1; HRMS (ESI) m/z calcd for C39H42NO2 [M + H]+ 556.3216, found 556.3241. 2,6-Di-tert-butyl-4-(6-(cyclohexylmethyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10l). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10l: Rf = 0.4 (5% EtOAc in hexane); white solid (21.4 mg, 60% yield); mp = 234−236 °C; 1 H NMR (400 MHz, CDCl3) δ 7.96−7.94 (m, 2H), 7.41−7.33 (m, 4H), 7.28−7.20 (m, 3H), 6.72 (s, 1H), 6.61 (s, 2H), 5.75 (s, 1H), 4.88 (s, 1H), 2.64 (dd, J = 13.8, 0.7, 1H), 2.24−2.18 (m, 1H), 1.49−1.32 (m, 3H), 1.21 (s, 18H), 1.06−0.68 (m, 7H), 0.5−0.4 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 151.6, 138.8, 136.7, 135.9, 134.6, 133.1, 132.4, 130.6, 130.56, 130.4, 130.3, 128.6, 128.3, 126.2, 124.1, 122.5, 120, 119.7, 8621


Note


7.16 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 3 Hz, 1H), 6.97 (s, 1H), 6.87 (s, 2H), 5.79 (s, 1H), 4.92 (s, 1H), 2.83−2.68 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.5, 140.7, 135.7, 135, 134.8, 134.1, 133.4, 131.4, 131.1, 130.6, 130.4, 129, 128.9, 128.8, 128.3, 127.6, 126.3, 126, 124, 121.4, 120.1, 119.5, 116.2, 47.1, 34.3, 30.4, 24, 13.9; FT-IR (neat) 3637, 3469, 2962, 1654, 1598, 1434, 1362, 1265, 1234, 1155, 1120 cm−1; HRMS (ESI) m/z calcd for C39H42NO [M + H]+ 540.3266, found 540.3246. 2,6-Di-tert-butyl-4-(2-methoxy-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11d). The reaction was performed in a 0.01 mmol scale of 8d. Compound 11d: Rf = 0.1 (5% EtOAc in hexane); white solid (34.2 mg, 63% yield); mp = 92−94 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.56−7.51 (m, 3H), 7.47−7.40 (m, 5H), 7.32−7.28 (m, 2H), 7.17 (d, J = 7.8 Hz, 1H), 6.9 (s, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.83 (s, 2H), 5.73 (s, 1H), 4.93 (s, 1H), 3.92 (s, 3H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.3, 151.9, 141.2, 140.7, 135.1, 134.8, 134.1, 133.4, 132.6, 132.2, 131.5, 130.5, 130.4, 129, 128.9, 128.8, 128.3, 128.3, 126.1, 124, 118.5, 113.4, 111.8, 99.7, 56.0, 46.9, 34.3, 30.4; FT-IR (neat) 3635, 3418, 2957, 1653, 1599, 1487, 1434, 1264, 1219, 1110, 1032 cm−1; HRMS (ESI) m/z calcd for C38H40NO2 [M + H]+ 542.3059, found 542.3048. 2,6-Di-tert-butyl-4-(4-ethyl-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11e). The reaction was performed in a 0.13 mmol scale of 8a. Compound 11e: Rf = 0.2 (5% EtOAc in hexane); white solid (48.6 mg, 69% yield); mp = 181−183 °C; 1 H NMR (400 MHz, CDCl3) δ 7.76−7.73 (m, 2H), 7.58 (d, J = 7.1 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.49−7.39 (m, 5H), 7.29 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.97 (s, 1H), 6.87 (s, 2H), 5.79 (s, 1H), 4.92 (s, 1H), 2.84−2.68 (m, 2H), 1.28 (t, J = 7.7 Hz, 3H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.5, 140.7, 135.8, 135.0, 134.8, 134.2, 133.4, 131.4, 131.1, 130.7, 130.4, 129.0, 128.9, 128.8, 128.3, 127.6, 126.3, 126.0, 124.0, 121.5, 120.1, 119.6, 116.2, 47.1, 34.3, 30.4, 24.0, 13.9; FT-IR (neat) 3650, 3370, 2959, 1441 cm−1; HRMS (ESI) m/z calcd for C39H42NO [M + H]+ 540.3266, found 540.3245. 2,6-Di-tert-butyl-4-(2-(phenoxymethyl)-6-phenyl-5,12dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11f). The reaction was performed in a 0.067 mmol scale of 8e. Compound 11f: Rf = 0.1 (5% EtOAc in hexane); white solid (37.2 mg, 90% yield); mp = 215−217 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.55−7.52 (m, 5H), 7.48−7.44 (m, 3H), 7.42−7.39 (m, 5H), 7.36 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.95 (dd, J = 8.7, 2.1 Hz, 1H), 6.91 (s, 1H), 6.83 (s, 2H), 5.72 (s, 1H), 5.20−5.13 (m, 2H), 4.93 (s, 1H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.6, 151.9, 141.2, 140.7, 137.7, 135, 134.8, 134, 133.4, 132.6, 132.4, 131.5, 130.5, 130.46, 129, 128.9, 128.8, 128.7, 128.7, 128.3, 128, 127.9, 126.1, 124, 118.5, 114, 111.7, 101.5, 71.1, 46.9, 34.3, 30.4; FT-IR (neat) 3633, 3424, 2958, 1651, 1485, 1451, 1225, 1110, 1025, 766, 737 cm−1; HRMS (ESI) m/z calcd for C44H42NO2 [M − H]+ 616.3216, found 616.3243. 2,6-Di-tert-butyl-4-(2-iodo-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11g). The reaction was performed in a 0.1 mmol scale of 8f. Compound 11g: Rf = 0.2 (5% EtOAc in hexane); white solid (44.3 mg, 70% yield); mp = 258−260 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.93 (s, 1H), 7.56−7.51 (m, 3H), 7.47−7.41 (m, 6H), 7.31 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.96 (s, 1H), 6.80 (s, 2H), 5.70 (s, 1H), 4.95 (s, 1H), 1.25 (s, 18 H); 13 C NMR (100 MHz, CDCl3) δ 152, 141.1, 140.3, 135.7, 134.9, 134.7, 133.5, 132.8, 132.6, 131.6, 131.5, 131.1, 130.5, 130.4, 129.2, 128.94, 128.9, 128.4, 127.3, 126.2, 123.9, 117.5, 112.9, 83.2, 46.7, 34.3, 30.3; FTIR (neat) 3634, 3422, 2958, 1598, 1434, 1361, 1301, 1265, 1232, 1155, 1119 cm−1; HRMS (ESI) m/z calcd for C37H37INO [M + H]+ 638.1920, found 638.1930. 4-(2-Bromo-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)-2,6-di-tert-butylphenol (11h). The reaction was performed in a 0.051 mmol scale of 8g. Compound 11h: Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (24 mg, 80% yield); mp = 90−92 °C; 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 1.5 Hz, 1H), 7.90 (s, 1H), 7.55−7.50 (m, 3H), 7.47−7.41 (m, 5H), 7.33−7.26 (m, 2H), 7.15 (d, J = 8.7 Hz, 1H), 6.95 (s, 1H), 6.79 (s, 2H), 5.69 (s, 1H), 4.93 (s, 1H), 1.24 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152, 141.1, 140.3, 135.3,

118.1, 110.8, 46, 44.5, 37.4, 34.2, 34.1, 32, 30.3, 26.5, 26.3, 26.2; FT-IR (neat) 3642, 3424, 2923, 2852, 1651, 1234, 1156, 879, 742 cm−1; HRMS (ESI) m/z calcd for C38H46NO [M + H]+ 532.3579, found 532.3557. 2,6-Di-tert-butyl-4-(9-methyl-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10m). The reaction was performed in an 0.085 mmol scale of 8a. Compound 10m: Rf = 0.3 (5% EtOAc in hexane); colorless gummy solid (39.7 mg, 88% yield); 1 H NMR (400 MHz, CDCl3) δ 7.89−7.85 (m, 2H), 7.56−7.54 (m, 2H), 7.48−7.40 (m, 4H), 7.28−7.16 (m, 5H), 6.92 (s, 1H), 6.89 (s, 2H), 5.77 (s, 1H), 4.92 (s, 1H), 2.39 (s, 3H), 1.26 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 140.8, 138.6, 136.8, 135.4, 134.8, 134.76, 134.5, 133.2, 132.0, 131.7, 130.9, 130.4, 129.9, 129.0, 128.8, 128.2, 127.9, 124.0, 122.8, 119.7, 118.9, 118.4, 110.8, 46.6, 34.3, 30.4, 21.0; FT-IR (neat) 3637, 2956, 1728, 1434, 1375, 1334, 1152, 748 cm−1; HRMS (ESI) m/z calcd for C38H40NO [M + H]+ 526.3110, found 526.3088. 2,6-Di-tert-butyl-4-(10-methoxy-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10n). The reaction was performed in an 0.085 mmol scale of 8a. Compound 10n: Rf = 0.1 (5% EtOAc in hexane); colorless gummy solid (30 mg, 65% yield); 1 H NMR (400 MHz, CDCl3) δ 7.88−7.84 (m, 2H), 7.53−7.50 (m, 2H), 7.46−7.37 (m, 4H), 7.28−7.24 (m, 1H), 7.22−7.15 (m, 2H), 7.07 (d, J = 2.6 Hz, 1H), 6.90 (brs, 3H), 6.85 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (s, 1H), 4.92 (s, 1H), 3.88 (s, 3H), 1.25 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 160.8, 152.0, 142.6, 140.8, 136.7, 134.9, 134.3, 133.1, 131.9, 131.4, 130.4, 129.0, 128.8, 128.2, 128.0, 127.9, 123.9, 122.7, 119.7, 118.2, 117.8, 115.3, 112.0, 110.8, 55.6, 47.3, 34.3, 30.4; FT-IR (neat) 3637, 2956, 1727, 1435, 1604, 1375, 1048, 748 cm−1; HRMS (ESI) m/z calcd for C38H40NO2 [M + H]+ 542.3059, found 542.3045. 2,6-Di-tert-butyl-4-(6-methyl-5H-benzo[b]carbazol-11-yl)phenol (10o). The reaction was performed in a 0.12 mmol scale of 8a. Compound 10o: Rf = 0.3 (5% EtOAc in hexane); white solid (21.6 mg, 41% yield); mp = 244−246 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 7.96−7.94 (m, 2H), 7.58−7.54 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.39−7.34 (m, 2H), 7.30 (s, 2H), 6.95−6.90 (m, 2H), 5.39 (s, 1H), 2.90 (s, 3H), 1.49 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.5, 142.3, 138.0, 136.4, 133.4, 131.1, 129.8, 128.1, 127.5, 127.1, 126.8, 124.8, 124.4, 123.5, 123.5, 122.8, 122.2, 119.1, 110.2, 110.0, 34.7, 30.7, 13.0; FT-IR (neat) 3630, 3433, 2957 cm−1; HRMS (ESI) m/z calcd for C31H34NO [M + H]+ 436.2640, found 436.2628. 2,6-Dimethyl-4-(6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2b]indol-12-yl)phenol (10p). The reaction was performed in a 0.068 mmol scale of 8a. Compound 10p: Rf = 0.5 (10% EtOAc in hexane); white solid (25 mg, 86% yield); mp = 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.56−7.51 (m, 3H), 7.47−7.38 (m, 5H), 7.33−7.28 (m, 2H), 7.25−7.18 (m, 2H), 6.93 (s, 1H), 6.55 (s, 2H), 5.77 (s, 1H), 4.34 (s, 1H), 2.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.3, 141.3, 140.6, 136.9, 134.9, 134.0, 133.5, 132.1, 131.4, 130.5, 130.2, 128.9, 128.88, 128.83, 128.3, 127.7, 127.5, 126.0, 123.0, 122.0, 120.0, 118.3, 118.2, 111.0, 45.7, 16.1; FT-IR (neat) 3568, 3414, 2923 cm−1; HRMS (ESI) m/z calcd for C31H26NO [M + H]+ 428.2014, found 428.2026. 2,6-Di-tert-butyl-4-(2-methyl-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11b). The reaction was performed in a 0.076 mmol scale of 8b. Compound 11b: Rf = 0.2 (5% EtOAc in hexane); white solid (38.2 mg, 96% yield); mp = 231−233 °C; 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.67 (s, 1H), 7.57−7.55 (m, 3H), 7.48−7.40 (m, 5H), 7.29 (td, J = 7.1, 1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.05 (dd, J = 8.2, 1 Hz, 1H), 6.94 (s, 1H), 6.87 (s, 2H), 5.79 (s, 1H), 4.94 (s, 1H), 2.52 (s, 3H), 1.27 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.3, 140.7, 135.3, 135, 134.8, 134, 133.4, 131.9, 131.5, 130.5, 130.4, 129, 128.92, 128.9, 128.8, 128.2, 128.1, 126, 124.6, 124, 118.2, 118, 110.6, 46.9, 34.3, 30.4, 21.8; FT-IR (neat) 3635, 3388, 2959, 2873, 1655, 1434, 1364, 1306, 1230, 765, 700 cm−1; HRMS (ESI) m/z calcd for C38H40NO [M + H]+ 526.3110, found 526.3088. 2,6-Di-tert-butyl-4-(2-ethyl-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11c). The reaction was performed in a 0.1 mmol scale of 8c. Compound 11c: Rf = 0.2 (5% EtOAc in hexane); white solid (40.9 mg, 76% yield); mp = 184−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.77−7.74 (m, 2H), 7.59−7.57 (m, 2H), 7.53 (d, J = 7.1 Hz, 1H), 7.49−7.39 (m, 5H), 7.29 (td, J = 7.5, 1.2 Hz, 1H), 8622


Note


133.5, 133.1, 132.8, 131.7, 131.6, 130.6, 129.3, 129, 128.9, 128.5, 127.6, 126.3, 124.3, 123.9, 121.9, 121.5, 119.5, 110.6, 52, 46.6, 34.3, 30.3; FT-IR (neat) 3636, 3332, 2955, 1698, 1652, 1619, 1246, 1121, 767, 700 cm−1; HRMS (ESI) m/z calcd for C39H40NO3 [M + H]+ 570.3008, found 570.3030. (E)-2,6-Di-tert-butyl-4-(6-phenyl-2-styryl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11n). The reaction was performed in a 0.068 mmol scale of 8n. Compound 11n: Rf = 0.1 (5% EtOAc in hexane); white solid (41.8 mg, 99% yield); mp = 254−256 °C; 1 H NMR (400 MHz, CDCl3) δ 8 (s, 1H), 7.9 (s, 1H), 7.61−7.54 (m, 5H), 7.49−7.42 (m, 6H), 7.39 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 6.4 Hz, 1H), 7.29−7.24 (m, 3H), 7.15 (d, J = 16.3 Hz, 1H), 6.95 (1H), 6.85 (s, 2H), 5.85 (s, 1H), 4.94 (s, 1H), 1.26 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.2, 140.5, 138.2, 136.7, 135, 134.9, 133.9, 133.2, 132.5, 131.5, 130.9, 130.5, 130.2, 129.5, 129.1, 129, 128.9, 128.8, 128.3, 128.28, 127.1, 126.4, 126.2, 126.1, 124, 121.8, 118.8, 116.9, 111.2, 46.7, 34.3, 30.4; FT-IR (neat) 3636, 3417, 2956, 2924, 2854, 1597, 1362, 1264, 1156, 960, 766, 699 cm−1; HRMS (ESI) m/z calcd for C45H42NO [M − H]+ 612.3266, found 612.3229. 2,6-Di-tert-butyl-4-(13-phenyl-7,14-dihydrobenzo[g]benzo[4,5]cyclohepta[1,2-b]indol-7-yl)phenol (11o). The reaction was performed in a 0.074 mmol scale of 8m. Compound 11o: Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (36.3 mg, 87% yield); mp = 103− 104 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.95 (t, J = 9 Hz, 2H), 7.87 (t, J = 7.9 Hz, 1H), 7.61−7.58 (m, 4H), 7.51−7.40 (m, 7H), 7.34−7.30 (m, 1H), 6.94 (s, 1H), 6.84 (s, 2H), 5.88 (s, 1H), 4.93 (s, 1H), 1.24 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.1, 140.8, 135.2, 134.8, 134, 133.3, 131.8, 131.4, 131.1, 130.5, 130.4, 129.9, 129.1, 129.03, 129, 128.9, 128.4, 126.1, 125.5, 124.3, 124, 123.7, 121.6, 120.9, 120.5, 119.7, 118.4, 47, 34.3, 30.4; FT-IR (neat) 3639, 3433, 2957, 1651, 1433, 1363, 1146, 802, 745, 701 cm−1; HRMS (ESI) m/z calcd for C41H38NO [M − H]+ 560.2953, found 560.2931. 2,6-Di-tert-butyl-4-(5-phenyl-2,3,4,11-tetrahydro-1H-benzo[4,5]cyclohepta[1,2-b]cyclopenta[g]indol-11-yl)phenol (11p). The reaction was performed in a 0.13 mmol scale of 8a. Compound 11p: Rf = 0.3 (5% EtOAc in hexane); white solid (52 mg, 79% yield); mp = 242−244 °C; 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J = 6.8 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.49−7.38 (m, 5H), 7.31−7.27 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 6.88 (s, 2H), 5.80 (s, 1H), 4.92 (s, 1H), 3.13−3.04 (m, 2H), 3.02−2.97 (m, 1H), 2.93−2.85 (m, 1H), 2.27−2.12 (m, 2H), 1.26 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.9, 141.4, 140.9, 139.7, 135.1, 134.8, 134.2, 133.5, 131.3, 130.8, 130.4, 130.2, 129.0 (2C), 128.8, 128.79, 128.2, 126.6, 125.9, 125.2, 124.0, 119.7, 116.8, 116.5, 47.3, 34.3, 33.4, 30.4, 27.1, 25.5; FT-IR (neat) 3642, 3454, 2956 cm−1; HRMS (ESI) m/z calcd for C40H42NO [M + H]+ 552.3266, found 552.3248. 2,6-Di-tert-butyl-4-(2,6-diphenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11q). The reaction was performed in a 0.077 mmol scale of 8l. Compound 11q: Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (30.3 mg, 65% yield); mp = 112−114 °C; 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.93 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.58−7.56 (m, 3H), 7.49−7.41 (m, 8H), 7.36−7.29 (m, 3H), 6.97 (s, 1H), 6.69 (s, 2H), 5.87 (s, 1H), 4.94 (s, 1H), 1.26 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 151.9, 142.7, 141.3, 140.6, 136.4, 135, 134.9, 133.9, 133.3, 133.2, 132.5, 131.5, 130.9, 130.5, 129.1, 129, 128.9, 128.8, 128.4, 128.3, 127.5, 126.5, 126.1, 124, 122.8, 118.9, 116.8, 111.2, 46.8, 34.3, 30.4; FT-IR (neat) 3632, 3419, 2958, 1651, 1598, 1472, 1265, 1155, 764, 699 cm−1; HRMS (ESI) m/z calcd for C43H40NO [M − H]+ 586.3110, found 586.3134. 4-(2-([1,1′-Biphenyl]-4-yl)-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)-2,6-di-tert-butylphenol (11r). The reaction was performed in a 0.14 mmol scale of 8a. Compound 11r: Rf = 0.1 (5% EtOAc in hexane); white solid (77 mg, 83% yield); mp = 282− 284 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.94 (s, 1H), 7.84−7.82 (m, 2H), 7.76−7.72 (m, 4H), 7.61−7.53 (m, 5H), 7.52−7.43 (m, 6H), 7.41−7.31 (m, 3H), 7.00 (s, 1H), 6.92 (s, 2H), 5.92 (s, 1H), 4.97 (s, 1H), 1.29 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.0, 141.6, 141.3, 141.1, 140.6, 139.3, 136.5, 135.0, 134.9, 133.9, 133.2, 132.7, 132.5, 131.5, 131.0, 130.5, 129.1, 129.0, 128.9, 128.86, 128.5, 128.3, 127.7, 127.6, 127.3, 127.2, 126.1, 124.0, 122.7, 118.9, 116.7, 111.3, 46.8,

134.9, 134.8, 133.5, 133.1, 132.9, 131.6, 131.5, 130.5, 129.6, 129.3, 129, 128.9, 128.4, 126.2, 125.7, 123.9, 121, 117.9, 113.1, 112.4, 46.7, 34.3, 30.3; FT-IR (neat) 3636, 3425, 2958, 1233, 1155, 1119, 983, 766, 738, 701 cm−1; HRMS (ESI) m/z calcd for C37H37BrNO [M + H]+ 590.2059, found 590.2045. 2,6-Di-tert-butyl-4-(2-chloro-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11i). The reaction was performed in a 0.057 mmol scale of 8h. Compound 11i: Rf = 0.2 (5% EtOAc in hexane); white solid (28.6 mg, 99% yield); mp = 200−202 °C; 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.83 (d, J = 1.3 Hz, 1H), 7.55−7.50 (m, 3H), 7.47−7.41 (m, 5H), 7.31 (td, J = 7.4, 1 Hz, 1H), 7.20−7.13 (m, 2H), 6.95 (s, 1H), 6.79 (s, 2H), 5.70 (s, 1H), 5.94 (s, 1H), 1.24 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152, 141.1, 140.3, 135.1, 134.9, 134.8, 133.6, 133.2, 132.9, 131.6, 131.5, 130.5, 129.2, 129, 129, 128.9, 128.4, 126.2, 125.5, 123.9, 123.2, 118, 117.9, 112, 46.8, 34.3, 30.3; FT-IR (neat) 3636, 3424, 2959, 1651, 1598, 1233, 1155, 1060, 766, 738 cm−1; HRMS (ESI) m/z calcd for C37H37ClNO [M + H]+ 546.2564, found 546.2543. 2,6-Di-tert-butyl-4-(3-chloro-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11j). The reaction was performed in a 0.051 mmol scale of 8i. Compound 11j: Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (28.4 mg, 99% yield); mp = 123−125 °C; 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.53−7.45 (m, 6H), 7.43−7.41 (m, 2H), 7.33−7.30 (m, 1H), 7.27−7.26 (m, 1H), 7.14 (dd, J = 8.5, 1.7 Hz, 1H), 6.95 (s, 1H), 6.77 (s, 2H), 5.73 (s, 1H), 4.93 (s, 1H), 1.23 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152, 141, 140.3, 137, 134.9, 134.86, 133.7, 133, 132.4, 131.5, 131.2, 130.5, 129.2, 128.93, 128.9, 128.6, 128.4, 126.5, 126.2, 123.9, 120.6, 119.3, 118.6, 110.9, 46.7, 34.3, 30.3; FT-IR (neat) 3637, 3418, 2959, 1652, 1364, 1234, 1155, 1063, 916, 766, 700 cm−1; HRMS (ESI) m/z calcd for C37H37ClNO [M + H]+ 546.2564, found 546.2542. 2,6-Di-tert-butyl-4-(2-fluoro-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11k). The reaction was performed in a 0.14 mmol scale of 8a. Compound 11k: Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (50 mg, 68% yield); mp = 233−235 °C; 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.56−7.51 (m, 4H), 7.49− 7.40 (m, 5H), 7.32 (td, J = 7.4, 0.7 Hz, 1H), 7.19 (dd, J = 8.8, 4.3 Hz, 1H), 6.98−6.93 (m, 2H), 6.83 (s, 2H), 5.70 (s, 1H), 4.95 (s, 1H), 1.26 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 158.1 (d, JC−F = 233.3 Hz), 152.0, 141.1, 140.4, 134.9 (2C), 133.8, 133.6, 133.3, 133.1, 131.5, 131.2, 130.5, 129.2, 129.0, 128.9, 128.4, 128.3 (d, JC−F = 9.6 Hz), 126.2, 123.9, 118.7 (d, JC−F = 4.9 Hz), 111.6 (d, JC−F = 9.4 Hz), 111.3 (d, JC−F = 26.3 Hz), 103.2 (d, JC−F = 23.5 Hz), 46.9, 34.3, 30.3; 19F NMR (376 MHz, CDCl3) δ −124.16; FT-IR (neat) 3635, 3452, 2957 cm−1; HRMS (ESI) m/z calcd for C37H37FNO [M + H]+ 530.2859, found 530.2833. 2 , 6 -D i- t e rt - bu ty l- 4 -( 3 -c h lo ro - 2-fl u o r o - 6 - p h e n y l - 5 , 1 2 dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11l). The reaction was performed in a 0.059 mmol scale of 8j. Compound 11l: Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (21.3 mg, 64% yield); mp = 135−137 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.58 (d, J = 9.7 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.49−7.47 (m, 4H), 7.45−7.38 (m, 3H), 7.35−7.28 (m, 2H), 6.96 (s, 1H), 6.76 (s, 2H), 5.63 (s, 1H), 4.95 (s, 1H), 1.24 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.3 (d, JC−F = 236.8 Hz), 152.1, 141.0, 140.2, 135.0, 134.8, 134.0, 133.4, 132.9, 132.8, 131.7 (d, JC−F = 2.9 Hz), 130.5, 129.3, 128.9 (d, JC−F = 1.5 Hz), 128.5, 126.9 (d, JC−F = 8.5 Hz), 126.4, 123.8, 118.6 (d, JC−F = 4.8 Hz), 116.4 (d, JC−F = 21.4 Hz), 112.1, 106.8, 104.3 (d, JC−F = 23.5 Hz), 46.8, 34.3, 30.3; 19F NMR (376 MHz, CDCl3) δ −126.45; FT-IR (neat) 3636, 3423, 2959, 1651, 1476, 1451, 1317, 1116, 854, 767, 738, 699 cm−1; HRMS (ESI) m/z calcd for C37H34ClFNO [M − H]+ 562.2313, found 562.2338. Methyl 12-(3,5-Di-tert-butyl-4-hydroxyphenyl)-6-phenyl-5,12dihydrobenzo[4,5]-cyclohepta[1,2-b]indole-2-carboxylate (11m). The reaction was performed in a 0.057 mmol scale of 8o. Compound 11m: Rf = 0.4 (10% EtOAc in hexane); pale yellow solid (30.3 mg, 93% yield); mp = 128−130 °C; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.08 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.52−7.50 (m, 2H), 7.48−7.41 (m, 5H), 7.33−7.27 (m, 2H), 6.98 (s, 1H), 6.79 (s, 2H), 5.85 (s, 1H), 4.93 (s, 1H), 3.96 (s, 3H), 1.23 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 168.3, 152, 141.1, 140.2, 139.2, 134.9, 134.8, 8623


Note

The Journal of Organic Chemistry 34.3, 30.4; FT-IR (neat) 3633, 3423, 2956 cm−1; HRMS (ESI) m/z calcd for C49H46NO [M + H]+ 664.3579, found 664.3546. 2,6-Di-tert-butyl-4-(5-methyl-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11s). The reaction was performed in a 0.076 mmol scale of 8k. Compound 11s: Rf = 0.4 (5% EtOAc in hexane); white solid (29 mg, 73% yield); mp = 217−219 °C; 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.5 Hz, 2H), 7.40−7.33 (m, 5H), 7.31−7.29 (m, 3H), 7.26−7.18 (m, 2H), 7.03 (s, 1H), 6.73 (s, 2H), 5.76 (s, 1H), 4.88 (s, 1H), 3.14 (s, 3H), 1.21 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.8, 143.5, 142.2, 139.6, 134.9, 134.6, 133.6, 133.4, 133.2, 132.5, 130.7, 129.9, 128.7, 128.6, 127.8, 127.6, 127.2, 125.9, 123.9, 122.5, 121.6, 119.5, 118.2, 109.5, 46.1, 34.3, 32.5, 30.3; FT-IR (neat) 3635, 2958, 1656, 1363, 1321, 1233, 1161, 741, 699 cm−1; HRMS (ESI) m/z calcd for C38H40NO [M + H]+ 526.3110, found 526.3094. 2,6-Di-tert-butyl-4-(5-ethyl-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11t). The reaction was performed in a 0.17 mmol scale of 8a. Compound 11t: Rf = 0.5 (10% EtOAc in hexane); pale yellow solid (63 mg, 68% yield); mp = 194−196 °C; 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 1H), 7.51−7.49 (m, 2H), 7.42 (dd, J = 7.4, 1.4 Hz, 1H), 7.39−7.36 (m, 4H), 7.35−7.31 (m, 3H), 7.30−7.26 (m, 1H), 7.25−7.21 (m, 1H), 6.99 (s, 1H), 6.78 (d, J = 0.7 Hz, 2H), 5.79 (s, 1H), 4.92 (s, 1H), 3.91−3.82 (m, 1H), 3.47−3.38 (m, 1H), 1.25 (s, 18H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 151.8, 143.5, 142.2, 138.8, 135.0, 134.6, 133.9, 133.6, 132.6, 132.5, 130.7, 129.9, 128.5 (2C), 128.47, 127.9, 127.6, 125.8, 123.9, 122.4, 122.3, 119.5, 118.3, 109.8, 46.1, 39.5, 34.3, 30.3, 14.6; FT-IR (neat) 3635, 2959 cm−1; HRMS (ESI) m/z calcd for C39H42NO [M + H]+ 540.3266, found 540.3252. 2,6-Di-tert-butyl-4-(2-(methoxymethyl)-5-methyl-6-phenyl-5,12dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (11u). The reaction was performed in an 0.11 mmol scale of 8a. Compound 11u: Rf = 0.5 (5% EtOAc in hexane); white solid (36 mg, 57% yield); mp = 219−221 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.41−7.36 (m, 5H), 7.34−7.23 (m, 4H), 7.03 (s, 1H), 6.73 (s, 2H), 5.76 (s, 1H), 4.88 (s, 1H), 4.66−4.60 (m, 2H), 3.42 (s, 3H), 3.13 (s, 3H), 1.21 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 151.8, 143.4, 142.1, 139.3, 134.9, 134.6, 133.8, 133.5, 133.3, 132.6, 130.7, 130.0, 129.1, 128.7, 128.6, 127.8, 127.6, 127.1, 125.9, 123.9, 123.2, 121.5, 118.1, 109.5, 75.8, 57.9, 46.1, 34.3, 32.6, 30.3; FT-IR (neat) 3637, 2955, 1453 cm−1; HRMS (ESI) m/z calcd for C40H44NO2 [M + H]+ 570.3372, found 570.3358. Preparation of 4-((1H-Indol-3-yl)(2-(phenylethynyl)phenyl)methyl)2,6-di-tert-butylphenol (9). A mixture of indole (8a) (1 equiv), 2-alkynylated p-quinone methide (7a) (1.1 equiv), and Bi(OTf)3 (0.05 equiv) in DCE (1.5 mL) was stirred at room temperature. After completion of the reaction, the solvent was removed under reduced pressure and the residue was directly loaded on a silica gel column and eluted using an EtOAc/hexane mixture to obtain pure 4-((1H-indol-3yl)(2-(phenylethynyl)phenyl)methyl)-2,6-di-tert-butylphenol (9): Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (17.2 mg, 80% yield); mp = 99−101 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.58−7.55 (m, 1H), 7.42−7.39 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.31−7.27 (m, 4H), 7.20−7.19 (m, 3H), 7.18−7.16 (m, 1H), 7.13 (s, 2H), 6.99 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 1.2 Hz, 1H), 6.20 (s, 1H), 5.05 (s, 1H), 1.34 (s, 18H); 13 C NMR (100 MHz, CDCl3) δ 152.1, 146.8, 136.9, 135.4, 133.5, 132.3, 131.7, 128.8, 128.4, 128.36, 128.2, 127.3, 126.1, 125.8, 124.2, 123.6, 123, 122.1, 120.8, 120.2, 119.4, 111, 94, 88.8, 46.7, 34.5, 30.5; FT-IR (neat) 3399, 3277, 2922, 2856, 2091, 1672, 1593, 1362, 1233, 1075, 998, 760 cm−1; HRMS (ESI) m/z calcd for C37H38NO [M + H]+ 512.2953, found 512.2941. Synthesis of 4-(6-Phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2b]indol-12-yl)phenol (16). AlCl3 (68 mg, 0.13 mmol) was added to a solution of 10a (177 mg, 1.3 mmol) in 5 mL of benzene, and the resulting mixture was stirred at 55 °C temperature until 10a was completely consumed (by TLC). The reaction mixture was quenched with water and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were evaporated using a rotary evaporator. The crude reaction mixture was loaded on a silica gel column and purified using a hexane/EtOAc mixture as an eluent to obtain pure 4-(6-phenyl-5,12-dihydrobenzo-

[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (16): Rf = 0.5 (30% EtOAc in hexane); pale yellow solid (41.2 mg, 80% yield); mp = 230−232 °C; 1 H NMR (400 MHz, CDCl3) δ 7.90−7.88 (m, 2H), 7.55 (d, J = 7.2 Hz, 1H), 7.50−7.37 (m, 7H), 7.35−7.19 (m, 4H), 6.93 (s, 1H), 6.77 (d, J = 8.2 Hz, 2H), 6.53−6.49 (m, 2H), 5.80 (s, 1H), 4.56 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 153.5, 140.8, 140.5, 136.8, 135.2, 135.1, 133.5, 132.0, 131.4, 130.5, 130.3, 129.0, 128.9, 128.9, 128.5, 128.3, 127.7, 126.2, 123.1, 120.0, 118.6, 118.3, 114.4, 111.1, 45.6; FT-IR (neat) 3412, 3057, 2926, 1610, 1508, 1447, 1335, 1262, 909, 745, 700 cm−1; HRMS (ESI) m/z calcd for C29H22NO [M + H]+ 400.1701, found 400.1694.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00607. 1 H, 13C, and 19F spectra of all new compounds and crystallographic data for compound 10a (PDF) Crystal data for compound 10a (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ramasamy Vijaya Anand: 0000-0001-9490-4569 Notes

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 a research fellowship. The NMR and HRMS facilities at IISER Mohali are gratefully acknowledged. The XtaLabmini single crystal X-ray facility of the Department of Chemical Sciences at IISER Mohali is acknowledged for the data collections.

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REFERENCES

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Synthesis of Cyclohepta[b]indoles - ACS Publications - American

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