Protocols for the Syntheses of 2,2'-Bis(indolyl)arylmethanes, 2

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Protocols for the Syntheses of 2,2'-Bis(indolyl)arylmethanes, 2-Benzylated Indoles, and 5,7-Dihydroindolo[2,3-b]carbazoles Ferruh Lafzi, Haydar Kilic, and Nurullah Saracoglu J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Aug 2019 Downloaded from pubs.acs.org on August 27, 2019

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The Journal of Organic Chemistry

Protocols for the Syntheses of 2,2'-Bis(indolyl)arylmethanes, 2-Benzylated Indoles, and 5,7-Dihydroindolo[2,3-b]carbazoles Ferruh Lafzi †, Haydar Kilic † ‡, Nurullah Saracoglu † * †

Department of Chemistry, Faculty of Sciences, Atatürk University, Erzurum 25240, Turkey

‡

Oltu Vocational Training School, Atatürk University, Erzurum 25400, Turkey ABSTRACT: The electrophilic substitution reaction of 4,7-dihydroindole with aryl-aldehydes as electrophilic partner followed by an oxidation step to deliver 2,2'-bis(indolyl)arylmethanes was studied for the first time. The reaction afforded regioselectivity at the 2,2'-positions of indole in an operationally simple, a variety of substrates and inexpensive procedure. To the best of our knowledge, this is the first examples of the 2,2'-bis(indolyl)arylmethanes in the manner of substituent-free. A facile method from the dipyrromethanes to the corresponding 2-benzylindoles was also reported. In addition, 2,2'-bis(indolyl)arylmethanes were converted to 5,7-dihydro indolo[2,3-b]carbazoles.

INTRODUCTION Indole derivatives are widely distributed in nature and have attracted considerable attention due to their chemical diversity and broad biological activities.1 In this context, bis(indolyl)methanes (BIMs) and related compounds show a wide range of biological activities, such as antibacterial, antitumor and antileishmanial properties.2 3,3'-Diindolylmethane (1), DIM, is a powerful substance found naturally in cruciferous vegetables, which promotes beneficial metabolism of estrogen in women and men (Figure 1a).3 Trisindoline (2) was isolated from marine bacterium Vibrio sp. (Figure 1a).4 Malassezin (3) which was obtained from the yeast Malassezia furfur and 6-formylindolo[3,2-b]carbazole (FICZ, 4) and indolo[3,2-b]carbazole (ICZ, 5) are an agonist of the arylhydrocarbon (AhR) receptor (Figure 1a).5 However, indolo[3,2-b]carbazoles show high-performance organic semiconductors properties for organic thin-film transistor applications (Figure 1a).6 Luzindole (6) is a drug acts as MT2 melatonin 1 ACS Paragon Plus Environment

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receptor antagonist (Figure 1a).7 2-Naphthyl indole compounds 7 and 8 show antidiabetic activity (Figure 1a).8 Due to the reactive C3-position of indole ring, the most BIMs reported are therefore 3,3’BIMs, and numerous methods have been reported for their synthesis using Lewis and Brønsted acids, solid-supported catalysts, and super-acidic systems (Figure 1b).9 Though the reported methods are satisfactory, the traditional methods include the synthesis of 3,3’BIMs, and the methods for 2,2’-BIMs suffer from certain drawbacks. When the C3-position of indoles was blocked, the generation of 2,2'-BIM regioisomers was used as a platform for catalyst applications (Figure 1c).10 Accordingly, the development of an efficient, rapid and direct method for the synthesis of a 2,2'-bis(indolyl)arylmethanes are highly desirable. There are very restricted studies concerning the synthesis of 2,2'-BIMs in the literature. Recently, an aromatizing cascade strategy was used to install a (2-indolyl)methyl group into target molecules via an Mn(I)-catalyzed (2-indolyl)methylation of heteroarenes.11 In our previous studies, we showed an efficient protocol and the most important option for accessing 2-substituted indoles via 4,7-dihydroindoles, which can be behaved as disubstituted pyrroles.12 This strategy in the racemic conjugate addition of 4,7-dihydroindole to Michael acceptors followed by an oxidation step led to the formation of the 2-substituted indoles in moderate yields.12 Consequently, elegant developments have been achieved in this chemistry for enantioselective Friedel–Crafts reactions,13 and we have also established a series of related transformations using ketones to the synthesis of a wide range of 2-alkylated indoles and some 2,2'bis(indolyl)dialkylmethanes which cannot be synthesized by previously reported methods.14 Bis(indolyl)methanes widely occur not only in a variety of biologically active molecules but also display usefulness for chemosensing and drug design.15 Therefore, the development of easily accessible, efficient, general and eco-friendly protocols for BIMs remains a continuous demand. In continuation to our efforts toward the development of efficient synthetic methodologies in the area of indole chemistry, here we have developed an efficient protocol for preparation of 3,3’-unsubstituted 2,2'bis(indolyl)methanes 12 (Figure 1d). In this study, we also obtained various 5,7-dihydroindolo[2,3b]carbazoles from 2,2'-bis(indolyl)methanes 12 we synthesized for the first time. The synthesis of 5,7dihydroindolo[2,3-b]carbazoles was previously achieved from 3,3’-BIMs via I2-catalyzed procedure.16

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Figure 1. Some important indole based compounds and synthesis of 3,3’-BIMs, 2,2’-BIMs, 2benzylated indoles and 5,7-dihydroindolo[2,3-b]carbazoles



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RESULTS AND DISCUSSIONS We began with the reaction of 4,7-dihydroindole (9)12a and 4-nitrobenzaldehyde (10i) as a model reaction to optimize conditions, and the results were indicated in Table 1. Initially, the reaction was carried out in dichloromethane (DCM) at room temperature. No product formation was observed in these conditions (Table 1, entry 1). The addition of LiOTf as catalyst gave desired product 11i in 30% yield (Table 1, entry 2).

Table 1. Optimization of Reaction Conditionsa

entry

catalyst

solvent

temp (oC)

time (h)

yield (%)b

1

-

CH2Cl2

rt

5

nr

2

LiOTf

CH2Cl2

rt

1

30

3

Bi(OTf)3

CH2Cl2

rt

1

63

4

Cu(OTf)2

CH2Cl2

rt

1

65

5

Bi(NO3)3.5H2O

CH2Cl2

rt

1

80

6

Zn(OTf)2

CH2Cl2

rt

1

82

7

Zn(TFA)2

CH2Cl2

rt

1

95

8

Sc(OTf)3

CH2Cl2

rt

1

85

9

TFA

CH2Cl2

rt

0.5

90

10

-

HFIP

rt

0.5

99

a

General conditions (unless otherwise specified): 9 (2.0 mmol), 10i (1.0 mmol), solvent (3.0 mL), rt, 0.5 h. bDetermined by 1H NMR Fortunately, the addition of Bi(OTf)3 and Cu(OTf)2 as catalyst increased the reaction yield to 63% and 65% respectively (Table 1, entries 3 and 4). Delightedly, metal salts, such as Bi(NO3)3.5H2O, Zn(OTf)2, zinc trifluoroacetate (Zn(TFA)2), Sc(OTf)3 and trifluoroacetic acid (TFA) showed the better catalytic ability to promote the reaction (Table 1, entries 5-9). Surprisingly, when the reaction was carried out in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) without any catalyst, the product formed in 99% yield (Table 1, entry 10). Consequently, the optimized conditions entail the use of the HFIP both as solvent and catalyst at rt for 0.5 h. 2,2’-BIM 12i was readily synthesized by stirring the corresponding 4 ACS Paragon Plus Environment

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dipyrromethane with 2.0 equiv. of para-benzoquinone (PBQ) in MeCN (Scheme 1), followed by separation on silica gel column. 2,2’-BIM 12i was fully characterized by 1H NMR, 13C NMR, and HRMS. It is important to note here that the given structure of 2,2’-BIM 12 in many of literature17 needs revision as 3,3’-BIM. When 4-hydroxybenzaldehyde used, the final oxidation product 12h was not purified by column chromatography and recrystallization. Therefore, the free phenolic group was acetylated with acetic anhydride to yield 4-acetoxybenzaldehyde. The ammonolysis of 12g with NH3 in MeOH gave the desired BIM 12h purely in 98% yield.

Scheme 1. Synthesis of BIMs 12a-o.



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Furthermore, catalytic hydrogenation of nitro group in 12i afforded corresponding aniline 12j in a yield of 94%. Aside from benzaldehyde derivatives, naphthyl-, pyrenyl-, pyridinyl- and indolyl-aldehydes were used to provide the desired BIMs 12k-12o (Scheme 1). As an extension of our work, we aimed the synthesis of tris(indolyl)methane (TIM) using 3-formylindole as electrophilic coupling partner. Unfortunately, when this aldehyde was used, the reaction did not proceed cleanly and unreacted starting materials recovered, and the corresponding product was obtained in low yield. Notably, we speculate that tautomeric structure causes declining reactivity of aldehyde. Optimized and acid-catalyzed reactions were not found useful for the formation of the desired product and a complex mixture provided. Preventing tautomerism and increase the reactivity of the aldehyde group, N-tosyl-indole aldehyde 13 was prepared18 and examined in this protocol (Scheme 2). We were pleased to observe that it was suitable as the carbonyl source, and desired product 14 was obtained in good yield under optimized reaction condition (Scheme 2). Oxidation of 14 gave the corresponding tris(indolyl)methane 15, which was submitted to the reductive detosylation19 with Mg/MeOH to give the desired product 12p (Scheme 2). It is worth mentioning that during the experiment involving 2-formylindole (10n)20 gave the related product 11n (Scheme 1). Briefly, 2formylindole is most reactive than 3-formylindole. We predict that possible tautomeric structure for 13 was reducing reactivity.

Scheme 2. Synthesis of TIM 12p.

Unexpectedly, when dipyrromethane 11a were heated, disproportionative cleavage readily occurred and thereby 2-benzylindole 16a could be obtained (Scheme 3). The scope of other dipyrromethanes was examined. As illustrated in Scheme 3, all of the corresponding substrates 11b-p were tolerated, and 2-benzylindoles 16ab-p were obtained in moderate to excellent yields. 6 ACS Paragon Plus Environment

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Scheme 3. Disproportionative cleavage of dipyrromethanes 16.

Scheme 4 shows a plausible mechanism. Initial nucleophilic addition of the 4,7-dihydroindole (9) with aryl-aldehydes 10 leads to the formation of alcohol intermediate [i], which undergoes dehydration via a second Friedel-Crafts alkylation, to give dipyrromethane 11. We suppose that the carbocation intermediate [ii] formed in the first step of the Friedel-Crafts reaction has directly influenced the progress of the reaction. We predict that the intermediate [ii] possess a planar structure and resonance stabilization, which can tolerate one from two pathways (the formation of 11 or 16), and the second Friedel-Crafts reaction to aromatization is preferred. The dipyrromethanes 11 further undergo disproportionative C–C bond cleavage to give dihydroindole 9 and intermediate [iii]. The isomerization of [iii] yields 2-benzylindole derivatives. The 16p we synthesized is a precursor compound that can be used in the synthesis of various natural products. Natural products Malassezin, 3 and FICZ, 4 can be converted from 16p to through known procedures (Scheme 3).21,22



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Scheme 4. Proposed mechanism.

We also carried out the synthesis of 6-mono substituted 5,7-dihydroindolo[2,3-b]carbazoles from 2,2’BIM’s obtained in this work (Scheme 5). Dehaen and coworkers had prepared 5,11-dihydroindolo[3,2b]carbazoles, based on the condensation of indole and an aldehyde with a catalytic amount of iodine, followed by an acid-catalyzed intramolecular cyclization with an orthoester.23 The cyclization of 2,2’BIM’s 12a-p to 5,7-dihydroindolo[2,3-b]carbazoles 18a-p is performed by treatment with triethylorthoformate and a catalytic amount of iodine in methylene chloride (Scheme 6). Compounds 18a-p were obtained in excellent yields. In contrast, the use of 2-pyridinyl BIM derivative 12m under identical conditions gave no desired 18m. We speculate the product is formed via intermediate 27 which is not isolated. 5,11-Dihydroindolo[3,2-b]carbazoles had been previously synthesized from 3,3’-BIM’s, after dimerization and oxidation when heated in the presence of molecular iodine (Scheme 6).6 When 2,2’BIM’s were heated in the presence of molecular iodine under similar conditions, the formation of 5,11dihydroindolo[3,2-b] carbazoles or any other product were not observed. We believe that this is because the benzene ring of intermediate 28 loses its aromaticity while the benzene ring of intermediate 23 preserves its aromaticity. Furthermore, the feasibility of 6,12-disubstituted 5,7dihydroindolo[2,3-b]carbazoles researched via BIM 2,2’-BIM’s concept. For example, the reaction of 14a and 10a gave 6,12-diphenyl-5,7-dihydroindolo[2,3-b]carbazole (26) in a high yield (94%) (Scheme 6).


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Scheme 5. Synthesis of 5,7-dihydroindolo[2,3-b]carbazoles 18a-p.



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Scheme 6. Formation of indolo[3,2-b]carbazole 24, indole[2,3-b]carbazoles 20a and 26

Finally, the synthesis of BIM's was attempted in a gram scale, where 2 g of 4,7-dihydroindole (9) was successfully converted into the corresponding BIM's 12a (2.5 g) and 12j (2.8 g) over two steps (92% and 95%overall yields respectively) (Scheme 7). These results clearly demonstrate the practical applicability of the developed methodology.


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Scheme 7. Scale-up experiments for the synthesis of 12a and 12j

CONCLUSION In conclusion, we have successfully established the coupling of 4,7-dihydroindole using aryl aldehydes as an electrophilic partner including an oxidation step. Importantly, the present methodology efficiently allowed the regioselective synthesis of central 2,2'-BIMs in high yields and with a broad substrate scope (up to 98% yield, 16 examples). Then, we displayed the transformations of dipyrromethanes to several 2-benzylindoles. Additionally, we have developed a new way for the synthesis 5,7-dihydroindolo[2,3-b]carbazoles using 2,2’-BIM’s. We believe that these synthetic protocols have the potential to be useful in organic chemistry, medicinal chemistry, and optoelectronic as well. EXPERIMENTAL SECTION General Experimental Methods. 1H NMR and 13C NMR experiments were performed on either 400 MHz Varian and 400 MHz Bruker Avance II instruments using CDCl3, DMSO-d6, MeOD, Acetone-d6 as the solvent with tetramethylenesilane (TMS) as an internal standard at room temperature, and the coupling constants J are given in hertz. The multiplicity is designated as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet. High-resolution mass spectrometry (HRMS) of all compounds were recorded on a QTOF (Quadrupole time-of-flight) spectrometry device. Column chromatography was performed using silica gel pore size 60 Å, 70-230 mesh (sigma). 4,7-Dihydroindole was synthesized using literature procedure.12a 1-Tosyl-1H-indole-3-carbaldehyde18 and 1H-indole-2-carbaldehyde20 were synthesized using the literature procedure. 11 ACS Paragon Plus Environment


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General Procedure 1 (GP1) for the Synthesis of 2,2’-BIMs 12a-o. To a solution of 4,7-dihydroindole (2.0 mmol, 2.0 equiv.) in HFIP (3.0 mL), aldehyde (1.0 mmol, 1.0 equiv.) was added. The reaction mixture was stirred for 0.5h at rt. The formation of 2,2'-((4aryl)methylene)bis(4,7-dihydro-1H-indole) was followed by thin layer chromatography (TLC). After the formation was completed solvent was removed under reduce pressure. The residue was resolved in CH3CN (10 mL) and then p-benzoquinone (2.0 mmol, 2.0 equiv.) was added to the solution. Latest reaction mixture was stirred at rt for 2h. After the reaction was completed, the reaction solvent was evaporated. The resulting product was purified from silica gel column chromatography. 2,2'-(Phenylmethylene)bis(1H-indole) (12a): Column chromatography (EtOAc/hexane; 1:9) gave the product as light browen solid (300 mg, 94% yield; mp 179.5−180.5 °C). 1H NMR (400 MHz, CDCl3): δ 7.87 (bs, NH, 2H), 7.59 (d, J = 7.7 Hz, =CH, 2H), 7.41 – 7.29 (m, 5H), 7.28 – 7.09 (m, 6H), 6.31 (s, =CH, 2H), 5.71 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.3, 138.7, 136.2, 128.9, 128.7, 128.3, 127.6, 122.0, 120.4, 120.0, 110.8, 102.4, 44.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H19N2, 323.1543; found 323.1535. 2,2'-((4-Fluorophenyl)methylene)bis(1H-indole) (12b): Column chromatography (EtOAc/hexane; 1:9) gave the product as browen solid (304 mg, 93% yield; mp 102−103 °C). 1H NMR (400 MHz, CDCl3): δ 7.91 (bs, NH, 2H), 7.57 (d, J = 7.7 Hz, =CH, 2H), 7.29 – 7.23 (m, =CH, 4H), 7.19 (t, J = 7.7 Hz, =CH, 2H), 7.13 (t, J = 7.7 Hz, =CH, 2H), 7.05 (t, J = 7.7 Hz, =CH, 2H), 6.27 (s, =CH, 2H), 5.71 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.3, 160.9, 137.3 (d, J = 227.7 Hz), 136.0 (d, J = 3.2 Hz), 130.2 (d, J = 8.1 Hz), 128.2, 122.1, 120.4, 120.1, 115.7 (d, J = 21.4 Hz), 110.8, 102., 44.2. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H18FN2, 341.1449; found 341.1446. 2,2'-((4-Chlorophenyl)methylene)bis(1H-indole) (12c): Column chromatography (EtOAc/hexane; 1:9) gave the product as yellow solid (315 mg, 93% yield; mp 99.5−100.5 °C). 1H NMR (400 MHz, CDCl3): δ 7.87 (bs, NH, 2H), 7.57 (d, J = 8.0 Hz, =CH, 2H), 7.34 (d, J = 8.0 Hz, =CH, 2H), 7.29 – 7.07 (m, 8H), 6.28 (s, =CH, 2H), 5.70 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.8, 138.1, 136.2, 133.4, 130.0, 129.0, 128.2, 122.2, 120.5, 120.2, 110.9, 102.5, 44.3. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H18ClN2, 357.1153; found 357.1169. 2,2'-((4-Bromophenyl)methylene)bis(1H-indole) (12d): Column chromatography (EtOAc/hexane; 1:9) gave the product as dark yellow solid (365 mg, 94% yield; mp 97.2−98.2 °C). 1H NMR (400 MHz, CDCl3): δ 7.87 (bs, NH, 2H), 7.57 (d, J = 7.8 Hz, =CH, 2H), 7.49 (d, J = 8.4 Hz, =CH, 2H), 7.29 – 7.24 (m, 2H), 7.20 – 7.11 (m, 6H), 6.27 (s, =CH, 2H), 5.68 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.3, 138.0, 136.2,


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131.9, 130.3, 128.2, 122.2, 121.5, 120.5, 120.2, 110.9, 102.5, 44.4. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H18BrN2, 401.0648; found 401.0638. 2,2'-((4-Iodophenyl)methylene)bis(1H-indole) (12e): Column chromatography (EtOAc/hexan; 1:9) gave the product as light brown solid (380 mg, 89% yield; mp 128.8−129.8 °C). 1H NMR (400 MHz, CDCl3): δ 7.82 (bs, NH, 2H), 7.65 (d, J = 8.3 Hz, =CH, 2H), 7.53 (d, J = 7.5 Hz, =CH, 2H), 7.22 (d, J = 7.5 Hz, =CH, 2H), 7.18 – 7.06 (m, =CH, 4H), 7.00 (d, J = 8.3 Hz, =CH, 2H), 6.28 – 6.17 (m, =CH, 2H), 5.62 (s, CH, 1H). 13

C{1H} NMR (100 MHz, CDCl3): δ 140.2, 138.1, 136.4, 130.8, 128.4 (2C), 122.4, 120.7, 120.4, 111.0,

102.7, 93.3, 44.7. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H18IN2, 449.0509; found 449.0511. 2,2'-((4-(Trifluoromethyl)phenyl)methylene)bis(1H-indole)

(12f):

Column

chromatography

(EtOAc/hexane; 1:9) gave the product as light brown solid (352 mg, 94% yield; mp 93.5−94.5 °C). 1H NMR (400 MHz, CDCl3): δ 7.89 (bs, NH, 2H), 7.65 – 7.61 (m, AA′ part of AA′BB′ system, =CH, 2H), 7.59 (d, J = 7.8 Hz, =CH, 2H), 7.44 – 7.40 (m, BB′ part of AA′BB′ system, =CH, 2H), 7.27 (d, J = 7.8 Hz, =CH, 2H), 7.24 – 7.18 (m, =CH, 2H), 7.18 – 7.12 (m, =CH, 2H), 6.28 (s, =CH, 2H), 5.77 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.4, 137.7, 136.3, 129.9 (q, J = 32.5 Hz), 129.1, 128.2, 125.8 (q, J= 4 Hz), 124.1 (q, J = 272.1 Hz), 122.4, 120.6, 120.3, 110.9, 102.8, 44.8. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H18F3N2, 391.1417; found 391.1403. 4-(Di(1H-indol-2-yl)methyl)phenyl acetate (12g): Column chromatography (EtOAc/hexane; 1:9) gave the product as light pink solid (330 mg, 92% yield; mp 229−230 °C). 1H NMR (400 MHz, Acetone-d6): δ 10.21 (bs, NH, 2H), 7.50 (d, J = 7.9 Hz, =CH, 2H), 7.40 (d, J = 8.5 Hz, =CH, 2H), 7.35 (d, J = 7.9 Hz, =CH, 2H), 7.14 – 7.04 (m, =CH, 4H), 7.00 (t, J = 7.5 Hz, =CH, 2H), 6.16 (s, =CH, 2H), 5.90 (s, CH, 1H), 2.27 (s, CH3, 3H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 169.7, 150.8, 140.8, 139.8, 137.8, 130.4, 129.2, 122.5, 121.9, 120.7, 119.9, 111.7, 102.1, 45.2, 20.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C25H21N2O2, 381.1598; found 381.1591. 4-(Di(1H-indol-2-yl)methyl)phenol (12h): A solution of 4-(di(1H-indol-2-yl)methyl)phenyl acetate (12g) (349 mg, 1.0 mmol) in MeOH (20 mL) was treatment with NH3 (g) at room temperature for 3h. Upon completion (determined by TLC) the reaction, solvent was removed on a rotary evaporator. The residue purified by column chromatography on silica gel eluted with EtOAc/hexane (1:9) to give the product (12h) as purple solid (331 mg, 98% yield; mp 106.2−107.2 °C). 1H NMR (400 MHz, CDCl3): δ 7.93 (bs, NH, 2H), 7.51 (d, J = 7.7 Hz, =CH, 2H), 7.23 – 7.15 (m, =CH, 2H), 7.14 – 7.03 (m, =CH, 6H), 6.72 (d, J = 8.5 Hz, =CH, 2H), 6.24-6. 20 (m, =CH, 2H), 6.00 (s, OH, 1H), 5.57 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 155.1, 139.2, 136.2, 132.3, 129.8, 128.3, 121.9, 120.3, 120.0, 115.7, 110.8, 102.1, 44.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H19N2O, 339.1492; found 339.1496.



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2,2'-((4-Nitrophenyl)methylene)bis(1H-indole) (12i): Column chromatography (EtOAc/hexane; 1:9) gave the product as light brown solid (358 mg, 98% yield; mp 225−226 °C). 1H NMR (400 MHz, Acetoned6): δ 10.29 (bs, NH, 2H), 8.28 – 8.24 (m, AA′ part of AA′BB′ system, =CH, 2H), 7.70 – 7.66 (m, BB′ part of AA′BB′ system, =CH, 2H), 7.51 (d, J = 7.7 Hz, =CH, 2H), 7.36 (d, J = 7.7 Hz, =CH, 2H), 7.10 (t, J = 7.7 Hz, =CH, 2H), 7.02 (t, J = 7.7 Hz, =CH, 2H), 6.20 (s, =CH, 2H), 6.09 (s, CH, 1H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 150.0, 148.0, 139.5, 137.9, 130.8, 129.2, 124.4, 122.2, 120.9, 120.2, 111.9, 102.6, 45.5. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H18N3O2, 368.1394; found 368.1386. 4-(Di(1H-indol-2-yl)methyl)aniline (12j): 2,2'-((4-Nitrophenyl)methylene)bis(1H-indole) (12i) (367 mg, 1.0 mmol) was dissolved in MeOH (10 mL), and 10% Pd/C (15 mg) was added. The mixture was stirred in H2 atmosphere for 12 h. The Pd/C was removed by filtration and the solvent was evaporated to obtained pure compound (12j) as a dark brown solid (318 mg, 94%; mp: 131.8-132.8°C). 1H NMR (400 MHz, CDCl3): δ 7.92 (bs, NH, 2H), 7.53 (d, J = 7.7 Hz, =CH, 2H), 7.23 (d, J = 7.7 Hz, =CH, 3H), 7.18 – 6.99 (m, =CH, 5H), 6.64 (d, J = 8.1 Hz, =CH, 2H), 6.28 (s, =CH, 2H), 5.64 (s, CH, 1H), 3.61 (bs, NH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.7, 139.4, 136.1, 130.2, 129.5, 128.3, 121.7, 120.3, 119.9, 113.3, 110.8, 102.0, 44.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C23H20N3, 338.1652; found 338.1652. 2,2'-(Naphthalen-2-ylmethylene)bis(1H-indole) (12k): Column chromatography (EtOAc/hexane; 1:9) gave the product as dark pink solid (325 mg, 92% yield; mp 124.2−125.2 °C). 1H NMR (400 MHz, CDCl3): δ 7.97 (bs, NH, 2H), 7.88 – 7.80 (m, =CH, 2H), 7.80 – 7.69 (m, =CH, 2H), 7.55 (d, J = 7.9 Hz, =CH, 2H), 7.52 – 7.42 (m, =CH, 3H), 7.31 – 7.26 (m, =CH, 2H), 7.22 – 7.03 (m, =CH, 4H), 6.39 – 6.29 (m, =CH, 2H), 5.95 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.6, 137.8, 136.2, 133.5, 132.7, 128.6, 128.3, 127.9, 127.7, 127.1, 126.9, 126.5, 126.3, 122.0, 120.5, 120.1, 110.9, 102.5, 45.0. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C27H21N2, 373.1699; found 373.1688. 2,2'-(Pyren-1-ylmethylene)bis(1H-indole) (12l): Column chromatography (EtOAc/hexane; 1:9 then CH2Cl2/hexane; 2:8) gave the product as light red solid (394 mg, 93% yield; mp 177−178 °C). 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 9.3 Hz, =CH, 1H), 8.23 (d, J = 7.5 Hz, =CH, 1H), 8.17 (d, J = 7.5 Hz, =CH, 1H), 8.14 – 7.99 (m, =CH, 5H), 7.96 (bs, NH, 2H), 7.76 (d, J = 8.0 Hz, =CH, 1H), 7.53 (d, J = 7.7 Hz, =CH, 2H), 7.29 – 7.20 (m, =CH, 2H), 7.20 – 7.08 (m, =CH, 4H), 6.78 (s, CH, 1H), 6.32 (s, =CH, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.0, 136.4, 133.8, 131.6, 131.2, 130.9, 129.2, 128.6, 128.6, 127.9, 127.6, 126.6, 126.4, 125.8, 125.6, 125.4, 125.3, 124.9, 122.9, 122.2, 120.7, 120.3, 111.1, 103.2, 41.9. HRMS (APCITOF) m/z: [M + H]+ calcd for C33H23N2, 447.1856; found 447.1841. 2,2'-(Pyridin-2-ylmethylene)bis(1H-indole) (12m): Column chromatography (EtOAc/hexane; 1:9) gave the product as light brown solid (288 mg, 92% yield; mp 171.4−172.4 °C). 1H NMR (400 MHz, CDCl3): δ 8.88 (bs, NH, 2H), 8.61 (d, J = 4.2 Hz, =CH, 1H), 7.64 (dt, J = 7.7, 1.6 Hz, =CH, 1H), 7.51 (d, J = 7.7 Hz, 14 ACS Paragon Plus Environment

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=CH, 2H), 7.33 (d, J = 7.7 Hz, =CH, 1H), 7.26 – 7.16 (m, =CH, 3H), 7.14 – 6.97 (m, =CH, 4H), 6.28 (s, =CH, 2H), 5.72 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.7, 149.5, 138.0, 137.5, 136.3, 128.2, 123.7, 122.6, 121.9, 120.4, 119.9, 111.1, 101.4, 46.4. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C22H18N3, 324.1495; found 324.1500. Tri(1H-indol-2-yl)methane (12n): Column chromatography (EtOAc/hexane; 1:9) gave the product as brown solid (321 mg, 94% yield; mp 221.7−222.7 °C). 1H NMR (400 MHz, CDCl3): δ 7.93 (bs, NH, 3H), 7.56 (d, J = 7.6 Hz, =CH, 3H), 7.24 – 7.07 (m, =CH, 9H), 6.43 (s, CH, 3H), 5.87 (s, CH, 1H).

13

C{1H} NMR

(100 MHz, CDCl3): δ 136.5, 136.2, 128.2, 122.4, 120.6, 120.3, 111.0, 102.2, 39.0. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C25H20N3, 362.1652; found 362.1651. 1,4-Bis(di(1H-indol-2-yl)methyl)benzene (12o): (4.0 mmol 4,7-dihydroindole was used for the synthesis of the product 12o) Column chromatography (EtOAc/hexane; 1:9) gave the product as light yellow solid (255 mg, 94% yield; mp 273.3−274.3 °C). 1H NMR (400 MHz, Acetone-d6): δ 10.02 (bs, NH, 4H), 7.33 (d, J = 7.5 Hz, =CH, 4H), 7.25 (s, =CH, 4H), 7.17 (d, J = 7.5 Hz, =CH, 4H), 6.95 – 6.87 (m, =CH, 4H), 6.83 (t, J = 7.5 Hz, =CH, 4H), 6.05 (s, =CH, 4H), 5.70 (s, CH, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 141.3, 141.0, 137.8, 129.7, 129.3, 121.9, 120.8, 120.0, 111.8, 102.1, 45.7. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C40H31N4, 567.2543; found 567.2535. 2,2'-((1-Tosyl-1H-indol-3-yl)methylene)bis(1H-indole) (15): Column chromatography (EtOAc/hexane; 1:9) gave the product as red solid (430 mg, 90% yield; mp 129.4−130.4 °C). 1H NMR (400 MHz, CDCl3): δ 8.10 – 7.96 (m, NH, =CH, 3H), 7.76 (d, J = 6.3 Hz, =CH, 2H), 7.57 (d, J = 7.4 Hz, =CH, 2H), 7.48 – 7.08 (m, =CH, 12H), 6.35 (s, =CH, 2H), 5.95 (s, CH, 1H), 2.40 (s, CH3, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.2, 136.9, 136.2, 135.5, 135.0, 130.0, 129.7, 128.3, 126.9, 125.2, 124.9, 123.5, 122.3, 122.1, 120.5 (2C), 120.2, 120.1, 113.9, 111.0, 102.0, 36.4. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C32H26N3O2S, 516.1740; found 516.1744. 2,2'-((1H-Indol-3-yl)methylene)bis(1H-indole) (12p): To a solution of 2,2'-((1-tosyl-1H-indol-3yl)methylene)bis(1H-indole) (15) (400 mg, 0.7 mmol) in MeOH (8 mL) was added Mg (170 mg, 7.0 mmol). The resulting suspension was sonicated for 1-2 h, Progress of the reaction was monitored by TLC. After completion of the reaction. The reaction was diluted with dichloromethane (15 mL) and poured into HCl (0.5 M, 10 mL). The organic phase was washed twice with NaHCO3 (1.0 M, 10 mL) and brine and then dried over Na2SO4. Filtering through a short silica column chromatography with EtOAc/hexane (1:9) gave the product as purple solid (265 mg, 94% yield; mp 200.1−201.1 °C). For substrates not soluble in MeOH, THF can be added. 1H NMR (400 MHz, CDCl3): δ 7.90 (bs, NH, 3H), 7.60 – 7.41 (m, =CH, 2H), 7.39 (d, J = 8.1 Hz, =CH, 1H), 7.32 (d, J = 8.1 Hz, =CH, 1H), 7.25 – 7.04 (m, =CH, 8H), 7.01 (t, J = 7.5 Hz, =CH, 1H), 6.36 (d, J = 1.8 Hz, =CH, 2H), 5.96 (s, CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): 15 ACS Paragon Plus Environment


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δ 138.9, 136.6, 136.0, 128.5, 126.5, 123.5, 122.7, 121.7, 120.4, 120.1, 119.9, 119.4, 115.6, 111.4, 110.9, 101.5, 36.5. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C25H20N3, 362.1652; found 362.1648. General Procedure 2 (GP2) for the Synthesis of 2-aryl indole 16a-p. Solution of 2,2'-(arylmethylene)bis(4,7-dihydro-1H-indole) (11) (1.0 mmol) in 1,2-dichloroethane (3.0 mL) was charged to a sealed tube and heated to 110 oC for 6h. The reaction mixture was cooled to room temperature and then the solvent was evaporated. The residue purified over silica gel column chromatography. 2-Benzyl-1H-indole (16a)24: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as brown solid (192 mg, 92% yield; mp 79.7−80.7 °C). 1H NMR (400 MHz, CDCl3): δ 7.77 (bs, NH, 1H), 7.54 (d, J = 7.3 Hz, =CH, 1H), 7.38 – 7.20 (m, =CH, 6H), 7.15 – 7.01 (m, =CH, 2H), 6.33 (s, =CH, 1H), 4.13 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.6, 137.9, 136.3, 128.9, 128.8, 128.7, 126.8, 121.4, 120.1, 119.8, 110.6, 101.2, 34.7. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H14N, 208.1121; found 208.1122. 2-(4-Fluorobenzyl)-1H-indole (16b)24: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (205 mg, 91% yield; mp 102.4−103.4 °C). 1H NMR (400 MHz, CDCl3): δ 7.77 (bs, NH, 1H), 7.55 (d, J = 7.6 Hz, =CH, 1H), 7.28 – 7.19 (m, =CH, 3H), 7.15 – 7.05 (m, =CH, 2H), 7.04 – 6.97 (m, =CH, 2H), 6.31 (s, =CH, 1H), 4.10 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.8 (d, J = 245.1 Hz), 137.61, 136.3, 134.2 (d, J = 3.4 Hz), 130.3 (d, J = 8.0 Hz), 128.6, 121.5, 120.1, 119.9, 115.5 (d, J = 21.3 Hz), 110.5, 101.2, 33.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H13FN, 226.1027; found 226.1030. 2-(4-Chlorobenzyl)-1H-indole (16c): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (220 mg, 91% yield; mp 110.4−111.4 °C). 1H NMR (400 MHz, CDCl3): δ 7.76 (bs, NH, 1H), 7.54 (d, J = 7.7 Hz, =CH, 1H), 7.31 – 7.23 (m, =CH, 3H), 7.18 (d, J = 8.3 Hz, =CH, 2H), 7.15 – 7.04 (m, =CH, 2H), 6.30 (s, =CH, 1H), 4.10 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 137.3, 137.1, 136.4, 132.6, 130.2, 128.9, 128.7, 121.6, 120.2, 119.9, 110.6, 101.4, 34.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H13ClN, 242.0731; found 242.0747. 2-(4-Bromobenzyl)-1H-indole (16d)24: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (260 mg, 90% yield; mp 136.3−137.3 °C). 1H NMR (400 MHz, CDCl3): δ 7.77 (bs, NH, 1H), 7.58 (d, J = 7.5 Hz, =CH, 1H), 7.53 – 7.42 (m, =CH, 2H), 7.31 – 7.25 (m, =CH, 1H), 7.19 – 7.04 (m, =CH, 4H), 6.34 (s, =CH, 1H), 4.10 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 137.5, 137.0, 136.3, 131.8, 130.6, 128.6, 121.6, 120.7, 120.1, 119.9, 110.6, 101.4, 34.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H13BrN, 286.0226; found 286.0200.


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2-(4-Iodobenzyl)-1H-indole (16e): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as dark brown solid (300 mg, 90% yield; mp 148.6−149.6 °C). 1H NMR (400 MHz, CDCl3): δ 7.74 (bs, NH, 1H), 7.67 – 7.59 (m, =CH, 2H), 7.54 (d, J = 7.6 Hz, =CH, 1H), 7.28 – 7.20 (m, =CH, 1H), 7.14 – 7.05 (m, =CH, 2H), 6.99 (d, J = 8.3 Hz, =CH, 2H), 6.30 (d, J = 1.0 Hz, =CH, 1H), 4.06 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.2, 137.8, 137.0, 136.3, 130.9, 128.6, 121.6, 120.1, 119.9, 110.5, 101.5, 92.0, 34.3. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H13IN, 334.0087; found 334.0070. 2-(4-(Trifluoromethyl)benzyl)-1H-indole (16f)24: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (252 mg, 91% yield; mp 75.4−76.4 °C). 1H NMR (400 MHz, CDCl3): δ 7.79 (bs, NH, 1H), 7.63 – 7.56 (m, =CH, 3H), 7.39 (d, J = 8.0 Hz, =CH, 2H), 7.35 – 7.24 (m, =CH, 1H), 7.20 – 7.09 (m, =CH, 2H), 6.36 (s, =CH, 1H), 4.21 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 142.7, 136.5, 136.4, 129.1, 128.8 (q, J = 33.4 Hz), 128.57, 125.7 (q, J = 3.9 Hz), 124.2 (q, J = 272.0 Hz), 121.7, 120.2, 120.0, 110.6, 101.7, 34.5. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C16H13F3N, 276.0995; found 276.1000. 4-((1H-Indol-2-yl)methyl)phenyl acetate (16g): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as dark brown oil (253 mg, 93% yield). 1H NMR (400 MHz, CDCl3): δ 7.83 (bs, NH, 1H), 7.53 (d, J = 7.5 Hz, =CH, 1H), 7.23 – 7.19 (m, =CH, 2H), 7.14 – 7.03 (m, =CH, 3H), 7.03 – 6.95 (m, =CH, 2H), 6.30 (d, J = 1.0 Hz, =CH, 1H), 4.07 (s, CH2, 2H), 2.28 (s, CH3, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.8, 149.4, 137.4, 136.4, 136.2, 129.8, 128.6, 121.8, 121.4, 120.0, 119.8, 110.6, 101.3, 34.0, 21.2. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C17H16NO2, 266.1176; found 266.1177. 4-((1H-Indol-2-yl)methyl)phenol (16h)25: Prepared according to the synthesis procedure of 12h. Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as brown solid (155 mg, 92% yield; mp 146.4−147.4 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.97 (bs, NH, 1H), 8.20 (s, OH, 1H), 7.46 (d, J = 7.8 Hz, =CH, 1H), 7.30 (d, J = 7.8 Hz, =CH, 1H), 7.13 (d, J = 8.1 Hz, =CH, 2H), 7.06 – 6.89 (m, =CH, 2H), 6.79 (d, J = 8.1 Hz, =CH, 2H), 6.20 (s, =CH, 1H), 4.04 (s, CH2, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 156.8, 140.4, 137.7, 131.1, 130.6, 129.9, 121.3, 120.3, 119.8, 116.1, 111.5, 100.6, 34.3. HRMS (APCITOF) m/z: [M + H]+ calcd for C15H14NO, 224.1070; found 224.1061. 2-(4-Nitrobenzyl)-1H-indole (16i)25: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as dark brown solid (230 mg, 91% yield; mp 104.5−105.5 °C). 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.7 Hz, =CH, 2H), 7.83 (bs, NH, 1H), 7.56 (d, J = 7.6 Hz, =CH, 1H), 7.40 (d, J = 8.7 Hz, =CH, 2H), 7.32 – 7.27 (m, =CH, 1H), 7.18 – 7.07 (m, =CH, 2H), 6.33 (d, =CH, J = 1.3 Hz, 1H), 4.23 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 146.9, 146.3, 136.5, 135.7, 129.6, 128.5, 123.9, 121.9, 120.2, 120.1, 110.7, 102.0, 34.5. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H13N2O2, 253.0972; found 253.0944.



Page 18 of 28

4-((1H-Indol-2-yl)methyl)aniline (16j): Prepared according to the synthesis procedure of 12j. Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as dark red solid (160 mg, 90% yield; mp 157−158 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.90 (bs, NH, 1H), 7.46 (d, J = 7.8 Hz, =CH, 1H), 7.30 (d, J = 7.8 Hz, =CH, 1H), 7.07 – 6.91 (m, =CH, 4H), 6.62 (d, J = 8.3 Hz, =CH, 2H), 6.19 (s, =CH, 1H), 4.48 (bs, NH2, 2H), 3.98 (s, CH2, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 147.7, 140.8, 137.7, 130.2, 129.9, 128.2, 121.2, 120.3, 119.7, 115.3, 111.5, 100.5, 34.4. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C15H15N2, 223.1230; found 223.1217. 2-(Naphthalen-2-ylmethyl)-1H-indole (16k)26: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as brown solid (230 mg, 89% yield; mp 151.6−152.6 °C). 1H NMR (400 MHz, CDCl3): δ 7.87 – 7.71 (m, =CH, 4H), 7.71 (bs, NH, 1H), 7.56 (d, J = 7.6 Hz, =CH, 1H), 7.51 – 7.40 (m, =CH, 2H), 7.39 – 7.32 (m, =CH, 1H), 7.22 (d, J = 7.6 Hz, =CH, 1H), 7.18 – 6.99 (m, =CH, 2H), 6.38 (s, =CH, 1H), 4.29 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 137.7, 136.3, 136.0, 133.6, 132.4, 128.7, 128.5, 127.7, 127.6, 127.3, 127.2, 126.3, 125.8, 121.4, 120.1, 119.8, 110.6, 101.3, 34.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C19H16N, 258.1277; found 258.1248. 2-(Pyren-1-ylmethyl)-1H-indole (16l): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (298 g, 90% yield; mp 181.7−182.7 °C). 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 9.2 Hz, =CH, 1H), 8.24 – 8.13 (m, =CH, 3H), 8.10 – 8.05 (m, =CH, 3H), 8.01 (t, J = 7.7 Hz, =CH, 1H), 7.95 (d, J = 7.7 Hz, =CH, 1H), 7.75 (bs, NH,1H), 7.54 – 7.48 (m, =CH, 1H), 7.17 – 7.13 (m, =CH, 1H), 7.10 – 7.00 (m, =CH, 2H), 6.37 (d, J = 1.0 Hz, =CH, 1H), 4.87 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.0, 136.1, 131.8, 131.4, 130.9, 130.7, 129.3, 128.8, 128.0, 127.9, 127.5, 127.3, 126.1, 125.3, 125.2, 125.0, 124.8, 123.2, 121.3, 120.0, 119.8, 110.5, 100.9, 32.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C25H18N, 332.1434; found 332.1432. 2-(Pyridin-2-ylmethyl)-1H-indole (16m)27: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as orange solid (193 mg, 93% yield; mp 71.3−72.3 °C). 1H NMR (400 MHz, CDCl3): δ 9.08 (bs, NH, 1H), 8.54 (d, J = 4.3 Hz, =CH, 1H), 7.58 (td, J = 7.6, 1.8 Hz, =CH, 1H), 7.53 (d, J = 7.6 Hz, =CH, 1H), 7.30 – 7.24 (m, =CH, 1H), 7.24 – 7.19 (m, =CH 1H), 7.16 – 7.00 (m, =CH 3H), 6.35 (d, J = 0.9 Hz, =CH 1H), 4.25 (s, CH2, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 158.9, 149.2, 137.1, 136.5, 136.3, 128.5, 123.2, 121.8, 121.3, 112.0, 119.6, 110.7, 100.5, 37.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C14H13N2, 209.1073; found 209.1070. Di(1H-indol-2-yl)methane (16n)11: Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as dark red solid (222 mg, 90% yield; mp 165.1−166.1 °C). 1H NMR (400 MHz, CDCl3): δ 7.73 (bs, NH, 2H), 7.60 – 7.51 (m, =CH, 2H), 7.23 – 7.02 (m, =CH, 6H), 6.39 (d, J = 0.9 Hz, =CH, 2H), 4.18 (s, CH2, 2H).


Page 19 of 28 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


13

C{1H} NMR (100 MHz, CDCl3): δ 136.3, 135.2, 128.5, 121.8, 120.2, 120.0, 110.8, 101.3, 27.7. HRMS

(APCI-TOF) m/z: [M + H]+ calcd for C17H15N2, 247.1230; found 247.1233. 1,4-Bis((1H-indol-2-yl)methyl)benzene (16o): Column chromatography (EtOAc/hexane; 1:9) gave the product as dark brown solid (300 mg, 88% yield; mp 208.3−209.3 °C). 1H NMR (400 MHz, DMSO-d6) δ 10.91 (bs, NH, 2H), 7.38 (d, J = 7.6 Hz, =CH, 2H), 7.27 – 7.21 (m, =CH, 6H), 6.97 (t, J = 7.4 Hz, =CH, 2H), 6.90 (t, J = 7.4 Hz, =CH, 2H), 6.10 (s, =CH, 2H), 4.01 (s, CH2, 4H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 139.0, 137.4, 136.2, 128.6, 128.2, 120.2, 119.2, 118.6, 110.7, 99.2, 33.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H21N2, 337.1699; found 337.1698. 3-((1H-Indol-2-yl)methyl)-1-tosyl-1H-indole (17): Column chromatography (EtOAc/hexane; 1:9) gave the product as pink solid (365 mg, 91% yield; mp 172.6−173.6 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.96 (bs, NH, 1H), 7.84 (d, J = 8.3 Hz, =CH, 1H), 7.70 (d, J = 8.3 Hz, =CH, 2H), 7.48 (s, =CH, 1H), 7.38 (d, J = 7.7 Hz, =CH, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.21 – 7.15 (m, 3H), 7.13 (d, J = 8.5 Hz, =CH, 1H), 7.03 (t, J = 7.7 Hz, =CH, 1H), 6.86 (t, J = 7.4 Hz, =CH, 1H), 6.80 (t, J = 7.4 Hz, =CH, 1H), 6.10 (s, =CH, 1H), 4.10 (s, CH2, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 146.3, 137.9 (2C), 137.7, 136.3, 136.1, 131.7, 130.9, 129.8, 127.8, 125.6, 125.3, 124.1, 121.6, 120.9, 120.5, 119.9, 114.4, 111.6, 101.0, 24.7, 21.4. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H21N2O2S, 401.1318; found 401.1316. 3-((1H-Indol-2-yl)methyl)-1H-indole (16p)21: Prepared according to the synthesis procedure of 12p. Column chromatography (EtOAc/hexane; 1:9) gave the product as red solid (175 g, 95% yield; mp 128.9−129.9 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.90 (s, NH, 1H), 9.78 (s, NH, 1H), 7.36 (d, J = 7.9 Hz, =CH, 1H), 7.29 (d, J = 7.5 Hz, =CH, 1H), 7.24 (d, J = 8.1 Hz, =CH, 1H), 7.11 (d, J = 7.9 Hz, =CH, 1H), 7.07 (s, =CH, 1H), 6.94 (t, J = 7.5 Hz, =CH, 1H), 6.87 – 6.75 (m, =CH, 3H), 6.12 (s, =CH, 1H), 4.13 (s, CH2, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 140.3, 137.8, 137.6, 123.0, 128.5, 124.1, 122.2, 121.1, 120.3, 119.7, 119.6, 119.5, 113.4, 112.2, 111.5, 100.3, 25.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C17H15N2, 247.1230; found 247.1208. General Procedure 3 (GP3) for the Synthesis of indolo[2,3-b]carbazoles 18a-p. Iodine (0.03 equiv.) was added to a mixture of 2,2’-BIMs (1.0 equiv.) and trimethyl orthoformate (1.1 equiv.) in CH2Cl2 (10 mL) at room temperature. The reaction mixture was stirred for 15 min at the same temperature. After completion of the reaction (as monitored by thin-layer chromatography, TLC), the solvent was removed under reduced pressure, and the residue was directly charged on a chromatography column to give the pure product 18. 6-Phenyl-5,7-dihydroindolo[2,3-b]carbazole (18a): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (200 mg, 97% yield; mp 248.5−249.5 °C). 1H NMR (400 MHz, 19 ACS Paragon Plus Environment


Page 20 of 28

CDCl3): δ 8.71 (s, =CH, 1H), 8.19 (d, J = 7.7 Hz, =CH, 2H), 8.10 (bs, NH, 2H), 7.79 (d, J = 7.1 Hz, =CH, 2H), 7.67 (t, J = 7.7 Hz, =CH, 2H), 7.53 (t, J = 7.4 Hz, =CH, 1H), 7.42 – 7.32 (m, =CH, 4H), 7.29 – 7.22 (m, =CH, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.0, 137.6, 135.4, 130.1, 129.3, 128.1, 125.0, 124.3, 119.8, 119.5, 118.7, 110.9, 110.2, 105.7. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H17N2, 333.1386; found 333.1387. 6-(4-Fluorophenyl)-5,7-dihydroindolo[2,3-b]carbazole (18b): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light yellow solid (198 mg, 96% yield; mp 273.3−274.3 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.85 (bs, NH, 2H), 8.70 (s, =CH, 1H), 8.06 (d, J = 7.6 Hz, =CH, 2H), 7.70 – 7.59 (m, =CH, 2H), 7.30 (d, J = 8.0 Hz, =CH, 2H), 7.27 – 7.11 (m, =CH, 4H), 7.04 (t, J = 7.6 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 163.2 (d, J = 244.5 Hz), 141.9, 139.1, 132.8 (d, J = 8.2 Hz), 132.7, 125.5, 125.0, 120.2, 119.7, 119.4, 117.1 (d, J = 21.4 Hz), 111.55, 111.50, 105.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H16FN2, 351.1292; found 351.1291. 6-(4-Chlorophenyl)-5,7-dihydroindolo[2,3-b]carbazole (18c): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as white off solid (198 mg, 96% yield; mp 243.1−244.1 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.92 (bs, NH, 2H), 8.72 (s, =CH, 1H), 8.08 (d, J = 7.9 Hz, =CH, 2H), 7.65 (d, J = 8.4 Hz, =CH, 2H), 7.47 (d, J = 8.4 Hz, =CH, 2H), 7.32 (d, J = 7.9 Hz, =CH, 2H), 7.18 (t, J = 7.5 Hz, =CH, 2H), 7.05 (t, J = 7.5 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 141.9, 139.0, 135.4, 133.7, 132.5, 130.4, 125.5, 125.0, 120.2, 119.7, 119.4, 111.7, 111.5, 105.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H16ClN2, 367.0997; found 367.0999. 6-(4-Bromophenyl)-5,7-dihydroindolo[2,3-b]carbazole (18d): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as white off solid (195 mg, 95% yield; mp 242.2−243.2 °C). 1H NMR (400 MHz, Acetone d6): δ 10.11 (bs, NH, 2H), 8.89 (s, =CH, 1H), 8.25 (d, J = 7.7 Hz, =CH, 2H), 7.82 – 7.65 (m, =CH, 4H), 7.50 (d, J = 7.7 Hz, =CH, 2H), 7.36 (t, J = 7.5 Hz, =CH, 2H), 7.23 (t, J = 7.5 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, Acetone d6): δ 141.9, 138.9, 135.8, 133.4, 132.9, 125.6, 125.0, 121.9, 120.3, 119.8, 119.4, 111.8, 111.6, 105.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H16BrN2, 411.0491; found 411.0490. 6-(4-Iodophenyl)-5,7-dihydroindolo[2,3-b]carbazole (18e): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (195 mg, 95% yield; mp 230.3−231.3 °C). 1H NMR (400 MHz, Acetone-d6): δ 9.96 (bs, NH, 2H), 8.72 (s, =CH, 1H), 8.08 (d, J = 7.8 Hz, =CH, 2H), 7.82 (d, J = 7.8 Hz, =CH, 2H), 7.46 (d, J = 8.0 Hz, =CH, 2H), 7.33 (d, J = 8.0 Hz, =CH, 2H), 7.23 – 7.15 (m, =CH, 2H), 7.06 (t, J = 7.4 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 141.9, 139.5, 138.8, 136.3, 132.9, 125.5, 124.9 (2C), 120.2, 119.7, 119.4, 111.8, 111.6, 93.5. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H16IN2, 459.0353; found 459.0356.


Page 21 of 28 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


6-(4-(Trifluoromethyl)phenyl)-5,7-dihydroindolo[2,3-b]carbazole

(18f):

Column

chromatography

(EtOAc/hexane; 0.5:9.5) gave the product as white off solid (198 mg, 96% yield; mp 265.9−266.9 °C). 1

H NMR (400 MHz, CDCl3): δ 8.69 (s, =CH, 1H), 8.17 (d, J = 7.7 Hz, =CH, 2H), 8.00 (bs, NH, 2H), 7.93 –

7.84 (m, =CH, 4H), 7.41 – 7.31 (m, =CH, 4H), 7.31 – 7.21 (m, =CH, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.0, 139.4, 137.4, 130.2 (q, J = 32.7 Hz), 129.7, 127.0 (q, J = 3.6 Hz), 125.2, 124.1 (q, J = 272.2 Hz), 124.2, 119.8, 119.7, 118.8, 111.7, 110.3, 104.2. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C25H16F3N2, 401.1260; found 401.1266. 4-(5,7-Dihydroindolo[2,3-b]carbazol-6-yl)phenyl

acetate

(18g):

Column

chromatography

(EtOAc/hexane; 0.5:9.5) gave the product as white off solid (197 mg, 96% yield; mp 282.7−283.7 °C). 1

H NMR (400 MHz, Acetone-d6): δ 10.18 (bs, NH, 2H), 8.88 (s, =CH, 1H), 8.25 (d, J = 7.6 Hz, =CH, 2H),

7.85 (d, J = 8.3 Hz, =CH, 2H), 7.50 (d, J = 8.3 Hz, =CH, 2H), 7.40 – 7.28 (m, =CH, 4H), 7.22 (t, J = 7.6 Hz, =CH, 2H), 2.37 (s, CH3, 3H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 170.0, 151.4, 141.9, 139.0, 134.0, 131.7, 125.5, 125.0, 123.7, 120.2, 119.7, 119.4, 111.6, 111.5, 106.0, 21.1. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C26H19N2O2, 391.1441; found 391.1441. 4-(5,7-Dihydroindolo[2,3-b]carbazol-6-yl)phenol (18h): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as brown solid (194 mg, 94% yield; mp 281.9−282.9 °C). 1H NMR (400 MHz, MeOD): δ 8.66 (s, =CH, 1H), 8.14 (d, J = 7.6 Hz, =CH, 2H), 7.62 (d, J = 8.4 Hz, =CH, 2H), 7.42 (d, J = 8.0 Hz, =CH, 2H), 7.30 (t, J = 7.6 Hz, =CH, 2H), 7.20 – 7.08 (m, =CH, 4H). 13C{1H} NMR (100 MHz, MeOD): δ 158.1, 142.3 (2C), 139.6, 132.0, 128.1, 125.4, 120.2, 119.6, 119.5, 117.4, 111.5, 110.5, 107.3. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H17N2O, 349.1335; found 349.1331. 6-(4-Nitrophenyl)-5,7-dihydroindolo[2,3-b]carbazole (18i): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as orange solid (196 mg, 95% yield; mp˃ 300 °C). 1H NMR (400 MHz, Acetoned6): δ 10.10 (bs, NH, 2H), 8.78 (s, =CH, 1H), 8.31 (d, J = 8.6 Hz, =CH, 2H), 8.09 (d, J = 7.6 Hz, =CH, 2H), 7.98 (d, J = 8.6 Hz, =CH, 2H), 7.32 (d, J = 8.0 Hz, =CH, 2H), 7.20 (t, J = 7.6 Hz, =CH, 2H), 7.08 (t, J = 7.6 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 148.0, 144.0, 141.8, 138.7, 132.0, 125.7, 125.4, 124.8, 120.3, 112.0, 119.6, 112.9, 111.6, 104.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H16N3O2, 378.1237; found 378.1236. 4-(5,7-Dihydroindolo[2,3-b]carbazol-6-yl)aniline (18j): Prepared according to the synthesis procedure of 12j. Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as dark brown solid (179 mg, 97% yield; mp 223.7−224.7 °C). 1H NMR (400 MHz, CDCl3): δ 8.67 (s, =CH, 1H), 8.18 (d, J = 7.7 Hz, =CH, 2H), 8.07 (s, NH, 2H), 7.56 (d, J = 8.4 Hz, =CH, 2H), 7.41 – 7.32 (m, 4H), 7.29 – 7.19 (m, =CH, 4H), 6.96 (d, J = 8.4 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 146.3, 140.0 (2C), 137.9, 130.3, 124.9,



Page 22 of 28

124.4, 119.8, 119.3, 118.5, 116.2, 110.19, 110.15, 105.9. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C24H18N3, 348.1495; found 348.1499. 6-(Naphthalen-2-yl)-5,7-dihydroindolo[2,3-b]carbazole

(18k):

Column

chromatography

(EtOAc/hexane; 0.5:9.5) gave the product as green solid (196 mg, 95% yield; mp 184.6−185.6 °C). 1H NMR (400 MHz, CDCl3): δ 8.72 (s, =CH, 1H), 8.25 – 8.16 (m, =CH, 3H), 8.12 (s, =CH, 1H), 8.10 (bs, NH, 2H), 8.01 – 7.90 (m, =CH, 2H), 7.87 – 7.82 (m, =CH, 1H), 7.64 – 7.53 (m, =CH, 2H), 7.39 – 7.29 (m, =CH, 4H), 7.29 – 7.20 (m, =CH, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.0, 137.8, 134.2, 133.0, 132.8, 129.9, 128.2, 128.0, 127.1, 126.9, 126.6, 125.0, 124.3, 119.8, 119.5, 118.7, 111.0, 110.3 (2C), 105.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C28H19N2, 383.1543; found 383.1543. 6-(Pyren-1-yl)-5,7-dihydroindolo[2,3-b]carbazole (18l): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as yellow wish solid (193 mg, 94% yield; mp 204−205 °C). 1H NMR (400 MHz, CDCl3): δ 8.86 (s, =CH, 1H), 8.38 (d, J = 7.7 Hz, =CH, 1H), 8.29 – 8.22 (m, =CH, 4H), 8.21 – 8.14 (m, =CH, 3H), 8.04 (t, J = 7.7 Hz, =CH, 1H), 7.92 (d, J = 9.2 Hz, =CH, 1H), 7.80 (d, J = 9.2 Hz, =CH, 1H), 7.73 (bs, NH, 2H), 7.35 – 7.21 (m, =CH, 4H), 7.17 (d, J = 7.7 Hz, =CH, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.1 (2C), 138.8, 131.7, 131.4, 131.1, 129.5, 129.3, 128.6, 128.4, 128.2, 127.4, 126.5, 125.7, 125.7, 125.6, 125.1, 125.0, 124.9, 124.3, 119.9, 119.5, 118.6, 111.3, 110.3, 104.2. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C34H21N2, 457.1699; found 457.1698. 6-(1H-Indol-2-yl)-5,7-dihydroindolo[2,3-b]carbazole (18n): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as green solid (197 mg, 95% yield; mp 267.8−268.8 °C). 1H NMR (400 MHz, CDCl3): δ 8.26 (s, =CH, 1H), 8.03 – 7.93 (m, =CH, NH, 4H), 7.84 (s, NH, 1H), 7.66 (d, J = 7.4 Hz, =CH, 1H), 7.37 – 7.29 (m, =CH, 3H), 7.29 – 7.17 (m, =CH, 6H), 6.68 (s, =CH, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.9, 137.4, 136.8, 132.4, 129.3, 125.1, 124.1, 122.7, 120.8, 120.5, 119.8, 119.7, 118.5, 111.7, 111.3, 110.5, 102.5, 97.0. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C26H18N3, 372.1495; found 372.1495. 1,4-Bis(5,7-dihydroindolo[2,3-b]carbazol-6-yl)benzene (18o): Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as white off solid (195 mg, 94% yield; mp˃ 300°C). 1H NMR (400 MHz, Acetone-d6): δ 10.19 (bs, NH, 4H), 8.97 (s, =CH, 2H), 8.31 (d, J = 7.6 Hz, =CH, 4H), 8.16 (s, =CH, 4H), 7.58 (d, J = 7.6 Hz, =CH, 4H), 7.40 (t, J = 7.0 Hz, =CH, 4H), 7.27 (t, J = 7.0 Hz, =CH, 4H). 13C{1H} NMR (100 MHz, Acetone-d6): δ 141.9, 138.9, 135.7, 131.5, 125.6, 125.1, 120.3, 119.8, 119.6, 111.7, 111.6, 106.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C42H27N4, 587.2230; found 587.2226. 6-(1-Tosyl-1H-indol-3-yl)-5,7-dihydroindolo[2,3-b]carbazole

(19):

Column

chromatography

(EtOAc/hexane; 0.5:9.5) gave the product as light brown solid (194 mg, 95% yield; mp 292.8−293.8 °C). 1

H NMR (400 MHz, CDCl3): δ 8.74 (s, =CH, 1H), 8.24 – 8.16 (m, =CH, 3H), 8.01 (s, =CH, 1H), 7.94 (s, =CH, 22 ACS Paragon Plus Environment

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1H), 7.92 (s, NH, 2H), 7.51 – 7.44 (m, =CH, 1H), 7.44 – 7.22 (m, =CH, 11H), 2.41 (s, CH3, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.6, 139.8, 138.3, 135.6, 135.2, 130.2, 129.5, 127.2, 125.6, 125.0, 124.8, 124.2, 123.9, 121.1, 119.8, 119.6, 118.5, 116.3, 114.2, 111.5, 110.3, 95.9, 21.7. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C33H24N3O2S, 526.1584; found 526.1582. 6-(1H-Indol-3-yl)-5,7-dihydroindolo[2,3-b]carbazole (18p): Prepared according to the synthesis procedure of 12p. Column chromatography (EtOAc/hexane; 0.5:9.5) gave the product as white off solid (130 mg, 96% yield; mp 294.2−295.2 °C). 1H NMR (400 MHz, DMSO-d6): δ 11.60 (s, NH, 1H), 10.48 (s, NH, 2H), 8.81 (s, =CH, 1H), 8.18 (d, J = 7.8 Hz, =CH, 2H), 7.79 (s, =CH, 1H), 7.61 (d, J = 8.1 Hz, =CH, 1H), 7.43 (d, J = 7.8 Hz, =CH, 2H), 7.33 – 7.18 (m, =CH, 4H), 7.14 (t, J = 7.4 Hz, =CH, 2H), 7.03 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 140.6, 139.0, 136.7, 126.7, 125.3, 124.1, 123.5, 121.4, 119.6, 119.2, 119.1, 118.1, 117.44, 111.8, 110.9, 109.6, 108.0, 99.3. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C26H18N3, 372.1495; found 372.1491. 6,12-Diphenyl-5,7-dihydroindolo[2,3-b]carbazole (26)16: To a stirred solution of 2,2’-BIMs (12) (322 mg, 1.0 mmol) and benzaldehyde (106 mg, 1.0 mmol) in MeCN (7 mL), I2 (6 mg, 0.02 mmol) was added to the mixture and it was refluxed for 2h. After completion of the reaction (as monitored by thin-layer chromatography, TLC), the solvent was removed under reduced pressure. The residue purifiede by column chromatography on silica gel eluted with EtOAc/hexane (0.5:9.5) to give the pure product 26 as purple solid (385 mg, 94% yield). 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 2H), 7.84 – 7.80 (m, 2H), 7.72 – 7.63 (m, 6H), 7.54 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.28 – 7.21 (m, 2H), 7.01 (d, J = 7.8 Hz, 2H), 6.96 – 6.87 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.1, 139.6, 137.4, 131.0, 130.1, 129.4, 129.4, 129.3, 128.1, 128.1, 124.7, 124.2, 121.6, 119.2, 117.0, 109.9, 104.6. HRMS (APCI-TOF) m/z: [M + H]+ calcd for C30H21N2, 409.1699; found 409.1699.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX NMR spectra for all compounds (PDF) AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] 23 ACS Paragon Plus Environment


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ORCID ID Nurullah Saracoglu: 0000-0002-1504-7480 Ferruh Lazfi: 0000-0002-3371-0899 Haydar Kilic: 0000-0002-7009-9953 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This study is funded by the Research Fund of Atatürk University, Turkey (Project number: 2015/109 and FAD-2017-6107). We would like to thank Atatürk University for its support. REFERENCES (1) (a) Ruiz‐Sanchis, P.; Savina, S. A.; Albericio, F.; Alvarez, M., Structure, Bioactivity and Synthesis of Natural Products with Hexahydropyrrolo[2,3‐b]indole. Chem. Eur. J. 2011, 17, 1388-1408. (b) Humphrey, G. R.; Kuethe, J. T., Practical Methodologies for the Synthesis of Indoles. Chem. Rev. 2006, 106, 2875-2911. (c) Bandini, M.; Eichholzer, A., Catalytic Functionalization of Indoles in a New Dimension. Angew. Chem. Int. Ed. 2009, 48, 9608-9644. (d) Kochanowska-Karamyan, A. J.; Hamann, M. T., Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010, 110, 4489-4497. (2) (a) Pathak, T. P.; Osiak, J. G.; Vaden, R. M.; Welm, B. E.; Sigman, M. S., Synthesis and Preliminary Biological Study of Bisindolylmethanes Accessed by an Acid-Catalyzed Hydroarylation of Vinyl Indoles. Tetrahedron 2012, 68, 5203-5208. (b) Contractor, R.; Samudio, I. J.; Estrov, Z.; Harris, D.; McCubrey, J. A.; Safe, S. H.; Andreeff, M.; Konopleva, M., A Novel Ring-Substituted Diindolylmethane, 1,1-Bis[3′-(5methoxyindolyl)]-1-(pt-butylphenyl) Methane, Inhibits Extracellular Signal-Regulated Kinase Activation and Induces Apoptosis in Acute Myelogenous Leukemia. Cancer Res. 2005, 65, 2890-2898. (c) Wang, Y.; Tang, X.; Shao, Z.; Ren, J.; Liu, D.; Proksch, P.; Lin, W., Indole-Based Alkaloids from Deep-Sea Bacterium Shewanella Piezotolerans with Antitumor Activities. J. Antibiot. 2014, 67, 395. (d) Reddy, B. S.; Rajeswari, N.; Sarangapani, M.; Prashanthi, Y.; Ganji, R. J.; Addlagatta, A., Iodine-catalyzed Condensation of Isatin with Indoles: A Facile Synthesis of Di(indolyl)indolin-2-Ones and Evaluation of Their Cytotoxicity. Bioorg. Med. Chem. Lett. 2012, 22, 2460-2463. (e) De Miranda, B. R.; Miller, J. A.; Hansen, R. J.; Lunghofer, P. J.; Safe, S.; Gustafson, D. L.; Colagiovanni, D.; Tjalkens, R. B., Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory Para-Phenyl Substituted Diindolylmethanes in A Mouse Model of Parkinson’s Disease. J. Pharmacol. Exp. Ther. 2013, 345, 125-138. (f) Praveen, i. J.; Parameswaran, P.; Majik, M., Bis(indolyl)Methane Alkaloids: Isolation, Bioactivity, and Syntheses. Synthesis 2015, 47, 1827-1837. (g) Grosso, C., Cardoso, A. L., Lemos, A., Varela, J., Rodrigues, M. J., Custódio, L., e Melo, T. M. P., Novel approach to bis(indolyl)methanes: De novo Synthesis of 1-Hydroxyiminomethyl Derivatives with anti-Cancer Properties. Eur. J. Med. Chem., 2015, 93, 9-15.


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Protocols for the Syntheses of 2,2'-Bis(indolyl)arylmethanes, 2

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