Synthesis of Cyclohepta[b]indoles

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Exploring Gold Catalysis in 1,6-Conjugate Addition/Domino Electrophilic Cyclization Cascade: Synthesis of Cyclohepta[b]indoles Abhijeet S Jadhav, Yogesh A Pankhade, and Ramasamy Vijaya Anand J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00607 • Publication Date (Web): 30 May 2018 Downloaded from http://pubs.acs.org on May 31, 2018

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The Journal of Organic Chemistry

Exploring Gold Catalysis in 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, Sector 81, Knowledge City, S. A. S. Nagar, Manauli (PO), Punjab –140306. India. E-mail: [email protected]

OH

O R2

R2

R2 R4

PPh 3AuCl (5 mol %) AgOTf (5 mol %)

R3

+ R1

R1

= aryl, alkyl R 2 = tBu, Me R 3 = alkyl, alkoxy, etc.

N R5

R2 R4

R3

THF, rt

R 4 = H, alkyl, halo, etc. R 5 = H, Me, Et

N R5 R1 50-99% yield (35 examples)

ABSTRACT: An effective method for the construction of 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.

Ring-fused indole is deliberated as one of the privileged structural motifs in the area of drug discovery.1 Especially, the cyclohepta[b]indole core (a seven-membered ring fused with an indole at 2 and 3 positions) attracted the synthetic community due to its prevalent occurrence in many biologically significant natural products (1-3, Fig. 1).2 Moreover, many unnatural/synthetic cyclohepta[b]indole derivatives, such as 4, 5 and 6 (Fig. 1), have shown

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

Figure 1. Some biologically active cyclohepta[b]indoles

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 cyclohepta[b]indole core,2 mostly through 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 Aucatalyzed electrophilic cyclizations,7 metal-catalyzed intramolecular cyclizations8 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 the above-mentioned processes are elegant, most of them involve a multi-step approach. Therefore, developing a one-pot domino process to access cyclohepta[b]indole core is indeed highly desirable. While exploring p-quinone methides (p-QMs)11 as electrophiles in 1,6-conjugate addition of a variety of nucleophiles to access unsymmetrical diaryl- and triarylmethanes,12 we envisaged that by using an appropriately modified p-QM having another electrophilic centre at the o-position of the aryl moiety, it could be possible to access cyclohepta[b]indole core through 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


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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 is a challenging task as both the steps require catalytic activation.

Scheme 1. Proposed domino process to access cyclohepta[b]indoles Keeping all 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 & 2). Since the combination of Ag and Au has been proven to be one of the best catalytic system 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 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 relatively longer time for



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completion (entry 7). The optimization studies were then extended using the combination of different silver and gold Table 1. Optimization studiesa O tBu

OH tBu

tBu

tBu

catalyst(s) [5-10 mol%]

+ Ph 7a (1.1 equiv)

N H

solvent, rt

8a (1 equiv)

NH 10a

Ph

entry

catalyst

solvent

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

Time [h] 24 24 2.5 24 24 2.5 14 3 5 3 2.5 4 24 24 2.5

yield [%] nd nd 88 20 92 96 88 94 76 90 88 85 nd nd 90

a Reaction conditions: All reactions were carried out with 0.075 mmol of 7a and 0.068 mmol of 8a in solvent (1.5 mL) at room temperature. b 5 mol% each of Ag and Au catalysts were used. c 2.5 mol% each of Ag and Au catalysts were used. d Reaction was carried out with 1.4 mmol of 7a and 1.28 mmol of 8a. DCE = 1,2dichloroethane. nd = not detected.

catalysts in THF at room temperature (entries 8-10). However, in all 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 & 12). These experiments clearly indicate that the cationic gold catalyst is responsible to drive 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 under explored area till 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.


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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 & 14). A relatively large scale reaction was performed using 7a (0.56 g, 1.4 mmol scale) and indole 8a (1.28 mmol) under the best conditions (entry 5) and, in this case, 10a was isolated in 90% yield (entry 15).

Scheme 2. Substrate scope O

OH

R1

R1

R3

R1

+

R2 7b-p (1.1 equiv.)

N H

THF, rt

NH R2 10b-p

OH tBu

tBu

R1

R3

8a (1 equiv.)

OH tBu

AgOTf (5 mol %) PPh 3AuCl (5 mol%)

OH tBu

tBu

OH tBu

tBu

tBu

Y NH

NH

NH

X

Me

NH Ph

10m, X = Me; Y = H, 5 h, 88% X 10n, X = H; Y = OMe, 12 h, 65% OMe 10b, X = 4-Ph, 4 h, 50% 10l, 1 h, 60% 10k, 3 h, 80% 10c, X = 4-Me, 2.5 h, 99% OH OH 10d, X = 4-tBu, 2.5 h, 90% tBu tBu Me Me 10e, X = 4-n-pentyl, 3 h, 86% 10f, X = 4-OMe, 2.5 h, 99% 10g, X = 4-OPh, 2.5 h, 94% 10h, X = 2-Cl, 2.5, 90% 10i, X = 3-F, 5 h, 91% NH N 10j, X = 4-COOMe, 8 h, 96% H Me Ph 2 10p, 5 h, 86% 10o, R = H, 5 h, 41%

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 & 7k), bearing electron-rich aryl substituents at the alkyne part, underwent smooth transformation to their respective cyclohepta[b]indole derivatives (10b-h & 10k) in moderate to excellent yields. Interestingly, other p-QMs (7i & 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 & 7n (substituted at the benzene ring) also provided the expected products



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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 & 8p) reacted smoothly and provided the corresponding products 11b-l & 11p in moderate to excellent yields (63-99%). Remarkably, electron-poor indole 8m also provided the corresponding product 11m in 93% yield. Aryl and vinyl substituted indoles (8n, 8o, 8q & 8r) furnished the corresponding cyclohepta[b]indole derivatives (11n, 11o, 11q & 11r) in the range of 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 the range of 57-73% yields.

Scheme 3. Substrate scope with different indoles O

OH

tBu

tBu

tBu

+ Ph 7a (1.1 equiv.)

N R1

8b-u (1 equiv) tBu

tBu

R2

THF, rt

N R1

11b-u OH

OH

OH tBu

tBu

AgOTf (5 mol %) PPh 3 AuCl (5 mol%)

R2

tBu

Ph tBu

Ph OH

tBu

tBu

tBu

X Y NH Ph

Z

NH

NH

11b, X = Me; Y, Z = H, 3 h, 96% 11c, X = Et; Y, Z = H, 2.5 h, 76% 11d, X = OMe; Y, Z = H, 3 h, 63% 11e, Z = Et; X, Y = H,3 h, 69% 11f, X = OBn; Y, Z = H, 2.5 h, 90% 11g, X = I; Y, Z = H, 3 h, 70% 11h, X = Br; Y, Z = H, 3 h, 80% 11i, X = Cl; Y, Z = H, 3 h, 99% 11j, Y = Cl; X, Z = H, 3 h, 99% 11k, X = F, Y, Z = H, 4 h, 68% 11l, X = F; Y = Cl; Z = H, 4 h, 64% 11m, X = CO 2Me, Y, Z = H, 7 h, 93%

NH

Ph 11o, 2 h, 87%

Ph 11n, 3 h, 99%

Ph 11p, 3 h, 79%

X OH tBu

OH tBu

tBu

tBu

NH Ph 11q, X = H, 2 h, 65% 11r, X = Ph, 3 h, 83%

X

N R Ph 11s, R = Me, X = H, 2.5 h, 73% 11t, R = Et, X = H,10 h, 68% 11u, R = Me, X = CH2OMe, 5 h, 57%


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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 a p-QM 7q [without the alkyne substituent] and indole 8a (Scheme 4). When 7q was treated with indole using 5 mol% of AgOTf in THF at rt, the 1,6-adduct 9a was obtained in 65% yield. However, the reaction took 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% of 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 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 in driving the 1,6-conjugate addition as well as electrophilic cyclization steps by acting as an oxophilic and alkynophilic catalyst, respectively. Moreover, these experiments also clearly confirm that the reaction is actually proceeding through the intermediate 9. O tBu

tBu

+ 7q

AgOTf (5 mol %), THF, rt

OH tBu

tBu

36 h, 65% OR N H 8a

AgOTf (5 mol %), PPh 3AuCl (5 mol %), THF, rt 5 min, 80%

9a

NH

---------------------------------------------------------------------------------------------------------------------------------------------

OH tBu

HO tBu

NH 9

Ph

AgOTf (5 mol %), THF, rt OR PPh 3 AuCl (5 mol %), THF, rt NO REACTION! AgOTf (5 mol %) PPh 3 AuCl (5 mol %) THF, rt, 2.5 h, 80%

tBu

tBu

NH 10a

Scheme 4. Control experiments


Ph


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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 the intermediate 12 undergoes 6-endo-dig cyclization through the activation of alkyne moiety by 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 active Au-catalyst. Another possibility is that the intermediate 12 undergoes 7-endo-dig cyclization to give intermediate 15,17 which on aromatization followed by protonation produces the product 10a with the elimination of active Au-catalyst (Path B in Scheme 5).

H+

[Au]

Ar

Ar

10a

H N

NH H

R

R [Au]

13

14

[Au] oxophilic

[Au] Path A 6-endo-dig

O tBu

tBu

Ar

Ar [Au] NH

7a

N H R

NH

R

8a

R 12

alkynophilic [Au]

9

Path B 7-endo-dig [Au]

H+

Ar

10a

N

[Au]

H R 15

H

Scheme 5. Plausible mechanism

To improve the substrate scope of this transformation further, we performed de-tertbutylation reaction of 10a with excess of AlCl3 in benzene, and the de-tert-butylated product 16 was obtained in 80% yield within an hour (Scheme 6).


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OH tBu

OH tBu

AlCl3 (10 equiv.) NH Ph 10a

C6H6, 55 oC, 1 h

NH Ph 16, 80%

Scheme 6. De-tert-butylation of 10a

In conclusion, we have developed an effective method for the synthesis of cyclohepta[b]indole derivatives through gold catalyzed 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. Experimental Section

General Information All reactions were carried out under argon atmosphere employing flame-dried glass wares. 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 (pQuinone methide) and 4-(2-bromobenzyl)-2,6-dimethylphenol were prepared by following a literature procedure.12a,18 Melting points were recorded on SMP20 melting point apparatus and are uncorrected. 1H, 13C 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 Hz. High resolution mass spectra were recorded on Waters Q-TOF Premier-HAB213 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.



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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). Organic layer was separated and the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, 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-2,5-dienone (7a) Rf = 0.6 (5% EtOAc in hexane); yellow solid (290 mg, 91% yield); m. p. = 140-142 ℃; 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);

13

C 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); m. p. = 127-129 ℃; 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-


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7.44 (m, 5H), 7.43-7.37 (m, 2H), 7.14 (s, 1H), 1.40 (s, 9H), 1.31 (s, 9H);

13

C 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-2,5-dienone (7c) Rf = 0.6 (5% EtOAc in hexane); orange solid (254 mg, 77% yield); m. p. = 148-150 ℃; 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);

13

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); m. p. = 85-87 ℃; 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); 13C 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); m. p. = 139-141 ℃; 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)

13

C 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,


Page 12 of 43

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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); m. p. = 130-132 ℃; 1H NMR (400 MHz, CDCl3) δ 7.71-7.67 (m, 2H), 7.57-7.55 (m, 1H), 7.52-7.50 (m, 1H), 7.467.38 (m, 4H), 7.31-7.24 (m, 2H), 7.12 (d, J = 1.6 Hz, 1H), 1.35 (s, 9H), 1.28 (s, 9H);

13

C

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); m. p. = 128-130 ℃; 1H NMR (400 MHz, CDCl3) δ 7.65-7.63 (m, 1H), 7.49-7.46 (m, 2H), 7.44-7.38 (m, 3H), 7.357.28 (m, 2H), 7.21-7.18 (m, 1H), 7.09-7.04 (m, 2H), 1.36 (s, 9H), 1.26 (s, 9H);

13

C 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, 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-1

ethynyl) benzoate (7j)


ylidene)methyl)phenyl)


Page 14 of 43

Rf = 0.3 (5% EtOAc in hexane); yellow solid (200 mg, 55% yield); m. p. = 159-161 ℃; 1H 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);

13

C 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-2,5dienone (7k) Rf = 0.4 (5% EtOAc in hexane); orange solid (288 mg, 81% yield); m. p. = 166-168 ℃; 1H 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); m. p. = 87-89 ℃; 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), 1.701.53 (m, 3H), 1.34 (s, 9H), 1.28 (s, 9H), 1.21-1.14 (m, 2H), 1.12-1.05 (m, 2H);

13

C 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,


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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);

13

C 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); m. p. = 153-155 ℃; 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);

13


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, ACS Paragon Plus Environment


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-2,5dienone 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 x 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-di-tert-butyl-4-(2-ethynylbenzylidene)cyclohexa-2,5-dienone 7o (184 mg, 90% yield) as a yellow solid; Rf = 0.6 (5% EtOAc in hexane); m. p. = 148-150 ℃; 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);

13

C 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)-2,6dimethylphenol18 (0.23 g, 0.79 mmol) in hexanes (25 mL) under inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. The aqueous layer was separated and extracted with hexanes (50 mL x 2). The combined organic layers dried over sodium sulfate, filtered and concentrated by rotary evaporation. The resulting crude mixture was filtered through a short plug of silica gel column to afford pure 4-(2-bromobenzylidene)-2,6-


Page 16 of 43

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dimethylcyclohexa-2,5-dienone (0.21 g, 92% yield) as a yellow solid; Rf = 0.4 (10% EtOAc in hexane); m. p. = 108-110 ℃; 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); 13

C 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 0.55 mmol scale of 18; 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 & 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) stirred under inert atmosphere and the 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 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 0.042 mmol scale of 8a; Rf = 0.3 (5% EtOAc in hexane); white solid (20.7 mg, 86% yield); m. p. = 223-225 ℃ ; 1H NMR (400 MHz, CDCl3) δ 7.917.89 (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), ACS Paragon Plus Environment


6.95 (s, 1H), 6.85 (s, 2H), 5.81 (s, 1H), 4.93 (s, 1H), 1.25 (s, 18H);

Page 18 of 43

13

C 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[1,2-b]indol-12-yl)-2,6-di-

tert-butylphenol (10b) The reaction was performed in 0.085 mmol scale of 8a; Rf = 0.1 (5% EtOAc in hexane); white solid (25 mg, 50% yield); m. p. = 223-225 ℃; 1H 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); 13C 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-12yl)phenol (10c) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.3 (5% EtOAc in hexane); white solid (35.6 mg, 99% yield); m. p. = 222-224 ℃; 1H NMR (400 MHz, CDCl3) δ 7.947.92 (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);

13

C

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,


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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 0.068 mmol scale of 8a; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (34.7 mg, 90% yield); m. p. = 220-222 ℃; 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);

13

C 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-12yl)phenol (10e) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (34 mg, 86% yield); m. p. = 90-92 ℃; 1H 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);

13


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,



Page 20 of 43

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]indol12-yl)phenol (10f) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.1 (5% EtOAc in hexane); white solid (36.4 mg, 99% yield); m. p. = 88-90 ℃; 1H 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);

13

C 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]indol12-yl)phenol (10g) The reaction was performed in 0.085 mmol scale of 8a; Rf = 0.1 (5% EtOAc in hexane); white solid (48.4 mg, 94% yield); m. p. = 116-118 ℃; 1H NMR (400 MHz, CDCl3) δ 7.927.90 (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);

13

C

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, 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.


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2,6-di-tert-butyl-4-(6-(2-chlorophenyl)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12yl)phenol (10h) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.2 (5% EtOAc in hexane); white solid (33.6 mg, 91% yield); m. p. = 236-238 ℃; 1H NMR (400 MHz, CDCl3) δ 7.957.93 (m, 1H), 7.58 (s, 1H), 7.54-7.43 (m, 4H), 7.37-7.33 (m, 4H), 7.26-7.24 (m, 1H), 7.217.19 (m, 2H), 6.85 (s, 1H), 6.71 (s, 2H), 5.85 (s, 1H), 4.92 (s, 1H), 1.22 (s, 18H); 13C 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-12yl)phenol (10i) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (32.6 mg, 91% yield); m. p. = 102-104 ℃; 1H 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;

19

F 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)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-

b]indol-6-yl)benzoate (10j) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.4 (10% EtOAc in hexane); pale yellow solid (37.5 mg, 97% yield); m. p. = 111-113 ℃; 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)-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12-yl)phenol (10k) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.2 (5% EtOAc in hexane); white solid (30.1 mg, 80% yield); m. p. = 191-193 ℃; 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);

13

C 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]indol12-yl)phenol (10l)


Page 22 of 43

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The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.4 (5% EtOAc in hexane); white solid (21.4 mg, 60% yield); m. p. = 234-236 ℃; 1H NMR (400 MHz, CDCl3) δ 7.967.94 (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);

13

C 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, 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-12yl)phenol (10m) The reaction was performed in 0.085 mmol scale of 8a; Rf = 0.3 (5% EtOAc in hexane); colourless gummy solid (39.7 mg, 88% yield); 1H 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]indol12-yl)phenol (10n) The reaction was performed in 0.085 mmol scale of 8a; Rf = 0.1 (5% EtOAc in hexane); colourless gummy solid (30 mg, 65% yield); 1H 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



Page 24 of 43

= 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);

13

C 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 0.12 mmol scale of 8a; Rf = 0.3 (5% EtOAc in hexane); white solid (21.6 mg, 41% yield); m. p. = 244-246 ℃; 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[1,2-b]indol-12-yl)phenol (10p) The reaction was performed in 0.068 mmol scale of 8a; Rf = 0.5 (10% EtOAc in hexane); white solid (25 mg, 86% yield); m. p. = 120-122 ℃; 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), 7.257.18 (m, 2H), 6.93 (s, 1H), 6.55 (s, 2H), 5.77 (s, 1H), 4.34 (s, 1H), 2.03 (s, 6H);

13

C 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,


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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-12yl)phenol (11b) The reaction was performed in 0.076 mmol scale of 8b; Rf = 0.2 (5% EtOAc in hexane); white solid (38.2 mg, 96% yield); m. p. = 231-233 ℃; 1H 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-12yl)phenol (11c) The reaction was performed in 0.1 mmol scale of 8c; Rf = 0.2 (5% EtOAc in hexane); white solid (40.9 mg, 76% yield); m. p. = 184-186 ℃; 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), 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]indol12-yl)phenol (11d) The reaction was performed in 0.01 mmol scale of 8d; Rf = 0.1 (5% EtOAc in hexane); white solid (34.2 mg, 63% yield); m. p. = 92-94 ℃; 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);

13

C 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-12yl)phenol (11e) The reaction was performed in 0.13 mmol scale of 8a; Rf = 0.2 (5% EtOAc in hexane); white solid (48.6 mg, 69% yield); m. p. = 181-183 ℃; 1H 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, 1441cm-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-5,12-dihydrobenzo[4,5]cyclohepta[1,2-

b]indol-12-yl)phenol (11f)


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The reaction was performed in 0.067 mmol scale of 8e; Rf = 0.1 (5% EtOAc in hexane); white solid (37.2 mg, 90% yield); m. p. = 215-217 ℃; 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);

13

C 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-12yl)phenol (11g) The reaction was performed in 0.1 mmol scale of 8f; Rf = 0.2 (5% EtOAc in hexane); white solid (44.3 mg, 70% yield); m. p. = 258-260 ℃; 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); 13C 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; FT-IR (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-tertbutylphenol (11h) The reaction was performed in 0.051 mmol scale of 8g; Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (24 mg, 80% yield); m. p. = 90-92 ℃; 1H 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, 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-12yl)phenol (11i) The reaction was performed in 0.057 mmol scale of 8h; Rf = 0.2 (5% EtOAc in hexane); white solid (28.6 mg, 99% yield); m. p. = 200-202 ℃; 1H 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); 13

C 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-12yl)phenol (11j) The reaction was performed in 0.051 mmol scale of 8i; Rf = 0.2 (5% EtOAc in hexane); pale yellow solid (28.4 mg, 99% yield); m. p. = 123-125 ℃; 1H 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);

13

C 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,


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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-12yl)phenol (11k) The reaction was performed in 0.14 mmol scale of 8a; Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (50 mg, 68% yield); m. p. = 233-235 ℃; 1H 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);

13

C

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;

19

F 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-di-tert-butyl-4-(3-chloro-2-fluoro-6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-

b]indol-12-yl)phenol (11l) The reaction was performed in 0.059 mmol scale of 8j; Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (21.3 mg, 64% yield); m. p. = 135-137 ℃; 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); 13

C 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-5,12-dihydrobenzo[4,5]-

cyclohepta[1,2-b]indole-2-carboxylate (11m) The reaction was performed in 0.057 mmol scale of 8o; Rf = 0.4 (10% EtOAc in hexane); pale yellow solid (30.3 mg, 93% yield); m. p. = 128-130 ℃; 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);

13

C NMR (100 MHz, CDCl3) δ 168.3, 152, 141.1, 140.2,

139.2, 134.9, 134.8, 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]indol12-yl)phenol (11n) The reaction was performed in 0.068 mmol scale of 8n; Rf = 0.1 (5% EtOAc in hexane); white solid (41.8 mg, 99% yield); m. p. = 254-256 ℃; 1H 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,


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30.4; FT-IR (neat): 3636, 3417, 2956, 2924, 2854, 1597, 1362, 1264, 1156, 960, 766, 699 cm1

; 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-7yl)phenol (11o) The reaction was performed in 0.074 mmol scale of 8m; Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (36.3 mg, 87% yield); m. p. = 103-104 ℃; 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); 13

C 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 0.13 mmol scale of 8a; Rf = 0.3 (5% EtOAc in hexane); white solid (52 mg, 79% yield); m. p. = 242-244 ℃; 1H 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.



Page 32 of 43

2,6-di-tert-butyl-4-(2,6-diphenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-12yl)phenol (11q) The reaction was performed in 0.077 mmol scale of 8l; Rf = 0.1 (5% EtOAc in hexane); pale yellow solid (30.3 mg, 65% yield); m. p. = 112-114 ℃; 1H 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), 7.367.29 (m, 3H), 6.97 (s, 1H), 6.69 (s, 2H), 5.87 (s, 1H), 4.94 (s, 1H), 1.26 (s, 18H); 13C 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-12yl)-2,6-di-tert-butylphenol (11r) The reaction was performed in 0.14 mmol scale of 8a; Rf = 0.1 (5% EtOAc in hexane); white solid (77 mg, 83% yield); m. p. = 282-284 ℃; 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);

13

C

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, 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-12yl)phenol (11s)


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The reaction was performed in 0.076 mmol scale of 8k; Rf = 0.4 (5% EtOAc in hexane); white solid (29 mg, 73% yield); m. p. = 217-219 ℃; 1H 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);

13

C

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-12yl)phenol (11t) The reaction was performed in 0.17 mmol scale of 8a; Rf = 0.5 (10% EtOAc in hexane); pale yellow solid (63 mg, 68% yield); m. p. = 194-196 ℃; 1H 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), 7.357.31 (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 0.11 mmol scale of 8a; Rf = 0.5 (5% EtOAc in hexane); white solid (36 mg, 57% yield); m. p. = 219-221 ℃; 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),



Page 34 of 43

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);

13

C

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) stirred at room temperature. 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 4-((1H-indol-3yl)(2-(phenylethynyl)phenyl)methyl)-2,6-di-tert-butylphenol; Rf

= 0.1 (5% EtOAc in

hexane); pale yellow solid (17.2 mg, 80% yield); m. p. = 99-101 ℃; 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), 7.317.27 (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[1,2-b]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


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


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. Rf = 0.5 (30% EtOAc in hexane); pale yellow solid (41.2 mg, 80% yield); m. p. = 230-232 ℃;; 1H 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.

Supporting Information 1

H, 13C and 19F spectra of all new compounds.

Notes

The Authors declare no competing financial interest. Acknowledgements The authors gratefully acknowledge DST-SERB (EMR/2015/001759) for the financial support and IISER Mohali for the infrastructure. ASJ and YAP thank IISER Mohali for a research fellowship. The NMR and HRMS facilities at IISER Mohali are gratefully acknowledged. XtaLabmini single crystal X-ray facility of the Department of Chemical Sciences at IISER Mohali is acknowledged for the data collections. References



Page 36 of 43

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Methides: Electrostatic Interaction and Steric, Inductive, and Resonance Effects


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of the ortho‐Substituent on the Optical Activity. Journal of Polymer Science Part A: Polymer Chemistry 2017, 55, 1048-1058.


Synthesis of Cyclohepta[b]indoles

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