FeCl3·6H2O as a Mild Catalyst for Nucleophilic Substitution of Symmetrical Bis(indoyl)methanes

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FeCl₃·6H₂O as a Mild Catalyst for Nucleophilic Substitution of

Symmetrical Bis(indoyl)methanes

Chayamon Chantana and Jaray Jaratjaroonphong*

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ABSTRACT: In this paper, unsymmetrical bis(indolyl)methane

(BIM) and 3-alkylindole derivatives are smoothly synthesized from

symmetrical BIMs with a variety of nucleophiles including

heteroaromatic/aromatic compounds, allylsilane and alkynylsilane.

FeCl₃·6H₂O is found to be a mild and highly eﬀective catalyst for

this nucleophilic substitution reaction in which N-methyl-2-

3

2

phenylindole behaves as a good leaving group in the C_sp−C_sp

bond cleavage reaction. The operational ease, nonexpensive and

environmentally friendly catalyst, mild reaction conditions, broad

functional group tolerance, and scalability of this reaction strategy are advantages of the present procedure.

tives (Scheme 1A,B).^4,8,9Recently, an acid-catalyzed hydro-

arylation reaction of vinyl indoles to access the unsymmetrical

BIMs in good to excellent yields has been developed (Scheme

1C).¹⁰Although the reported methods are satisfactory, some

of the methods suﬀer from certain drawbacks such as the need

for expensive catalysts,^{5a,7b,8a,d,e,10e}high catalyst loadings,^8a,c

longer reaction times,^7b,8a,10a,eharsh reaction conditions (e.g.,

high temperatures),^5a,8a,d−gand poor yields of some desired

products.^8e9Moreover, it has some limitations in terms of

substrate preparation and also 2,3′-BIM production bearing

aliphatic substituents at the central sp³-hybridized carbon

atom, which are frequently found in natural sources.

INTRODUCTION

■

The indole scaﬀold represents one of the important

heterocyclic structures in nature that is frequently found in

many biologically active natural products, pharmaceuticals, and

functional materials.¹Among the various structural indole

alkaloids, 3,3′- and 2,3′-BIMs as well as 3-alkylindole skeletons

are arguably among the most prevalent as they are ubiquitous

in numerous biologically active marine²and terrestrial³natural

sources (Figure 1).

In the past decade, the commercially available FeCl₃·6H₂O

has proven to be versatile to mediate a wide variety of organic

transformation due to the numerous advantages, namely, the

relatively high eﬃciency, low toxicity, water compatibility, mild

reaction conditions, and an eco-friendly catalytic reaction.^11,12

Moreover, iron is the fourth most abundant element in the

Earth’s crust and the second most abundant metal (after

aluminum) and is certainly the most important for biological

processes. All living beings, i.e., plants, animals, humans, and

bacteria need iron to grow and survive. Combining the above

two concepts, here, we report the ﬁrst use of FeCl₃·6H₂O as a

mild catalyst for nucleophilic substitution of symmetrical BIMs

with a variety of nucleophiles such as indoles, 2-alkylfuran, 2-

alkylthiophene, ethyl 1H-pyrrole-2-carboxylate, 1,2,4-trime-

Figure 1. Selected BIM natural products.

Although symmetrical 3,3′-BIM skeletons can be readily

synthesized by condensation reactions of carbonyl compounds

with 2 equiv of indoles in the presence of acid,^2g,4,5the

development of a strategy for the eﬃcient construction of

unsymmetrical 2,3′- and 3,3′-BIMs is rare and remains a great

challenge.⁶⁻¹⁰For the past decade, methods for the

construction of unsymmetrical 2,3′- and 3,3′-BIMs have been

developed mainly centered on indolylation of 3-indolylmethyl

alcohol, sulfone, sulfonamide, dimethylamine, Meldrum’s acid,

N,N-dimethylbarbituric acid, malononitrile, and 2,4,6-trime-

thoxybenzene or 2-indolylmethyl alcohol with indole deriva-

Received: October 18, 2020

Published: January 22, 2021

https://dx.doi.org/10.1021/acs.joc.0c02466

J. Org. Chem. 2021, 86, 2312−2327

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Scheme 1. (A−D) Synthesis of Unsymmetrical BIMs

RESULTS AND DISCUSSION

■

Initially, the BIM 1a and indole 2a were chosen as model

substrates to optimize the reaction conditions (Table 1 and

Table S1 in the Supporting Information). After optimization

studies had identiﬁed FeCl₃·6H₂O as the optimal catalyst

(entries 1−5), further study is focused on the evaluation and

eﬃciency of various solvents (entries 1 and 6−8). Among the

solvents tested, toluene was shown to be the best in terms of

yield and reaction eﬃciency for this reaction. Subsequently,

diﬀerent reaction temperatures, times, and catalyst loadings

were investigated (entries 9−12). We found that lowering the

reaction temperature (0 or 18 °C) led to decreased yields of

the product 3a (entries 9 and 10) and increasing the reaction

temperature resulted in slightly lower yields due to increasing

formation of 4a (entries 1 vs 11). Decreasing the catalyst

loading to 2.5 mol % FeCl₃·6H₂O was also not good for the

reaction (entry 12). A control experiment was carried out in

the absence of FeCl₃·6H₂O for 24 h, and both starting

materials were recovered in near quantitative yields (entry 13).

Although 4a was obtained as a minor product under the

reaction conditions, the isolated 4a could be converted to the

desired product 3a in good yield by treatment with MPI in the

presence of 5 mol % FeCl₃·6H₂O as the catalyst in toluene at

100 °C for 24 h. Note that in the reaction of 4a with MPI, only

minor traces of the double-indole substitution adduct 1a were

detected.

To better understand the reaction time-dependent tran-

sindolylation of 1a, which is shown in the Supporting

Information, Table S2 and Figure S1, the competitive reaction

between mono- and double transindolylation was systemati-

cally studied using the model reaction under optimal

conditions (Table 1, entry 1). The reaction was quenched at

diﬀerent times, and the quantity of all compounds was

monitored by HPLC analysis. The compound distribution in

thoxybenzene, ortho-methoxyaniline, aniline, allylsilane, and

alkynylsilane under “open-ﬂask” conditions at room temper-

ature to aﬀord a variety of functionalized unsymmetrical 3,3′-

and 2,3′-BIMs as well as 3-alkylindole derivatives (Scheme

1D).

a b

,

Table 1. Selected Optimization Studies

b

entry

catalyst (mol %)

mol %

solvent

temp (°C)

time (h)

3a (%)

4a (%)

1

2

3

4

5

6

7

8

9

10

11

12

13

FeCl₃·6H₂O

FeCl₃

FeCl₂·4H₂O

Fe(OTf)₃

5

10

5

toluene

DCE

CH₃CN

CH₃NO₂

toluene

rt (32)

1

5

24

2

1

2

24

1

24

80

54

23

70

44

60

50

65

20

5

c

rt

0

18

50

rt

23

42

40

38

32

trace

7

TFA

FeCl₃·6H₂O

trace

26

71

5

2.5

26

c

50

22

d

−

a

b

c

d

Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), FeCl₃·6H₂O (5 mol %), and solvent (10 mL). Isolated yield. Under a N₂atmosphere. No

e

reaction based on TLC analysis. Reaction conditions: 4a (0.5 mmol), MPI (0.5 mmol), and toluene (10 mL).

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the reaction mixture at diﬀerent reaction times shown in Figure

S1 indicates that the yield of monoindolylation product 3a

dramatically increased from 2% at 10 min to 81% at 50 min,

while the double transindolylation product 4a dominated the

reaction below 25 min and then decreased to 16% at 60 min.

The results in Figure S1 also showed the dramatic increase of

MPI (expulsion from 1a) to 95% at 25 min followed by a slight

decrease to 91% at 60 min. From the above experimental

results, these might be indicated that thermodynamics might

be driving the reaction.

in this procedure, upon heating the reaction, in some cases,

good yields of the unsymmetrical 2,3′-BIMs 5a−5c were

exclusively obtained without further nucleophilic substitution

adduct. It is worth noting that this methodology has potential

to produce pharmaceutically signiﬁcant marine 2,3′-bisindole

alkaloids under mild conditions and simple operation.

Next, the symmetrical BIM scope was investigated (Scheme

3). The present procedure was also shown to proceed well for

a b

,

Scheme 3. Symmetrical BIM Scope

To evaluate the scope of the present nucleophilic

substitution procedure, its generality was assessed by employ-

ing 1a with a variety of indoles 2 (Scheme 2). Overall, the

a b

,

Scheme 2. Indole Scope

a

Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), FeCl₃·6H₂O (5

b

c

mol %), and toluene (10 mL). Isolated yield. Toluene (10 mL) and

CH₃CN (3 mL) were used as solvents. 60 °C and 3 h. Toluene (5

mL) and CH₃CN (1.5 mL) at 80 °C and 24 h.

d

e

reaction conditions were found to be general. The reaction of

1a with indoles 2 containing a halogen moiety at the C-5 or C-

6 position furnished the desired products 3b−3f in high yields

(74−84%). The ability to tolerate halides shows that this

process is fully orthogonal to classical cross-couplings and can

enable further C−C, C−O, and C−N bond formations to

proceed. Other electron-withdrawing groups at the C-5

position of 2 such as 5-nitroindole and 1H-indole-5-carboxylic

acid gave 3g and 3h in 65 and 62% yields, respectively, and

only small amounts of 4h were observed. In the case of

electron-donating groups at the C-5 position of 2 aﬀorded 3i

and 3j in 69 and 68% yields, respectively, and the byproducts

4i and 4j were obtained in 23 and 26% yields, respectively.

When C-2-substituted indole was used, a modest yield of 3k

could still be obtained although bulky substituents might cause

steric hindrance for the nucleophilic attack. The reaction of 1a

was then demonstrated on a range of C-3-substituted indoles

2, owing to their lower nucleophilic potentials and increase

steric enhancement, and enabled the presence of methyl,

carboxymethyl, and N-acetylaminoethyl groups. Gratifyingly,

a

Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), FeCl₃·6H₂O (5

b

c

d

mol %), and toluene (10 mL). Isolated yield. rt and 3 h. 60 °C and

3 h. rt and 24 h. Reaction conditions: 1a (4.0 mmol), 2a (4.0

e

f

g

mmol), FeCl₃·6H₂O (5 mol %), and toluene (40 mL). Reaction

conditions: 3a (0.5 mmol), 5-methoxyindole (0.5 mmol), FeCl₃·

6H₂O (5 mol %), and toluene (10 mL).

symmetrical BIMs 1, which contained a variety of substituents

of diﬀerent electronic properties on the aryl group, with a

collection of indoles 2 giving 3l−3r in yields of 72−84%. An

electron-donating group such as hydroxyl was beneﬁcial to the

yields (3q and 3r), whereas the reaction mixture had to be

heated to 60 °C to obtain decent yields for the substrates with

strong electron-withdrawing groups on the phenyl ring (3p).

These phenomena might be rationalized by the fact that the

cationic alkylideneindoleninium intermediate can be destabi-

lized by electron-withdrawing substituents and stabilized by

electron-donating substituents on the phenyl ring.¹³Addition-

ally, a substrate with an alkyl moiety was also found to proceed

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a b

,

Scheme 4. Scope of Symmetrical BIMs and Diverse Nucleophiles

a

b

c

d

Reaction conditions: 1 (0.5 mmol), 7 (0.5 mmol), FeCl₃·6H₂O (5 mol %), and toluene (5 mL). Isolated yield. 60 °C and 24 h. Toluene (10

e

f

g

mL). 80 °C and 24 h. Allyltrimethylsilane (1 equiv) or trimethyl(2-methylallyl)silane (10 equiv) was used as NuH. Trimethyl(prop-yn-1-

yl)silane (10 equiv) was used as NuH.

well and to aﬀord 3s−3u in 80−84% yields. It is worth noting

that the tolerance of a phenol moiety under these reaction

conditions provides potential for further functional group

transfomations. Symmetrical BIMs without C-2 substitution

gave the adducts 3y−3ac in low to modest yields. These results

indicated that an expulsion of the N-methyl-2-phenylindole

(MPI) ring of 1a could preferably occur due to the decreased

steric repulsion between two bulky MPI rings and the fast

trapping of the resulting carbocation intermediate with indoles

2 could lead to the desired product 3. Notably, unsymmetrical

BIM 3ac bearing quaternary carbon, which has been reported

to exhibit cytotoxic activity against MCF-7 cells,^10awas also

smoothly synthesized via FeCl₃·6H₂O-catalyzed transindolyla-

tion of tert-butyl 4,4-bis(1-methyl-1H-indol-3-yl)piperidine-1-

carboxylate with indole (Scheme 3).

We next set out to explore the role of the nucleophile in the

reaction. Reactions involving FeCl₃·6H₂O-catalyzed indole

substitution of 1a with aromatic and nonaromatic π-systems

leading to a series of 3-alkylindole derivatives were studied.

These compounds have been widely applied in diverse areas of

chemistry such as medicinal chemistry, the dye industry, and

materials science (Scheme 4).^4,14Heteroaromatic compounds

such as 2-ethylfuran, 2-ethylthiophene, and ethyl 1H-pyrrole-2-

carboxylate were all well tolerated and could be conveniently

merged into indole skeletons, furnishing the desired products

8a, 8b, and 8d in good yields, respectively. Meanwhile,

nucleophilic substitution of 1a with electron-rich 2-ethyl-

pyrrole gave only the undesired product 9c, which involved a

double-indole substitution of 1a with two molecules of 2-

ethylpyrrole. It should be noted that unsymmetrical tris-

(indolyl)methane 8e as well as tris(heteroaryl)methanes 8f and

8g were synthesized smoothly under monoindole substitution

of 3,3′-BIMs 1x−1z, respectively. Subsequently, arenes were

also tested for this reaction. For instance, electron-rich 1,2,4-

trimethoxybenzene was reacted with 1a to provide the desired

product 8h in 65% yield after 1 h at room temperature.

However, for less nucleophilic ortho-methoxyaniline and

aniline, a higher temperature (80 °C) was required to obtain

decent yields of 8i and 8j, respectively. To further expand the

substrate scope of this protocol, allylsilanes and trimethyl-

(prop-2-yn-1-yl)silane were investigated and the desired

products 8k−8m were obtained in moderate to good yields.

The active methylene compound Meldrum’s acid was also

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checked for this reaction. Unfortunately, the reaction to give

8n was unsuccessful.

methoxyindole was studied (Scheme 6). As expected, the

treatment of 3a with 0.1 M 5-methoxyindole in the presence of

To probe the scalability of the nucleophilic substitution

reaction, a gram-scale reaction was performed between 1b (4

mmol) and 2a (4 mmol) under the optimized reaction

conditions in the presence of 5 mol % FeCl₃·6H₂O. The

reactions smoothly proceeded to provide the desired product

3ad in 85% yield (1.46 g). It is to be noted that in the reaction,

only 12% yield of 4ad was detected (Scheme 5).

Scheme 6. (A, B) Selective Transindolylation of 3a and

8a

a b

,

Scheme 5. Gram-Scale Synthesis of 3ad

The one-pot multicomponent reaction is one of the most

powerful tools in synthetic organic chemistry. The main

advantages of this process are step economy, operational

simplicity, and reduced waste. To our knowledge, there is no

report of acid-catalyzed multicomponent one-pot synthesis of

unsymmetrical BIMs.¹⁵Next, our strategy for the unsym-

metrical BIM synthesis via the one-pot sequential multi-

component reaction was examined and the results are shown in

Table 2. First, the experiment in step 1 was performed with a

very simple diindolylation reaction of 2 equiv of MPI and 1

equiv of 4-ﬂuorobenzaldehyde in the presence of 10 mol %

FeCl₃·6H₂O in CH₃CN at room temperature for 3 h to aﬀord

1b (monitored by TLC). Subsequently, the reaction mixture

was evaporated under vacuum and treated with a solution of

indole 2a in toluene for 1 h, leading to the desired products

3ad and 4ad in 87 and 12% isolated yields, respectively (Table

2, entry 1). Without changing the toluene as the solvent in step

2, the reaction also proceeded well with slightly decreased

product yield but with simpliﬁed mode of operation (entry 2).

Changing to toluene as the solvent in diindolylation step 1

could not be done due to the insolubility of MPI in toluene

(entry 3).

a

Reaction condition: 3a or 8a (0.5 mmol) and 5-methoxyindole (0.5

b

mmol) in toluene. Isolated yield.

FeCl₃·6H₂O (5 mol %) in toluene gave the selectively desired

product 3ae via the selective substitution of MPI. Increasing

the reaction concentration to 0.2 M in toluene led to decreased

both yield and selectivity of 3ae and gave 3j as a byproduct

(Scheme 6A). It should be noted that the reaction of 8a

bearing one indole ring and one furan ring (Scheme 6B) with

5-methoxyindole in the presence of FeCl₃·6H₂O (5 mol %) in

toluene at room temperature was unsuccessful as only the

starting materials were observed. Upon heating the reaction to

100 °C, the desired product 8o was obtained as a sole product

with 57% yield. These results indicated that high selectivity can

be achieved when employing an MPI unit as a leaving group in

3

2

a C_sp−C_spbond cleaving variant of the indole substitution of

3,3′-BIMs.

Considering the ability of the FeCl₃·6H₂O-catalyzed

nucleophilic substitution of BIMs with indoles (called

transindolylation), the mechanism of this transformation was

investigated. In order to aid with the interpretation of the

The eﬀect of two diﬀerent indole moieties (i.e., indole and

steric bulky indole, MPI) on the selective substitution with 5-

a b

,

Table 2. One-Pot Sequential Synthesis of 3ad

step 1

step 2

b

entry

solvent

time (h)

solvent

toluene

time (h)

3ad (%)

4ad (%)

1

2

3

CH₃CN

toluene

3

24

1

87

79

−

12

21

−

c

−

a

b

c

Reaction conditions: MPI (2.0 mmol), 4-ﬂuorobenzaldehyde (1.0 mmol), 2a (1.2 mmol), FeCl₃·6H₂O (10 mol %), and rt. Isolated yield. No

reaction based on TLC analysis.

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Scheme 7. (A−H) Mechanistic Studies

mechanism, a series of experiments were performed, as shown

in Scheme 7.

hetero-Michael addition reaction.^16aIn the current work, the

reaction was carried out in the presence of HCl, which could

be generated in situ under our standard conditions (Scheme

7D). Surprisingly, the reaction in the presence of 15 and 80

mol % HCl at room temperature for 1 h gave only traces of the

products 3a and 4a. Increasing the reaction time to 24 h in the

presence of 15 mol % HCl increased the yields of the products

3a and 4a to 22 and 7%, respectively. The reaction in the

presence of 80 mol % HCl for 4 h increased the yields of the

products 3a and 4a to 49 and 10%, respectively. Using strong

Initially, a deuterium incorporation experiment employing a

mixture of FeCl₃(0.05 mmol, 5 mol %) and D₂O (0.33 mmol)

instead of FeCl₃·6H₂O to catalyze the reaction was performed

(Scheme 7A,B). The D-incorporation at the C-3 position of

1

MPI (H/D = 76:24, detected by H NMR) suggested that

water plays a role in this transformation. The reaction of

commercially available FeCl₃with no attempt at drying of the

catalyst and without water as an additive gave lower yields of

3a and 4a (Scheme 7C). Wabnitz et al. demonstrated that

protons can be the active catalysts in Lewis acid-mediated

Bro̷nsted acid such as 5 mol % triﬂuoromethane sulfonic acid,

TfOH (Table S1, entry 8) gave the comparable yields of 3a

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Scheme 8. Plausible Reaction Mechanism

and 4a with the reaction employing FeCl₃·6H₂O (Table S1,

hydrolysis of the iron salt under the reaction conditions, gives

species A′.^16aMPI elimination of A′ proceeds to aﬀord the

indolylmethylium ion B′. A second molecule of indoles 2

thereafter reacts with B′ to produce the products 3 via

deprotonation of reactive species C′. Indeed, the reaction

employing catalytic amounts of HCl (Scheme 7D) proceeds to

aﬀord the desired product 3a but with only moderate yields

and a longer reaction time is required. It seems that although a

entry 1). These experimental results might be indicated that

the Bro̷nsted acid could replicate the reaction. For steric

reasons, the addition of di-t-butyl-4-methylpyridine is capable

of sequestering a proton but not a Lewis acid. This was also

tested (Scheme 7E).¹⁶In the presence of this additive at room

temperature for 24 h, the reaction did not proceed; however,

heating the reaction mixture up to 80 °C, the compounds 3a

and 4a were observed in 62 and 21% yields, respectively, after

24 h. The experiments shown in Scheme 7A−E indicate that

the reactions could be catalyzed by both a Lewis acid, FeCl₃·

hidden Bro̷nsted acid mechanism operates, there is a modest

synergistic eﬀect due to the iron salt.

6H₂O, and a Bro̷nsted acid, likely to have formed by hydrolysis

CONCLUSIONS

■

of the iron salt.¹⁶Furthermore, we found that unsymmetrical

BIM 3a and MPI were found in 90 and 4% yields, respectively,

in the reaction mixture of two symmetrical BIMs, 1a and 4a, in

the presence of 5 mol % FeCl₃·6H₂O. This strongly indicates

that the reaction proceeded via the indolylmethylium ion

intermediates generated in situ under the reaction conditions

(Scheme 7G).^12a,13Interestingly, the reaction of 2,2′-BIM 6d

did not proceed to aﬀord 5d even though the reaction was

performed under reﬂuxing at 110 °C in toluene for 24 h. This

suggests that the indol-2-yl group could not be eliminated

under these reaction conditions to provide the carbocation

intermediate III (Scheme 7H).^7b

In summary, we have successfully developed a novel, eﬃcient,

and expedient approach for the construction of unsymmetrical

BIMs and 3-alkylindole derivatives via the FeCl₃·6H₂O-

catalyzed nucleophilic substitution reaction of symmetrical

BIMs with a wide variety of nucleophiles including

heteroaromatic/aromatic compounds, allylsilane and alkynylsi-

lane, under “open-ﬂask”and mild reaction conditions at room

temperature. Additionally, the reactions also proceeded well

with bis(3-indolyl)alkanes bearing aliphatic substituents at the

central sp³-hybridized carbon atom, which are frequently found

in natural products. Notably, high selectivity and chemical

yield of the products were obtained when employing an N-

methyl-2-phenylindol-3-yl (MPI) unit as a leaving group in a

Based on our experimental observations and the information

in the relevant literature,^{8g−i,12−14}a plausible mechanism for

this transformation is that it may occur via two pathways

(Scheme 8). In the presence of Lewis acid iron(III) salt

(pathway I in Scheme 8), activation of 1 with an iron catalyst

by interacting with the ipso position of the C-3 indole ring

yields species A.^8g,i,17Electron-donating assistance from the

other indol-3-yl group combined with decreasing steric

interaction between two steric bulky MPIs of species A is an

important factor that enhances the formation of indolylme-

thylium ion B by elimination of 3-Fe-MPI species.^13aThe

nucleophilic addition of a second molecule of the indoles 2

then attacks the electrophilic center of B to give species C.

Deprotonation of C with 3-Fe-MPI species may lead to the

formation of unsymmetrical BIMs 3, which consequently

releases the MPI leaving group. The other pathway for the

formation of 3 (pathway II in Scheme 8) is proposed via the

3

2

C_sp−C_spbond cleaving variant of the nucleophilic substitution

of 3,3′-BIMs and the eliminated MPI, is an inexpensive,

nontoxic compound and can be recycled. The operational ease,

environmentally friendly catalyst, broad functional group

tolerance, and scalability of this reaction strategy make it

suitable for adoption in both academic and industrial settings.

The further development of the asymmetric reaction and

synthesis of bioactive indole alkaloid natural products is on-

going and will be reported in due course.

EXPERIMENTAL SECTION

■

General Procedure. All reagents were purchased from

commercial suppliers (Aldrich or TCI) and used without further

puriﬁcation. All solvents were puriﬁed and dried according to

standard methods prior to use. Thin-layer chromatography (TLC)

monitored all reactions with silica gel-coated plates. Radial

chromatography on a Chromatotron was performed using Merck

silica gel 60 PF₂₅₄with CaSO₄·1/2H₂O and was activated by heating

Bro

nation of 1 with hydrochloric acid, which is formed by

̷

nsted acid-catalyzed transindolylation reaction.^13a,16Proto-

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in an oven at 80 °C for 45 min. NMR spectra were recorded on a

Bruker AVANCE (400 MHz). ¹H NMR spectra were recorded at 400

MHz. Chemical shifts are reported in parts per million (ppm) from

tetramethylsilane with the solvent resonance as the internal standard

(deuterochloroform: δ 7.26 ppm; dimethyl sulfoxide-d₆: δ 3.35).

¹³C{¹H} NMR spectra were recorded at 100 MHz with complete

proton decoupling. Chemical shifts are reported in parts per million

(ppm) from tetramethylsilane with the solvent resonance as the

internal standard (deuterochloroform: δ 77.0 ppm; dimethyl

sulfoxide-d₆: δ 39.9). ¹⁹F NMR spectra were recorded with 376

MHz spectrometers. High-resolution mass spectrometry (HRMS)

data were obtained with a Finnigan MAT 95 and liquid chromato-

graph-quadrupole time-of-ﬂight mass spectrometer (LC-QTOF/MS),

1290 Inﬁnity II LC-65455 quadrupole-TOF, Agilent Technologies,

USA. Infrared spectra were determined on a PerkinElmer FT/IR-

2000S spectrophotometer and are reported in wavenumber (cm⁻¹).

Melting points were measured using a melting point apparatus

(Griﬃn) and are reported uncorrected. The heat source for our

reactions is an oil bath.

(ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂FN₂, 429.1762; found,

429.1760.

3-((6-Fluoro-1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-

1H-indole (3c). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3c (165.9 mg, 77% yield)

as an orange solid (mp: 98−100 °C) and 4c (18.0 mg, 20% yield) as a

red solid in which the spectral data of 4c were in agreement with

those previously reported in the literature.²³3c: ¹H NMR (400 MHz,

CDCl₃): δ 7.84 (s, 1H), 7.48−7.39 (m, 3H), 7.38−7.29 (m, 4H),

7.28−7.23 (m, 2H), 7.23−7.12 (m, 4H), 7.01−6.89 (m, 3H), 6.76 (s,

1H), 6.68 (td, J = 9.2, 2.0 Hz, 1H), 5.70 (s, 1H), 3.62 (s, 3H);

1

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 159.9 (C−F, J_C−F= 235.0

Hz), 144.3, 138.2, 137.6, 136.4 (C−F, ³J_C−F= 12.0 Hz), 131.9, 130.7,

4

128.7, 128.4, 128.2, 128.0, 127.1, 125.8, 124.1 (C−F, J_C−F= 3 Hz),

3

124.0, 121.4, 121.0, 120.5 (C−F, J_C−F= 12.0 Hz), 119.7, 119.1,

115.2, 109.3, 107.8 (C−F, ²J_C−F= 24.0 Hz), 97.2 (C−F, ²J_C−F= 27.0

Hz), 39.9, 31.0; ¹⁹F NMR (376 MHz, CDCl₃): δ −121.6 to −121.8

(m); IR-ATR: 3409, 3056, 1625, 1493, 1465, 1360, 1339, 1137, 1087,

742 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂FN₂,

429.1762; found, 429.1762.

General Procedure for Synthesis of Unsymmetrical BIMs 3

and 5. A toluene solution (10 mL) of BIMs 1 (0.5 mmol, 1 equiv),

indole derivatives 2 (0.5 mmol, 1 equiv), and FeCl₃·6H₂O (0.025

mmol, 5 mol %) in a round-bottom ﬂask open to air was stirred at

appropriate temperature. After the reaction was stirred until

completion (TLC analysis), the reaction mixture was quenched

with aqueous NaHCO₃(10 mL) and extracted with EtOAc (2 × 10

mL). The combined organic layer was washed with brine (10 mL),

dried over anhydrous Na₂SO₄, and ﬁltered. The solvent was removed

under reduced pressure (aspirator then in vacuo) to give a crude

product, which was puriﬁed by radial chromatography (SiO₂, 100%

hexane to 70% EtOAc/hexane as the eluent) to give the racemic

mixture of corresponding unsymmetrical BIMs 3 or 5 and/or 4 or 6 as

a .

3-((5-Chloro-1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-

1H-indole (3d). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3d (174.8 mg, 78% yield)

as a red solid (mp: 108−110 °C) and byproduct 4d (19.6 mg, 20%

yield) as a red solid in which the spectral data of 4d were in

agreement with those previously reported in the literature.²³3d: H

1

NMR (400 MHz, CDCl₃): δ 7.93 (s, 1H), 7.51−7.40 (m, 3H), 7.40−

7.31 (m, 4H), 7.28−7.15 (m, 7H), 7.10−7.02 (m, 2H), 6.94 (t, J =

7.6 Hz, 1H), 6.84 (s, 1H), 5.70 (s, 1H), 3.63 (s, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 144.0, 138.3, 137.6, 134.8, 131.8, 130.7, 128.7,

128.5, 128.3, 128.1, 127.8, 127.0, 125.9, 125.1, 124.8, 122.1, 121.4,

121.0, 119.4, 119.2, 119.1, 115.0, 111.9, 109.4, 39.6, 30.9; IR-ATR:

3420, 3056, 1601, 1463, 1443, 1360, 1201, 1095, 1025, 740 cm⁻¹;

HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂ClN₂, 445.1466;

found, 445.1472.

Spectral data of compounds 4a,¹⁸4b,²²4c−4e,²³4f,²⁴4h,²⁵4i,²⁶

4j,²⁷4k,²⁶4m,²⁸4n,²⁹4p,³⁰4q,²⁸4s,³¹3v,¹⁵3y,¹⁵4ad,¹⁹3ac,^10a9c,²⁰

and 9h²¹were in agreement with those in the literature.

3-((1H-Indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-1H-indole

(3a). Following the general procedure, the products were puriﬁed by

radial chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 3a (165.2 mg, 80% yield) as an orange

solid (mp: 98−100 °C) and byproduct 4a (16.5 mg, 20% yield) as a

red solid in which the spectral data of 4a were in agreement with

those previously reported in the literature.¹⁸3a: ¹H NMR (400 MHz,

CDCl₃): δ 7.90 (s, 1H), 7.45−7.39 (m, 3H), 7.38−7.31 (m, 5H), 7.24

(brs, 1H), 7.21−7.09 (m, 7H), 6.95−6.89 (m, 2H), 6.83 (dd, J = 2.3,

1.0 Hz, 1H), 5.74 (s, 1H), 3.62 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 144.6, 138.3, 137.8, 136.6, 132.1, 130.8, 128.9, 128.4,

128.3, 128.0, 127.6, 127.4, 125.8, 124.0, 121.8, 121.5, 121.3, 120.0,

119.5, 119.2, 115.7, 111.0, 109.4, 40.0, 30.9; IR-ATR: 3410, 3054,

2923, 1601, 1456, 1418, 1360, 1335, 1092, 1012, 738, 714, 698 cm⁻¹;

HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₃N₂, 411.1856;

found, 411.1863.

3-((5-Bromo-1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-

1H-indole (3e). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3e (204.1 mg, 83% yield)

as a red solid (mp: 104−106 °C) and byproduct 4e (19.2 mg, 16%

yield) as a red solid in which the spectral data of 4e were in agreement

with those previously reported in the literature.²³3e: H NMR (400

1

MHz, CDCl₃): δ 7.91 (s, 1H), 7.48−7.42 (m, 3H), 7.37−7.31 (m,

4H), 7.28−7.23 (m, 3H), 7.22−7.14 (m, 6H), 6.94 (t, J = 7.9 Hz,

1H), 6.83 (dd, J = 2.3, 0.9 Hz, 1H), 5.69 (s, 1H), 3.63 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 143.9, 138.3, 137.6, 135.0,

131.8, 130.7, 129.2, 128.6, 128.5, 128.4, 128.1, 127.0, 125.9, 124.9,

124.7, 122.3, 121.4, 121.0, 119.4, 119.1, 114.9, 112.5, 112.4, 109.4,

39.5, 31.0; IR-ATR: 3410, 3025, 1601, 1463, 1360, 1337, 1092, 1015,

741 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂BrN₂,

489.0961; found, 489.0970.

3-((6-Bromo-1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-

1H-indole (3f). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3f (206.8 mg, 84% yield) as

a red solid (mp: 102−104 °C) and byproduct 4f (16.9 mg, 14% yield)

as a red solid in which the spectral data of 4f were in agreement with

those previously reported in the literature.²⁴3f: ¹H NMR (400 MHz,

CDCl₃): δ 7.86 (brs, 1H), 7.47−7.39 (m, 4H), 7.36−7.28 (m, 4H),

7.26−7.14 (m, 6H), 7.02 (d, J = 8.5 Hz, 1H), 6.97−6.90 (m, 2H),

6.77 (s, 1H), 5.69 (s, 1H), 3.63 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 144.1, 138.2, 137.6, 137.3, 131.8, 130.7, 128.7, 128.4,

128.3, 128.1, 127.0, 126.3, 125.9, 124.4, 122.5, 121.5, 121.1, 121.0,

119.8, 119.2, 115.4, 115.1, 113.8, 109.4, 39.7, 31.0; IR-ATR: 3404,

3056, 1603, 1466, 1450, 1359, 1332, 1093, 740 cm⁻¹; HRMS (ESI-

TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂BrN₂, 489.0961; found,

489.0966.

3-((5-Fluoro-1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-

1H-indole (3b). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3b (159.4 mg, 74% yield)

as a pink solid (mp: 184−186 °C) and byproduct 4b (21.6 mg, 21%

yield) as a red solid in which the spectral data of 4b were in

agreement with those previously reported in the literature.²²3b: H

1

NMR (400 MHz, CDCl₃): δ 7.77 (s, 1H), 7.52−7.44 (m, 3H), 7.44−

7.36 (m, 4H), 7.36−7.30 (m, 2H), 7.29−7.15 (m, 5H), 6.98 (t, J =

7.5 Hz, 1H), 6.90 (td, J = 9.1, 2.2 Hz, 1H), 6.83 (s, 1H), 6.81 (dd, J =

9.9, 1.7 Hz, 1H), 5.73 (s, 1H), 3.66 (s, 3H); ¹³C{¹H} NMR (100

MHz, CDCl₃): δ 157.5 (C−F, ¹J_C−F= 233.0 Hz), 144.2, 138.3, 137.6,

3

133.0, 131.9, 130.7, 128.7, 128.5, 128.4, 128.1, 127.8 (C−F, J_C−F

=

4

10.0 Hz), 127.1, 125.9, 125.6, 121.5, 121.1, 119.8 (C−F, J_C−F= 5.0

Hz), 119.2, 115.1, 111.5 (C−F, ³J_C−F= 9.0 Hz), 110.1 (C−F, ²J_C−F

=

26.0 Hz), 109.5, 104.7 (C−F, ²J_C−F= 23.0 Hz), 39.9, 31.0; ¹⁹F NMR

(376 MHz, CDCl₃): δ −124.8 to −125.0 (m); IR-ATR: 3383, 3025,

1577, 1483, 1467, 1362, 1158, 1024, 747, 710, 699 cm⁻¹; HRMS

2319

https://dx.doi.org/10.1021/acs.joc.0c02466

J. Org. Chem. 2021, 86, 2312−2327

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

1

1-Methyl-3-((5-nitro-1H-indol-3-yl)(phenyl)methyl)-2-phenyl-

1H-indole (3g). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3g (149.0 mg, 65% yield)

as a yellow solid (mp: 232−234 °C); ¹H NMR (400 MHz, CDCl₃): δ

8.34 (s, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 8.9, 2.1 Hz, 1H),

7.53−7.46 (m, 3H), 7.45−7.31 (m, 6H), 7.30−7.17 (m, 5H), 6.97−

6.90 (m, 2H), 5.77 (s, 1H), 3.65 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 143.5, 141.4, 139.5, 138.7, 137.6, 131.6, 130.7, 128.64,

128.62, 128.57, 128.3, 126.91, 126.8, 126.32, 126.25, 122.8, 121.5,

120.8, 119.2, 117.6, 117.1, 114.1, 110.9, 109.6, 39.8, 31.0; IR-ATR:

3391, 3053, 1602, 1516, 1467, 1421, 1326, 1243, 1088, 1016, 736

cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂N₃O₂,

456.1707; found, 456.1721.

3-((1-Methyl-2-phenyl-1H-indol-3-yl)(phenyl)methyl)-1H-indole-

5-carboxylic Acid (3h). Following the general procedure, the

products were puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 3h (141.6

mg, 62% yield) as a pink solid (mp: 264−266 °C) and byproduct 4h

(5.2 mg, 5% yield) as a red solid in which the spectral data of 4h were

in agreement with those previously reported in the literature.²⁵3h: ¹H

NMR (400 MHz, DMSO-d₆): δ 12.28 (brs, 1H), 11.20 (s, 1H),

7.70−7.62 (m, 2H), 7.57−7.35 (m, 7H), 7.30−7.07 (m, 7H), 6.92−

6.82 (m, 2H), 5.63 (s, 1H), 3.60 (s, 3H); ¹³C{¹H} NMR (100 MHz,

DMSO-d₆): δ 168.7, 144.4, 139.5, 138.1, 137.6, 131.7, 130.8, 129.1,

129.0, 128.60, 128.57, 126.8, 126.4, 126.0, 122.8, 121.9, 121.7, 121.3,

120.7, 119.4, 119.2, 114.8, 111.8, 110.5, 39.8, 31.2; IR-ATR: 3463,

3027, 2923, 1664, 1615, 1468, 1424, 1307, 1282, 1243, 1092, 821

cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₁H₂₃N₂O₂,

455.1754; found, 455.1768.

agreement with those previously reported in the literature.²⁶3k: H

NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 7.52−7.40 (m, 4H),

7.33−7.13 (m, 8H), 7.08 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H),

6.86 (t, J = 6.9 Hz, 1H), 6.78 (t, J = 7.7 Hz, 1H), 6.67−6.55 (m, 2H),

5.67 (s, 1H), 3.58 (s, 3H), 1.74 (s, 3H); ¹³C{¹H} NMR (100 MHz,

DMSO-d₆): δ 144.9, 138.5, 137.5, 135.5, 132.6, 132.0, 130.7, 129.0,

128.9, 128.8, 128.51, 128.45, 127.3, 126.4, 121.5, 120.7, 119.9, 119.2,

119.1, 118.3, 114.8, 112.9, 110.8, 110.4, 39.9, 31.2, 12.2; IR-ATR:

3393, 3056, 2909, 1598, 1461, 1445, 1358, 1338, 1055, 745 cm⁻¹;

HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₁H₂₅N₂, 425.2012;

found, 425.2008.

3-((5-Fluoro-1H-indol-3-yl)(4-ﬂuorophenyl)methyl)-1-methyl-2-

phenyl-1H-indole (3l). Following the general procedure, the products

were puriﬁed by radial chromatography using a gradient of 0−70%

EtOAc in hexanes, furnishing the desired product 3l (188.8 mg, 84%

yield) as a red solid (mp: 198−200 °C) and byproduct 4l (14.1 mg,

1

15% yield) as a red solid (mp: 94−96 °C). 3l: H NMR (400 MHz,

CDCl₃): δ 7.93 (s, 1H), 7.46−7.40 (m, 3H), 7.37−7.28 (m, 3H),

7.28−7.25 (m, 1H), 7.25−7.15 (m, 4H), 6.96−6.83 (m, 5H), 6.70

(dd, J = 9.8, 2.3 Hz, 1H), 5.62 (s, 1H), 3.63 (s, 3H); ¹³C{¹H} NMR

1

(100 MHz, CDCl₃): δ 161.2 (C−F, J_C−F= 243.0 Hz), 157.5 (C−F,

¹J_C−F= 233.0 Hz), 139.7 (C−F, ⁴J_C−F= 3.0 Hz), 138.2, 137.5, 133.0,

131.7, 130.6, 130.0 (C−F, ³J_C−F= 8.0 Hz), 128.4, 128.3, 127.6 (C−F,

³J_C−F= 10.0 Hz), 126.9, 125.5, 121.5, 120.8, 119.7 (C−F, ⁴J_C−F= 3.0

Hz), 119.2, 114.8, 114.76, 114.74 (C−F, ²J_C−F= 20.0 Hz), 111.5 (C−

F, ³J_C−F= 10.0 Hz), 110.3 (C−F, ²J_C−F= 26.0 Hz), 109.4, 104.7 (C−

2

F, J_C−F= 24.0 Hz) 39.1, 30.9; ¹⁹F NMR (376 MHz, CDCl₃): δ

−117.7 to −117.9 (m), −124.6 to −124.7 (m); IR-ATR: 3386, 2935,

1542, 1503, 1468, 1457, 1219, 1094, 936 cm⁻¹; HRMS (ESI-TOF)

m/z: [M − H]⁺calcd for C₃₀H₂₁F₂N₂, 447.1667; found, 447.1671.

1

3-((1-Methyl-2-phenyl-1H-indol-3-yl)(phenyl)methyl)-1H-indol-

5-ol (3i). Following the general procedure, the products were puriﬁed

by radial chromatography using a gradient of 0−70% EtOAc in

hexanes, furnishing the desired product 3i (148.3 mg, 69% yield) as a

brown solid (mp: 122−124 °C) and byproduct 4i (20.4 mg, 23%

yield) as a red solid in which the spectral data of 4i were in agreement

3,3′-((4-Fluorophenyl)methylene)bis(5-ﬂuoro-1H-indole) (4l). H

NMR (400 MHz, CDCl₃): δ 8.00 (s, 2H), 7.33−7.25 (m, 4H), 7.04−

6.90 (m, 6H), 6.72 (brd, J = 2.2 Hz, 2H), 5.75 (s, 1H); ¹³C{¹H}

1

NMR (100 MHz, CDCl₃): δ 161.5 (C−F, J_C−F= 243.0 Hz), 157.6

(C−F, ¹J_C−F= 233.0 Hz), 138.9 (C−F, ⁴J_C−F= 3.0 Hz), 133.2, 130.0

3

(C−F, J_C−F= 8.0 Hz), 127.2 (C−F, J_C−F= 9.0 Hz), 125.2, 119.3

with those previously reported in the literature.²⁶3i: H NMR (400

1

4

2

(C−F, J_C−F= 5.0 Hz), 115.2 (C−F, J_C−F= 21.0 Hz), 111.8 (C−F,

³J_C−F= 9.0 Hz), 110.5 (C−F, ²J_C−F= 27.0 Hz), 104.7 (C−F, ²J_C−F

=

MHz, DMSO-d₆): δ 10.51 (s, 1H), 8.45 (s, 1H), 7.57−7.36 (m, 6H),

7.27−7.18 (m, 3H), 7.18−7.07 (m, 5H), 6.84 (t, J = 7.5 Hz, 1H),

6.63 (s, 1H), 6.54 (dd, J = 8.6, 1.9 Hz, 1H), 6.26 (brd, J = 1.9 Hz,

1H), 5.47 (s, 1H), 3.60 (s, 3H); ¹³C{¹H} NMR (100 MHz, DMSO-

d₆): δ 150.4, 144.9, 137.9, 137.5, 131.8, 131.5, 130.9, 129.0, 128.8,

128.6, 128.4, 127.8, 126.9, 126.1, 124.9, 121.5, 120.9, 119.2, 116.6,

115.3, 112.3, 111.8, 110.4, 103.4, 40.2, 31.2; IR-ATR: 3420, 3024,

2935, 1623, 1464, 1456, 1358, 1176, 1092, 1025, 743 cm⁻¹; HRMS

(ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₃N₂O, 427.1805; found,

427.1816.

23.0 Hz), 39.5; ¹⁹F NMR (376 MHz, CDCl₃): δ −116.8 to −116.9

(m), −124.3 to −124.4 (m); IR-ATR: 3424, 1581, 1505, 1482, 1451,

1213, 1092, 798 cm⁻¹; HRMS* (ESI-TOF) m/z: [M − H]⁻calcd for

C₂₃H₁₄F₃N₂, 375.1115; found, 375.1115.

3-((5-Bromo-1H-indol-3-yl)(4-ﬂuorophenyl)methyl)-1-methyl-2-

phenyl-1H-indole (3m). Following the general procedure, the

products were puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 3m (206.8

mg, 81% yield) as a red solid (mp: 105−107 °C) and byproduct 4m

(22.4 mg, 18% yield) as a red solid in which the spectral data of 4m

were in agreement with those previously reported in the literature.²⁸

3-((5-Methoxy-1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phe-

nyl-1H-indole (3j). Following the general procedure, the products

were puriﬁed by radial chromatography using a gradient of 0−70%

EtOAc in hexanes, furnishing the desired product 3j (150.9 mg, 68%

yield) as an orange solid (mp: 104−106 °C) and byproduct 4j (23.0

mg, 26% yield) as a red solid in which the spectral data of 4j were in

1

3m: H NMR (400 MHz, CDCl₃): δ 7.92 (s, 1H), 7.48−7.43 (m,

3H), 7.37−7.29 (m, 4H), 7.24−7.14 (m, 6H), 6.96 (t, J = 7.5 Hz,

1H), 6.92−6.86 (m, 2H), 6.83 (brd, J = 1.3 Hz, 1H), 5.66 (s, 1H),

3.63 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.2 (C−F,

agreement with those previously reported in the literature.²⁷3j: H

1

4

¹J_C−F= 242.0 Hz) 139.6 (C−F, J_C−F= 3.0 Hz), 138.3, 137.6, 135.1,

131.7, 130.6, 130.0 (C−F, ³J_C−F= 8.0 Hz), 129.0, 128.5, 128.4, 126.8,

124.9, 124.8, 122.2, 121.5, 120.8, 119.23, 119.20, 114.78 (C−F, ²J_C−F

= 21 Hz), 114.76, 112.6, 112.4, 109.5, 38.8, 31.0; ¹⁹F NMR (376

MHz, CDCl₃): δ −117.7 to −117.8 (m); IR-ATR: 3421, 3031, 2935,

1601, 1503, 1457, 1358, 1217, 1094, 1014, 740 cm⁻¹; HRMS (ESI-

TOF) m/z: [M − H]⁺calcd for C₃₀H₂₁BrFN₂, 507.0867; found,

507.0880.

NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 7.60−7.50 (m, 3H),

7.50−7.39 (m, 3H), 7.32−7.16 (m, 7H), 7.12 (t, J = 7.4 Hz, 1H),

6.87 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J = 8.5 Hz, 1H), 6.28

(s, 1H), 5.57 (s, 1H), 3.64 (s, 3H), 3.51 (s, 3H); ¹³C{¹H} NMR (100

MHz, DMSO-d₆): δ 153.1, 144.8, 138.0, 137.7, 132.0, 131.8, 130.8,

129.1, 128.9, 128.7, 128.5, 127.5, 126.9, 126.2, 124.9, 121.6, 121.0,

119.2, 117.5, 115.1, 112.6, 111.3, 110.4, 100.9, 55.5, 39.9, 31.3; IR-

ATR: 3411, 3017, 2963, 1582, 1482, 1465, 1360, 1210, 1171, 1049,

1027, 742 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for

C₃₁H₂₅N₂O, 441.1961; found, 441.1965.

1-Methyl-3-((2-methyl-1H-indol-3-yl)(phenyl)methyl)-2-phenyl-

1H-indole (3k). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3k (143.3 mg, 67% yield)

as a pink solid (mp: 242−244 °C) and byproduct 4k (16.6 mg, 19%

yield) as a pink solid in which the spectral data of 4j were in

3-((4-Fluorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)methyl)-

1H-indol-5-ol (3n). Following the general procedure, the products

were puriﬁed by radial chromatography using a gradient of 0−70%

EtOAc in hexanes, furnishing the desired product 3n (183.5 mg, 82%

yield) as a brown solid (mp: 124−126 °C) and byproduct 4n (10.2

mg, 11% yield) as a red solid in which the spectral data of 4n were in

agreement with those previously reported in the literature.²⁹3n: H

1

NMR (400 MHz, CDCl₃): 7.81 (s, 1H), 7.46−7.36 (m, 3H,), 7.35−

7.28 (m, 4H), 7.22−7.12 (m, 4H), 6.93 (t, J = 7.5 Hz, 1H), 6.85 (t, J

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= 8.7 Hz, 2H), 6.79 (brd, J = 1.2 Hz, 1H), 6.71 (dd, J = 8.6, 2.4 Hz,

1H), 6.45 (brd, J = 2.3 Hz, 1H), 5.61 (s, 1H), 4.37 (brs, 1H), 3.61 (s,

(100 MHz, DMSO-d₆): δ 155.6, 150.3, 137.61, 137.56, 135.2, 131.9,

131.6, 130.9, 129.5, 129.0, 128.7, 127.9, 127.0, 124.8, 121.5, 121.0,

119.1, 117.3, 115.9, 115.2, 112.2, 111.7, 110.3, 103.5, 39.4, 31.2; IR-

ATR: 3539, 3482, 3055, 2938, 1612, 1508, 1466, 1431, 1357, 1165,

1025, 793 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for

C₃₀H₂₃N₂O₂, 443.1754; found, 443.1759.

1

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.1 (C−F, J_C−F

=

4

242.0 Hz), 149.0, 139.9 (C−F, J_C−F= 3.0 H), 138.1, 137.5, 131.8,

130.7, 130.1 (C−F, ³J_C−F= 8.0 Hz), 128.4, 128.2, 127.9, 126.9, 125.1,

2

121.5, 120.9, 119.1, 118.6, 115.2, 114.6 (C−F, J_C−F= 21.0 Hz),

111.60, 111.59, 109.4, 104.4, 39.1, 30.9; ¹⁹F NMR (376 MHz,

CDCl₃): δ −118.0 to −118.1 (m); IR-ATR: 3420, 3032, 2940, 1602,

1503, 1465, 1358, 1217, 1155, 1093, 1014, 791 cm⁻¹; HRMS (ESI-

TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂FN₂O, 445.1711; found,

445.1715.

3-((5-Bromo-1H-indol-3-yl)(cyclohexyl)methyl)-1-methyl-2-phe-

nyl-1H-indole (3s). Following the general procedure, the products

were puriﬁed by radial chromatography using a gradient of 0−70%

EtOAc in hexanes, furnishing the desired product 3s (204.2 mg, 82%

yield) as a green solid (mp: 196−200 °C) and byproduct 4s (15.8 mg,

13% yield) as a red solid in which the spectral data of 4s were in

3-((4-Fluorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)methyl)-5-

methoxy-1-methyl-1H-indole (3o). Following the general procedure,

the product was puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 3o (183.1

agreement with those previously reported in the literature.³¹3s: H

1

NMR (400 MHz, CDCl₃): δ 7.95 (d, J = 7.8 Hz, 1H,), 7.65−7.39 (m,

4H), 7.39−7.21 (m, 5H), 7.06 (dd, J = 8.5, 1.8 Hz, 1H), 6.97 (s, 1H),

6.76 (s, 1H), 6.55 (d, J = 7.8 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.44

(s, 3H), 2.47−2.33 (m, 1H), 1.82−1.72 (m, 1H), 1.72−1.58 (m, 4H),

1.34−1.08 (m, 3H), 0.99−0.74 (m, 2H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 138.4, 137.6, 133.8, 131.9, 129.3, 128.6, 126.1, 124.2,

121.8, 121.5, 121.4, 120.7, 119.8, 119.1, 115.9, 112.2, 112.1, 109.7,

42.4, 40.0, 32.8, 32.7, 30.7, 26.8, 26.7, 26.6; IR-ATR: 3368, 2919,

2846, 1457, 1359, 1318, 1209, 1098, 794, 739 cm⁻¹; HRMS (ESI-

TOF) m/z: [M + Na]⁺calcd for C₃₀H₂₉BrN₂Na, 519.1406; found,

519.1420.

1

mg, 77% yield) as a pink solid (mp: 100−102 °C); H NMR (400

MHz, CDCl₃): 7.46−7.37 (m, 3H), 7.37−7.27 (m, 4H), 7.22−7.12

(m, 4H), 6.95 (t, J = 7.6 Hz, 1H), 6.89−6.79 (m, 3H), 6.67 (s, 1H),

6.50 (brd, J = 2.3 Hz, 1H), 5.65 (s, 1H), 3.65 (s, 3H), 3.63 (s, 6H);

1

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.1 (C−F, J_C−F= 241.0

4

Hz), 153.4, 140.1 (C−F, J_C−F= 3.0 Hz), 138.1, 137.6, 132.6, 131.9,

130.7, 130.1 (C−F, ³J_C−F= 8.0 Hz), 129.1, 128.4, 128.2, 127.9, 126.9,

2

121.5, 121.1, 119.1, 117.1, 115.5, 114.6 (C−F, J_C−F= 21.0 Hz),

111.5, 109.8, 109.4, 101.7, 55.8, 38.9, 32.9, 31.0; ¹⁹F NMR (376 MHz,

CDCl₃): δ −118.2 to −118.3 (m); IR-ATR: 3053, 2938, 1602, 1503,

1466, 1418, 1359, 1216, 1155, 1015, 817 cm⁻¹; HRMS (ESI-TOF)

m/z: [M − H]⁺calcd for C₃₂H₂₆FN₂O, 473.2024; found, 473.2031.

3-((5-Bromo-1H-indol-3-yl)(4-nitrophenyl)methyl)-1-methyl-2-

phenyl-1H-indole (3p). Following the general procedure, the

products were puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 3p (193.8

mg, 72% yield) as an orange solid (mp: 110−112 °C) and byproduct

4p (26.3 mg, 20% yield) as an orange solid in which the spectral data

of 4p were in agreement with those previously reported in the

3-(1-(5-Bromo-1H-indol-3-yl)-2-ethylbutyl)-1-methyl-2-phenyl-

1H-indole (3t). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3t (203.9 mg, 84% yield) as

a brown solid (mp: 230−232 °C) and byproduct 4t (18.6 mg, 10%

1

yield) as a brown oil (mp: 230−232 °C). 3t: H NMR (400 MHz,

CDCl₃): δ 7.98 (d, J = 7.9 Hz, 1H), 7.80 (brs, 1H), 7.59−7.48 (m,

3H), 7.32 (d, J = 7.9 Hz, 1H), 7.29−7.07 (m, 7H), 7.07−6.98 (m,

1H), 4.09 (d, J = 11.5 Hz, 1H), 3.49 (s, 3H), 2.63−2.49 (m, 1H),

1.55−1.46 (m, 1H), 1.46−1.35 (m, 1H), 1.33−1.23 (m, 2H), 0.76−

0.65 (m, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 138.2, 137.5,

134.0, 132.0, 130.6, 129.5, 128.5, 126.4, 124.3, 122.2, 121.8, 121.3,

120.8, 120.6, 119.0, 116.2, 112.2, 109.6, 44.2, 36.4, 30.7, 22.8, 22.4,

10.18, 10.15; IR-ATR: 3364, 3048, 2960, 2932, 2871, 1607, 1457,

1366, 1101, 1056, 794 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺

calcd for C₂₉H₂₉BrN₂Na, 507.1406; found, 507.1410.

literature.³⁰3p: H NMR (400 MHz, DMSO-d₆): δ 11.16 (s, 1H),

1

8.12 (d, J = 8.4 Hz, 2H), 7.58−7.45 (m, 4H), 7.44−7.30 (m, 5H),

7.20 (d, J = 8.4 Hz, 1H), 7.17−7.11 (m, 2H), 7.00 (brd, J = 1.8 Hz,

1H), 6.93−6.86 (m, 2H), 5.72 (s, 1H), 3.61 (s, 3H); ¹³C{¹H} NMR

(100 MHz, DMSO-d₆): δ 152.4, 146.3, 138.6, 137.6, 135.6, 131.4,

130.8, 129.9, 129.2, 129.1, 128.7, 126.4, 126.3, 124.2, 123.8, 121.9,

121.0, 120.3, 119.7, 116.3, 114.2, 113.4, 111.6, 110.7, 39.7, 31.3; IR-

ATR: 3404, 3056, 2923, 1594, 1513, 1463, 1341, 1096, 1014, 740

cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₁BrN₃O₂,

534.0812; found, 534.0810.

3,3′-(2-Ethylbutane-1,1-diyl)bis(5-bromo-1H-indole) (4t). ¹H

NMR (400 MHz, CDCl₃): δ 7.98 (s, 2H), 7.72 (brd, J = 1.5 Hz,

2H), 7.24−7.15 (m, 4H), 7.09 (brd, J = 2.3 Hz, 2H), 4.39 (d, J = 8.6

Hz, 1H), 2.26−2.16 (m, 1H), 1.56−1.46 (m, 2H), 1.41−1.28 (m,

2H), 0.88 (t, J = 7.4 Hz, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

134.9, 129.2, 124.6, 123.0, 122.0, 118.7, 112.6, 112.4, 44.5, 36.4, 23.3,

11.2; IR-ATR: 3421, 1615, 1457, 1417, 1226, 1101, 1096, 793 cm⁻¹;

HRMS* (ESI-TOF) m/z: [M − H]⁻calcd for C₂₂H₂₁Br₂N₂,

471.0077; found, 471.0077.

4-((5-Bromo-1H-indol-3-yl)(1-methyl-2-phenyl-1H-indol-3-yl)-

methyl)phenol (3q). Following the general procedure, the products

were puriﬁed by radial chromatography using a gradient of 0−70%

EtOAc in hexanes, furnishing the desired product 3q (181.0 mg, 71%

yield) as a red solid (mp: 122−124 °C) and byproduct 4q (32.2 mg,

26% yield) as a red solid in which the spectral data of 4q were in

3-(2-Ethyl-1-(1-methyl-2-phenyl-1H-indol-3-yl)butyl)-1H-indol-

5-ol (3u). Following the general procedure, the product was puriﬁed

by radial chromatography using a gradient of 0−70% EtOAc in

hexanes, furnishing the desired product 3u (168.9 mg, 80% yield) as a

agreement with those previously reported in the literature.²⁸3q: H

1

NMR (400 MHz, CDCl₃): δ 7.92 (s, 1H), 7.49−7.38 (m, 3H), 7.36−

7.28 (m, 4H), 7.22−7.14 (m, 4H), 7.12−7.06 (m, 2H), 6.92 (td, J =

7.5, 0.7 Hz, 1H), 6.84 (brd, J = 1.4 Hz, 1H), 6.70−6.64 (m, 2H), 5.60

(s, 1H), 4.55 (s, 1H), 3.62 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 153.7, 138.2, 137.6, 136.2, 135.1, 131.8, 130.7, 129.7,

129.1, 128.4, 128.3, 126.9, 124.8, 124.6, 122.3, 121.4, 121.0, 119.7,

119.0, 115.1, 114.9, 112.40, 112.37, 109.4, 38.7, 30.9; IR-ATR: 3403,

3053, 2920, 1608, 1508, 1457, 1359, 1217, 1168, 1092, 741 cm⁻¹;

HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂BrN₂O,

505.0910; found, 505.0918.

1

gray solid (mp: 108−110 °C); H NMR (400 MHz, CDCl₃): δ 8.0

(d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.54−7.35 (m, 4H), 7.31 (d, J = 8.2

Hz, 1H), 7.28−7.20 (m, 2H), 7.20−7.11 (m, 2H), 7.10−7.04 (m,

1H), 6.66 (d, J = 8.2 Hz, 1H), 6.35 (brd, J = 2.1 Hz, 1H), 4.29 (brs,

1H), 4.14 (d, J = 11.4 Hz, 1H), 3.50 (s, 3H), 2.57−2.46 (m, 1H),

1.58−1.49 (m, 1H), 1.47−1.37 (m, 1H), 1.35−1.24 (m, 2H), 0.75−

0.64 (m, 6H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 148.8, 138.0,

137.6, 132.5, 130.9, 129.4, 128.5, 128.2, 128.1, 126.7, 122.3, 121.2,

120.8, 120.4, 118.9, 116.3, 111.3, 111.1, 109.5, 103.9, 44.4, 36.4, 30.8,

22.8, 22.4, 10.3, 10.1; IR-ATR: 3393, 2958, 2935, 2870, 1542, 1457,

1359, 1208, 1175, 1019, 743 cm⁻¹; HRMS (ESI-TOF) m/z: [M +

Na]⁺calcd for C₂₉H₃₀N₂NaO, 445.2250; found, 445.2253.

3-((4-Hydroxyphenyl)(1-methyl-2-phenyl-1H-indol-3-yl)methyl)-

1H-indol-5-ol (3r). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3r (187.1 mg, 84% yield) as

1

a red solid (mp: 214−216 °C); H NMR (400 MHz, DMSO-d₆): δ

3-((1H-Indol-3-yl)(phenyl)methyl)-1,2-dimethyl-1H-indole (3v).

Following the general procedure, the products were puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 3v (98.5 mg, 56% yield) as a pink solid

and byproduct 4a (14.6 mg, 18% yield) as a red solid. The spectral

10.44 (s, 1H), 9.12 (s, 1H), 8.41 (s, 1H), 7.56−7.36 (m, 6H), 7.22 (d,

J = 7.6 Hz, 1H), 7.15−7.05 (m, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.83 (t,

J = 7.6 Hz, 1H), 6.64−6.56 (m, 3H), 6.52 (dd, J = 8.5, 2.3 Hz, 1H),

6.25 (brd, J = 2.1 Hz, 1H), 5.36 (s, 1H), 3.60 (s, 3H); ¹³C{¹H} NMR

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data of the known compounds 3v¹⁵and 4a¹⁸were in agreement with

those previously reported in the literature.

HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₂₄H₁₈N₃O₂, 380.1394;

found, 380.1392.

3-((5-Bromo-1H-indol-3-yl)(4-ﬂuorophenyl)methyl)-1,2-dimeth-

yl-1H-indole (3w). Following the general procedure, the products

were puriﬁed by radial chromatography using a gradient of 0−70%

EtOAc in hexanes, furnishing the desired product 3w (107.9 mg, 48%

yield) as a red solid (mp: 92−94 °C) and byproduct 4m (15.7 mg,

15% yield) as a red solid in which the spectral data of 4m were in

tert-Butyl 4-((1H-Indol-3-yl)(1-methyl-1H-indol-3-yl)methyl)-

piperidine-1-carboxylate (3ab). Following the general procedure,

the product was puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 3ab (108.7

1

mg, 49% yield) as a yellow solid (mp: 124−126 °C); H NMR (400

MHz, CDCl₃): δ 8.00 (s, 1H), 7.67 (dd, J = 8.0, 3.2 Hz, 2H), 7.32 (d,

J = 8.0 Hz, 1H), 7.27−7.23 (m, 1H), 7.22−7.12 (m, 2H), 7.12−7.03

(m, 3H), 6.96 (s, 1H), 4.27 (d, J = 9.3 Hz, 1H), 3.71 (s, 3H), 2.76−

2.58 (m, 2H), 2.42−2.29 (m, 1H), 1.82−1.68 (m, 2H), 1.42 (s, 9H),

1.35−1.17 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 154.9,

137.0, 136.3, 128.0, 127.5, 126.5, 121.8, 121.6, 121.4, 119.6, 119.5,

119.2, 119.0, 118.6, 117.3, 111.1, 109.2, 79.2, 41.7, 39.5, 32.7, 31.6,

31.4, 28.5; IR-ATR: 3416, 2922, 2852, 1664, 1422, 1365, 1277, 1162,

1012, 736 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₂₈H₃₃N₃NaO₂, 466.2465; found, 466.2473.

agreement with those previously reported in the literature.²⁸3w: H

1

NMR (400 MHz, CDCl₃): 8.05 (s, 1H), 7.40 (s, 1H), 7.32−7.23 (m,

4H), 7.22−7.17 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.99−6.89 (m,

3H), 6.68 (dd, J = 2.2, 0.8 Hz, 1H), 5.87 (s, 1H), 3.69 (s, 3H), 2.34

1

(s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.3 (C−F, J_C−F

=

4

242.0 Hz), 139.5 (C−F, J_C−F= 3.0 Hz), 136.8, 135.2, 133.2, 130.0

(C−F, ³J_C−F= 8.0 Hz), 129.1, 127.2, 125.0, 124.9, 122.2, 120.4, 119.3,

2

119.0, 118.7, 114.9 (C−F, J_C−F= 21.0 Hz), 112.8, 112.7, 112.5,

108.6, 38.7, 29.6, 10.6; ¹⁹F NMR (376 MHz, CDCl₃): δ −117.6 to

−117.7 (m); IR-ATR: 3398, 2926, 1601, 1503, 1457, 1366, 1216,

1094, 1014, 794 cm⁻¹; HRMS (ESI-TOF) m/z: [M]⁺calcd for

C₂₅H₂₀BrFN₂, 446.0794; found, 446.0797.

tert-Butyl 4-(1H-Indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-

piperidine-1-carboxylate (3ac). Following the general procedure,

the product was puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 3ac (150.5

mg, 70% yield) as a red solid. The spectral data of the known

compound 3ac^10awere in agreement with those previously reported in

the literature.

4-((5-Bromo-1H-indol-3-yl)(1,2-dimethyl-1H-indol-3-yl)methyl)-

phenol (3x). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3x (113.7 mg, 50% yield)

as a red solid (mp: 132−134 °C) and byproduct 4q (21.1 mg, 17%

yield) as a red solid in which the spectral data of 4q were in

3-((4-Fluorophenyl)(1H-indol-3-yl)methyl)-1-methyl-2-phenyl-

1H-indole (3ad). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 3ad (1.4591 g, 85% yield)

as an orange solid (mp: 106−108 °C) and byproduct 4ad (80.1 mg,

12% yield) as a red solid in which the spectral data of 4ad were in

1

agreement with those previously reported in the literature.²⁸3x: H

NMR (400 MHz, CDCl₃): δ 7.97 (s, 1H), 7.42 (s, 1H), 7.26−7.20

(m, 3H), 7.20−7.14 (m, 1H), 7.14−7.05 (m, 3H), 6.87 (t, J = 7.5 Hz,

1H), 6.72−6.65 (m, 3H), 5.79 (s, 1H), 3.67 (s, 3H), 2.29 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 153.7, 136.8, 136.1, 135.2,

133.1, 129.7, 129.2, 127.3, 125.0, 124.8, 122.3, 120.3, 119.4, 118.6,

116.0, 115.0, 113.2, 112.6, 112.5, 108.5, 38.6, 29.5, 10.6; IR-ATR:

3394, 3038, 2927, 1610, 1508, 1457, 1366, 1331, 1215, 1158, 1092,

738 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for

C₂₅H₂₀BrN₂O, 443.0754; found, 443.0756.

agreement with those previously reported in the literature.¹⁹3ad: H

1

NMR (400 MHz, CDCl₃): δ 7.92 (s, 1H), 7.46−7.38 (m, 3H), 7.38−

7.27 (m, 5H), 7.22−7.07 (m, 5H), 6.98−6.90 (m, 2H), 6.90−6.80

(m, 3H), 5.71 (s, 1H), 3.62 (s, 3H); ¹³C{¹H} NMR (100 MHz,

1

4

CDCl₃): δ 161.1 (C−F, J_C−F= 242.0 Hz), 140.1 (C−F, J_C−F= 3.0

3

Hz), 138.1, 137.5, 136.5, 131.8, 130.7, 130.1 (C−F, J_C−F= 8.0 Hz),

128.4, 128.2, 127.2, 126.9, 123.9, 121.9, 121.4, 120.9, 119.9, 119.3,

119.2, 119.1, 115.3, 114.6 (C−F, ²J_C−F= 21.0 Hz), 110.9, 109.3, 39.1,

30.9; ¹⁹F NMR (376 MHz, CDCl₃): δ −118.1 to −118.2 (m); IR-

ATR: 3409, 3055, 1602, 1504, 1456, 1360, 1336, 1218, 1093, 1013,

822 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₀H₂₂FN₂,

429.1762; found, 429.1769.

3-((1H-Indol-3-yl)(phenyl)methyl)-5-methoxy-1H-indole (3ae).

Following the general procedure, the product was puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 3ae (141.1 mg, 80% yield) as an

orange solid (mp: 92−94 °C); ¹H NMR (400 MHz, CDCl₃): 7.91 (s,

1H), 7.81 (s, 1H), 7.42−7.33 (m, 4H), 7.32−7.25 (m, 2H), 7.24−

7.14 (m, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.86−6.79 (m, 2H), 6.70−

6.62 (m, 2H), 5.83 (s, 1H), 3.69 (s, 3H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 153.7, 144.0, 136.7, 131.9, 128.7, 128.2, 127.5, 127.1,

126.2, 124.4, 123.7, 121.9, 120.0, 119.4, 119.2, 112.0, 111.9, 111.7,

111.1, 101.9, 55.9, 40.3; IR-ATR: 3406, 2936, 1577, 1482, 1456,

1206, 1170, 1040, 793 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺

calcd for C₂₄H₂₀N₂NaO, 375.1468; found, 375.1477.

3-((1H-Indol-3-yl)(phenyl)methyl)-1-methyl-1H-indole (3y). Fol-

lowing the general procedure, the products were puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 3y (87.9 mg, 52% yield) as a red solid

and byproduct 4a (14.5 mg, 18% yield) as a red solid. The spectral

data of the known compounds 3y¹⁵and 4a¹⁸were in agreement with

those previously reported in the literature.

4-((1H-Indol-3-yl)(1-methyl-1H-indol-3-yl)methyl)phenol (3z).

Following the general procedure, the product was puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 3z (61.0 mg, 34% yield) as a red solid

1

(mp: 122−124 °C); H NMR (400 MHz, CDCl₃): δ 7.90 (s, 1H),

7.41−7.33 (m, 3H), 7.29 (d, J = 8.2 Hz, 1H), 7.23−7.14 (m, 4H),

7.04−6.96 (m, 2H), 6.77−6.71 (m, 2H), 6.67 (dd, J = 2.3, 0.7 Hz,

1H), 6.51 (s, 1H), 5.83 (s, 1H), 4.58 (brs, 1H), 3.68 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 153.8, 137.4, 136.7, 136.6,

129.8, 128.2, 127.4, 127.1, 123.5, 121.9, 121.4, 120.2, 120.1, 120.0,

119.2, 118.6, 118.4, 115.0, 111.0, 109.1, 39.3, 32.7; IR-ATR: 3416,

3056, 2922, 1611, 1511, 1457, 1370, 1232, 1167, 1012, 742 cm⁻¹;

HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₂₄H₁₉N₂O, 351.1492;

found, 351.1508.

3-((1H-Indol-3-yl)(4-nitrophenyl)methyl)-1-methyl-1H-indole

(3aa). Following the general procedure, the product was puriﬁed by

radial chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 3aa (39.0 mg, 20% yield) as a red solid

(mp: 102−104 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.14 (d, J = 8.5

Hz, 2H), 8.02 (s, 1H), 7.54−7.48 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H),

7.36−7.30 (m, 3H), 7.26−7.18 (m, 2H), 7.06−6.99 (m, 2H), 6.70

(brd, J = 1.6 Hz, 1H), 6.53 (s, 1H), 5.99 (s, 1H), 3.71 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 152.1, 146.5, 137.5, 136.7,

1-Methyl-3-((3-methyl-1H-indol-2-yl)(phenyl)methyl)-2-phenyl-

1H-indole (5a). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 5a (149.5 mg, 70% yield)

1

as a green solid (mp: 94−96 °C); H NMR (400 MHz, CDCl₃): δ

7.93 (s, 1H), 7.57−7.50 (m, 1H), 7.48−7.38 (m, 4H), 7.38−7.28 (m,

1H), 7.27−7.23 (m, 1H), 7.23−7.14 (m, 4H), 7.14−7.06 (m, 5H),

7.00 (td, J = 7.5, 0.8 Hz, 1H), 5.76 (s, 1H), 3.65 (s, 3H), 2.02 (s, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 142.3, 139.5, 137.6, 136.3,

135.3, 131.3, 130.7, 128.5, 128.21, 128.18, 127.8, 126.7, 126.2, 121.8,

121.0, 120.0, 119.9, 118.9, 118.2, 113.3, 110.7, 109.8, 107.4, 39.6,

31.0, 8.4; IR-ATR: 3444, 3055, 2913, 1602, 1462, 1361, 1333, 1016,

738 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₃₁H₂₅N₂,

425.2012; found, 425.2023.

129.5, 128.3, 127.1, 126.7, 123.7, 123.6, 122.3, 121.9, 119.7, 119.61,

119.58, 119.1, 118.3, 116.5, 111.3, 109.4, 40.2, 32.8; IR-ATR: 3404,

3056, 2932, 1594, 1512, 1456, 1341, 1217, 1107, 1011, 737 cm⁻¹;

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2-(2-((1-Methyl-2-phenyl-1H-indol-3-yl)(phenyl)methyl)-1H-

indol-3-yl)acetic Acid (5b). Following the general procedure, the

product was puriﬁed by radial chromatography using a gradient of 0−

70% EtOAc in hexanes, furnishing the desired product 5b (148.4 mg,

63% yield) as a green solid (mp: 126−128 °C); ¹H NMR (400 MHz,

CDCl₃): δ 8.13 (s, 1H), 7.66−7.59 (m, 1H), 7.45−7.15 (m, 16H),

7.04 (t, J = 7.5 Hz, 1H), 5.89 (s, 1H), 3.68 (s, 3H), 3.49 (s, 2H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 177.5, 141.9, 139.7, 138.1,

137.6, 135.0, 131.0, 130.6, 128.7, 128.6, 128.41, 128.37, 128.0, 126.7,

126.5, 121.9, 121.6, 120.2, 119.9, 119.7, 118.5, 112.5, 111.0, 109.9,

104.2, 39.9, 31.0, 30.0; IR-ATR: 3439, 3058, 2922, 1701, 1601, 1461,

1361, 1338, 1217, 1016, 737 cm⁻¹; HRMS (ESI-TOF) m/z: [M +

Na]⁺calcd for C₃₂H₂₆N₂NaO₂, 493.1886; found, 493.1898.

5,5′-(Phenylmethylene)bis(2-ethyl-1H-pyrrole) (9c). Following

the general procedure, the product was puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 9c (47.5 mg, 68% yield) as a brown oil.

The spectral data of the known compound 9c²⁰were in agreement

with those previously reported in the literature.

Ethyl 5-((1-Methyl-2-phenyl-1H-indol-3-yl)(phenyl)methyl)-1H-

pyrrole-2-carboxylate (8d). Following the general procedure, the

product was puriﬁed by radial chromatography using a gradient of 0−

70% EtOAc in hexanes, furnishing the desired product 8d (121.7 mg,

56% yield) as an orange solid (mp: 90−92 °C); ¹H NMR (400 MHz,

CDCl₃): δ 8.88 (brs, 1H), 7.49−7.41 (m, 3H), 7.37−7.29 (m, 3H),

7.28−7.24 (m, 2H), 7.24−7.18 (m, 4H), 7.18−7.12 (m, 1H), 6.96

(td, J = 7.5, 0.9 Hz, 1H), 6.72−6.68 (m, 1H), 6.62−6.58 (m, 1H),

5.40 (s, 1H), 4.28 (q, J = 7.0 Hz, 2H), 3.60 (s, 3H), 1.30 (t, J = 7.0

Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 161.3, 144.7, 138.4,

137.5, 131.9, 130.8, 129.2, 128.5, 128.4, 128.3, 128.0, 126.7, 125.8,

122.6, 122.0, 121.4, 121.3, 119.2, 115.6, 115.5, 109.3, 60.2, 40.9, 30.9,

14.5; IR-ATR: 3292, 3058, 2934, 1674, 1602, 1466, 1403, 1363, 1209,

1100, 1017, 964, 739 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺calcd

for C₂₉H₂₆N₂NaO₂, 457.1886; found, 457.1897.

tert-Butyl 3-((5-Methoxy-1H-indol-3-yl)(1-methyl-2-phenyl-1H-

indol-3-yl)methyl)-1H-indole-1-carboxylate (8e). Following the

general procedure, the products were puriﬁed by radial chromatog-

raphy using a gradient of 0−70% EtOAc in hexanes, furnishing the

desired product 8e (226.9 mg, 78% yield) as a red solid (mp: 172−

174 °C) and byproduct 9e (22.2 mg, 17% yield) as an orange solid

(mp: 128−130 °C). 8e: ¹H NMR (400 MHz, CDCl₃): δ 8.03 (brd, J

= 7.3 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.44−7.28 (m,

7H), 7.26−7.11 (m, 4H), 7.02 (td, J = 7.5, 0.8 Hz, 1H), 6.96 (td, J =

7.5, 0.8 Hz, 1H), 6.90 (brd, J = 1.9 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz,

1H), 6.61 (brd, J = 2.4 Hz, 1H), 5.85 (s, 1H), 3.65 (s, 6H), 1.62 (s,

9H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 153.6, 150.1, 137.8,

137.7, 135.7, 131.9, 131.6, 130.7, 130.6, 128.4, 128.1, 127.4, 127.3,

124.7, 124.2, 123.9, 122.1, 121.5, 120.9, 120.2, 119.1, 118.19, 118.16,

115.0, 113.9, 112.0, 111.6, 109.3, 101.3, 83.4, 55.8, 31.3, 31.0, 28.2;

IR-ATR: 3421, 3051, 2979, 2827, 1727, 1450, 1365, 1247, 1151,

1078, 1018 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₃₈H₃₅N₃NaO₃, 604.2571; found, 604.2570.

N-(2-(2-((1-Methyl-2-phenyl-1H-indol-3-yl)(phenyl)methyl)-1H-

indol-3-yl)ethyl)acetamide (5c). Following the general procedure,

the product was puriﬁed by radial chromatography using a gradient of

0−70% EtOAc in hexanes, furnishing the desired product 5c (156.8

1

mg, 63% yield) as a green solid (mp: 114−116 °C); H NMR (400

MHz, CDCl₃): δ 8.03 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.51−7.43

(m, 3H), 7.40 (d, J = 8.1 Hz, 1H), 7.27−7.07 (m, 12H), 7.01 (t, J =

7.5 Hz, 1H), 5.75 (s, 1H), 5.05 (s, 1H), 3.63 (s, 3H), 3.46−3.34 (m,

1H), 3.13−3.00 (m, 1H), 2.78−2.67 (m, 1H), 2.66−2.55 (m, 1H),

1.44 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 170.0, 142.8,

139.3, 137.5, 137.4, 135.4, 131.2, 130.6, 129.1, 128.8, 128.7, 128.6,

128.3, 126.7, 126.6, 122.0, 121.5, 120.2, 119.5, 118.5, 113.2, 111.0,

110.0, 108.8, 39.7, 39.5, 31.0, 24.1, 22.8; IR-ATR: 3440, 3290, 3055,

2925, 2852, 1651, 1461, 1431, 1362, 1264, 1017, 734 cm⁻¹; HRMS

(ESI-TOF) m/z: [M + Na]⁺calcd for C₃₄H₃₁N₃NaO, 520.2359;

found, 520.2363.

General Procedure for Synthesis of 3-Alkylindole Deriva-

tives 8 or 9. A toluene solution (10 mL) of BIMs 1 (0.5 mmol, 1

equiv), nucleophile 7 (0.5 mmol, 1 equiv), and FeCl₃·6H₂O (0.025

mmol 5 mol %) in a round-bottom ﬂask open to air was stirred at

appropriate temperature. After the reaction was stirred until

completion (TLC analysis), the reaction mixture was quenched

with aqueous NaHCO₃(10 mL) and extracted with EtOAc (2 × 10

mL). The combined organic layer was washed with brine (10 mL),

dried over anhydrous Na₂SO₄, and ﬁltered. The solvent was removed

under reduced pressure (aspirator then in vacuo) to give a crude

product, which was puriﬁed by radial chromatography (SiO₂, 100%

hexane to 70% EtOAc/hexane as the eluent) to give the racemic

mixture of the corresponding 3-alkylindole 8 or 9.

tert-Butyl 3-(Bis(5-methoxy-1H-indol-3-yl)methyl)-1H-indole-1-

1

carboxylate (9e). H NMR (400 MHz, CDCl₃): δ 8.09 (brd, J =

7.1 Hz, 1H), 7.83 (s, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.27−7.22 (m,

4H), 7.10 (t, J = 7.6 Hz, 1H), 6.94 (brd, J = 2.2 Hz, 2H), 6.83 (dd, J =

8.8, 2.34 Hz, 2H), 6.77 (brd, J = 1.7 Hz, 2H), 5.97 (s, 1H), 3.72 (s,

6H), 1.61 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 153.8,

150.1, 135.9, 131.9, 130.4, 127.4, 124.4, 124.2, 124.1, 123.8, 122.2,

120.3, 117.8, 115.2, 111.9, 111.8, 101.8, 83.5, 56.0, 31.0, 28.2; IR-

ATR: 3411, 2981, 1726, 1450, 1366, 1249, 1209, 1151, 1079, 746

cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for C₃₂H₃₁N₃NaO₄,

544.2207; found, 544.2207.

3-((5-Ethylfuran-2-yl)(phenyl)methyl)-1-methyl-2-phenyl-1H-in-

dole (8a). Following the general procedure, the product was puriﬁed

by radial chromatography using a gradient of 0−70% EtOAc in

hexanes, furnishing the desired product 8a (127.3 mg, 65% yield) as a

1

red solid (mp: 92−94 °C); H NMR (400 MHz, CDCl₃): δ 7.57−

7.36 (m, 7H), 7.35−7.19 (m, 6H), 7.09 (t, J = 7.5 Hz, 1H), 5.98−

5.91 (m, 2H), 5.58 (s, 1H), 3.67 (s, 3H), 2.66 (q, J = 7.5 Hz, 2H),

1.26 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 156.8,

155.1, 143.0, 138.7, 137.4, 131.8, 130.9, 128.4, 128.3, 128.1, 127.0,

126.1, 121.6, 121.3, 119.3, 113.3, 109.3, 108.3, 104.2, 42.4, 30.9, 21.5,

12.3; IR-ATR: 3050, 2933, 1601, 1467, 1445, 1359, 1334, 1056, 1009,

795 cm⁻¹; HRMS (ESI-TOF) m/z: [M − H]⁺calcd for C₂₈H₂₄NO,

390.1852; found, 390.1869.

3-((5-Ethylfuran-2-yl)(thiophen-2-yl)methyl)-1-methyl-2-phenyl-

1H-indole (8f). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 8f (125.2 mg, 63% yield) as

1

a brown solid (mp: 102−104 °C); H NMR (400 MHz, CDCl₃): δ

7.61 (d, J = 8.1 Hz, 1H), 7.57−7.46 (m, 5H), 7.41 (d, J = 8.1 Hz,

1H), 7.32−7.26 (m, 1H), 7.17 (d, J = 5.0 Hz, 1H), 7.11 (t, J = 7.5 Hz,

1H), 6.94 (dd, J = 5.0, 3.5 Hz, 1H), 6.89−6.85 (m, 1H), 6.05 (brd, J

= 2.9 Hz, 1H), 5.93 (brd, J = 2.9 Hz, 1H), 5.73 (s, 1H), 3.66 (s, 3H),

2.65 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 156.8, 154.3, 147.0, 138.6, 137.4, 131.5, 130.9,

128.51, 128.49, 126.4, 126.3, 125.2, 123.9, 121.7, 121.5, 119.3, 113.1,

109.4, 107.6, 104.3, 38.1, 30.9, 21.5, 12.2; IR-ATR: 3052, 2972, 2937,

1603, 1467, 1362, 1337, 1228, 1057, 1009, 740 cm⁻¹; HRMS (ESI-

TOF) m/z: [M + Na]⁺calcd for C₂₆H₂₃NNaOS, 420.1393; found,

420.1399.

3-((5-Ethylthiophen-2-yl)(phenyl)methyl)-1-methyl-2-phenyl-1H-

indole (8b). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 8b (112.3 mg, 60% yield)

as a yellow solid (mp: 102−104 °C); ¹H NMR (400 MHz, CDCl₃): δ

7.54−7.45 (m, 3H), 7.44−7.35 (m, 4H), 7.34−7.29 (m, 2H), 7.29−

7.18 (m, 4H), 7.04 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.56

(d, J = 3.3 Hz, 1H), 5.66 (s, 1H), 3.63 (s, 3H), 2.79 (q, J = 7.5 Hz,

2H), 1.28 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

146.1, 145.9, 144.2, 138.7, 137.5, 131.7, 130.9, 128.6, 128.44, 128.41,

128.1, 126.6, 126.2, 125.4, 122.4, 121.6, 121.5, 119.3, 115.3, 109.4,

44.0, 30.9, 23.5, 15.8; IR-ATR: 3055, 2963, 2871, 1600, 1465, 1442,

1366, 1337, 1072, 1014, 796 cm⁻¹; HRMS (ESI-TOF) m/z: [M]⁺

calcd for C₂₈H₂₅NS, 407.1708; found, 407.1708.

tert-Butyl 2-((5-Ethylfuran-2-yl)(1-methyl-2-phenyl-1H-indol-3-

yl)methyl)-1H-pyrrole-1-carboxylate (8g). Following the general

procedure, the product was puriﬁed by radial chromatography using

a gradient of 0−70% EtOAc in hexanes, furnishing the desired

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product 8g (149.0 mg, 62% yield) as a brown solid (mp: 114−116

°C); ¹H NMR (400 MHz, CDCl₃): δ 7.47−7.30 (m, 8H), 7.22 (t, J =

7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.05 (t, J = 3.3 Hz, 1H), 6.04−

6.58 (m, 2H), 5.80 (s, 1H), 5.67 (brd, J = 2.9 Hz, 1H), 3.63 (s, 3H),

2.51 (q, J = 7.5 Hz, 2H), 1.27 (s, 9H), 1.13 (t, J = 7.5 Hz, 3H);

¹³C{¹H} NMR (100 MHz, CDCl₃): δ 155.8, 155.0, 149.7, 138.7,

137.3, 134.3, 131.8, 130.9, 128.2, 128.1, 127.3, 121.7, 121.4, 120.9,

119.3, 114.6, 112.1, 109.7, 109.2, 106.6, 104.3, 83.5, 36.7, 30.9, 27.5,

21.4, 12.4; IR-ATR: 2976, 2936, 1723, 1468, 1367, 1333, 1251, 1108,

1005, 736 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₃₁H₃₂N₂NaO₃, 503.2305; found, 503.2319.

hexanes, furnishing the desired product 8l (144.1 mg, 82% yield) as a

yellow oil; ¹H NMR (400 MHz, CDCl₃): δ 7.67 (d, J = 7.9 Hz, 1H),

7.51−7.41 (m, 3H), 7.40−7.29 (m, 5H), 7.27−7.21 (m, 3H), 7.15 (t,

J = 7.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 4.57 (s, 1H), 4.44 (s, 1H),

4.33 (t, J = 7.8 Hz, 1H), 3.56 (s, 3H), 3.03−2.86 (m, 2H), 1.49 (s,

3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 145.6, 144.0, 138.5,

137.5, 132.2, 131.0, 128.3, 128.2, 128.1, 127.8, 126.6, 125.6, 121.3,

120.8, 119.0, 115.3, 112.0, 109.4, 43.1, 40.6, 30.8, 22.3; IR-ATR:

3057, 2934, 1602, 1467, 1365, 1338, 1155, 1018, 766 cm⁻¹; HRMS

(ESI-TOF) m/z: [M + Na]⁺calcd for C₂₆H₂₅NNa, 374.1879; found,

374.1890.

1-Methyl-2-phenyl-3-(1-phenylbuta-2,3-dien-1-yl)-1H-indole

(8m). Following the general procedure, the product was puriﬁed by

radial chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 8m (60.4 mg, 36% yield) as a yellow

1-Methyl-2-phenyl-3-(phenyl(2,4,5-trimethoxyphenyl)methyl)-

1H-indole (8h). Following the general procedure, the products were

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 8h (150.7 mg, 65% yield)

as a green solid (mp: 116−118 °C) and byproduct 9h (14.9 mg, 14%

yield) as a white solid in which the spectral data of 9h were in

1

solid (mp: 70−72 °C); H NMR (400 MHz, CDCl₃): δ 7.54−7.37

(m, 7H), 7.37−7.31 (m, 2H), 7.30−7.22 (m, 3H), 7.23−7.5 (m, 1H),

7.07 (td, J = 7.3, 0.9 Hz, 1H), 5.83 (dt, J = 8.1, 6.6 Hz, 1H), 4.94 (d, J

= 8.1 Hz, 1H), 4.77−4.66 (m, 2H), 3.65 (s, 3H); ¹³C{H} NMR (100

MHz, CDCl₃): δ 208.8, 143.7, 138.6, 137.5, 131.8, 130.9, 128.4,

128.3, 128.04, 127.99, 126.4, 126.0, 121.6, 120.9, 119.3, 114.3, 109.5,

93.6, 76.0, 42.2, 30.9; IR-ATR: 3057, 2919, 2850, 1958, 1600, 1467,

1430, 1363, 1249, 1017, 838 cm⁻¹; HRMS (ESI-TOF) m/z: [M +

Na]⁺calcd for C₂₅H₂₁NNa, 358.1566; found, 358.1572.

agreement with those previously reported in the literature.²¹8h: H

1

NMR (400 MHz, CDCl₃): δ 7.51−7.41 (m, 3H), 7.41−7.30 (m, 3H),

7.30−7.21 (m, 4H), 7.21−7.14 (m, 3H), 6.99 (t, J = 7.5 Hz, 1H),

6.96 (s, 1H), 6.55 (s, 1H), 5.94 (s, 1H), 3.93 (s, 3H), 3.65 (s, 3H),

3.63 (s, 3H), 3.56 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ

151.4, 148.0, 144.6, 142.9, 139.0, 137.5, 132.3, 130.9, 128.8, 128.1,

128.0, 127.9, 127.6, 125.6, 124.9, 121.3, 121.0, 119.2, 115.2, 115.0,

109.4, 98.1, 56.59, 56.55, 56.2, 41.0, 30.9; IR-ATR: 3022, 2997, 2932,

2829, 1602, 1508, 1463, 1313, 1202, 1031, 740 cm⁻¹; HRMS (ESI-

TOF) m/z: [M + Na]⁺calcd for C₃₁H₂₉NNaO₃, 486.2040; found,

486.2049.

3-((5-Ethylfuran-2-yl)(phenyl)methyl)-5-methoxy-1H-indole (8o).

Following the general procedure, the product was puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 8o (94.5 mg, 57% yield) as a red oil;

¹H NMR (400 MHz, CDCl₃): δ 7.91 (s, 1H), 7.37−7.30 (m, 4H),

7.30−7.26 (m, 1H), 7.25 (d, J = 8.7 Hz, 1H), 6.87 (dd, J = 8.7, 2.2

Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 5.93 (d, J

= 3.0 Hz, 1H), 5.89 (d, J = 3.0 Hz, 1H), 5.61 (s, 1H), 3.77 (s, 3H),

2.65 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 156.9, 154.9, 153.8, 142.2, 131.7, 128.5, 128.3,

127.3, 126.5, 124.1, 117.5, 112.2, 111.8, 107.9, 104.3, 101.7, 55.8,

42.8, 21.5, 12.2; IR-ATR: 3420, 2970, 2937, 1583, 1485, 1453, 1439,

1208, 1171, 1050, 1011, 793 cm⁻¹; HRMS (ESI-TOF) m/z: [M −

H]⁺calcd for C₂₂H₂₀NO₂, 330.1489; found, 330.1492.

General Procedure for Reaction of Symmetrical BIMs 1a

and 4a. A toluene solution (10 mL) of 1a (0.5 mmol, 1 equiv), 4a

(0.5 mmol, 1 equiv), and FeCl₃·6H₂O (0.025 mmol, 5 mol %) in a

round-bottom ﬂask was stirred at room temperature. The reaction

mixture was quenched at diﬀerent times (0 and 60 min) and the

quantity of all compounds was monitored by HPLC analysis. The

sample was prepared by pipetting 100.0 μL of the reaction mixture

into the vial followed by addition of CH₃CN (5000.0 μL). A 1000.0

μL of the solution was further diluted with 5000.0 μL of CH₃CN.

Finally, the dilute solution (10.0 μL) was injected into HPLC using

acetronitrile/water (97:3, isocretic) as the mobile phase (ﬂow rate, 1

mL min⁻¹; detector UV diode array (λ = 254 nm); and column

temperature, 30 °C).

2-2-Methoxy-4-((1-methyl-2-phenyl-1H-indol-3-yl)(phenyl)-

methyl)aniline (8i). Following the general procedure, the product was

puriﬁed by radial chromatography using a gradient of 0−70% EtOAc

in hexanes, furnishing the desired product 8i (83.8 mg, 40% yield) as

1

a red solid (mp: 88−90 °C); H NMR (400 MHz, CDCl₃): 7.50−

7.41 (m, 3H), 7.39−7.30 (m, 3H), 7.26−7.14 (m, 7H), 6.98 (t, J =

7.5 Hz, 1H), 6.68 (s, 1H), 6.66−6.59 (m, 2H), 5.48 (s, 1H), 3.66 (s,

3H), 3.62 (s, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 147.2,

145.1, 138.8, 137.5, 134.9, 133.9, 132.1, 130.9, 129.1, 128.3, 128.2,

127.9, 127.1, 125.7, 121.7, 121.4, 121.3, 119.2, 115.8, 114.8, 111.8,

109.3, 55.4, 47.8, 30.9; IR-ATR: 3363, 3027, 2933, 1617, 1513, 1457,

1338, 1277, 1148, 1031, 738 cm⁻¹; HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₂₉H₂₇N₂O, 419.2118; found, 419.2124.

4-((1-Methyl-2-phenyl-1H-indol-3-yl)(phenyl)methyl)aniline (8j).

Following the general procedure, the product was puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 8j (83.6 mg, 43% yield) as a red solid

1

(mp: 166−168 °C); H NMR (400 MHz, CDCl₃): 7.46−7.40 (m,

3H), 7.36−7.27 (m, 3H), 7.23−7.12 (m, 7H), 6.98−6.90 (m, 3H),

6.57 (d, J = 8.4 Hz, 2H), 5.44 (s, 1H), 3.59 (s, 3H); ¹³C{¹H} NMR

(100 MHz, CDCl₃): δ 145.0, 144.2, 138.8, 137.5, 134.6, 132.0, 130.9,

130.0, 129.1, 128.3, 128.2, 128.0, 127.1, 125.7, 121.4, 121.3, 119.2,

115.8, 115.1, 109.3, 47.4, 30.9; IR-ATR: 3447, 3368, 3023, 2925,

1601, 1512, 1463, 1359, 1335, 1014, 788 cm⁻¹; HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₂₈H₂₅N₂, 389.2012; found, 389.2024.

1-Methyl-2-phenyl-3-(1-phenylbut-3-en-1-yl)-1H-indole (8k).

Following the general procedure, the product was puriﬁed by radial

chromatography using a gradient of 0−70% EtOAc in hexanes,

furnishing the desired product 8k (129.0 mg, 77% yield) as a yellow

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02466.

■

sı

1

¹H, ¹³C{¹H}, and ¹⁹F NMR spectra of all prepared

products (PDF)

solid (mp: 80−82 °C); H NMR (400 MHz, CDCl₃): δ 7.67 (d, J =

8.0 Hz, 1H), 7.51−7.41 (m, 3H), 7.38−7.28 (m, 5H), 7.28−7.19 (m,

3H), 7.17−7.05 (m, 2H), 5.76−5.62 (m, 1H), 4.94 (dd, J = 17.1, 2.0

Hz, 1H), 4.85 (dd, J = 9.7, 2.0 Hz, 1H), 4.18 (dd, J = 9.7, 6.8 Hz,

1H), 3.55 (s, 3H), 3.09−2.99 (m, 2H); ¹³C{¹H} NMR (100 MHz,

CDCl₃): δ 145.3, 138.6, 137.7, 137.4, 132.2, 131.0, 128.30, 128.25,

128.1, 127.7, 126.6, 125.6, 121.4, 120.7, 119.1, 115.6, 114.9, 109.4,

42.4, 39.0, 30.8; IR-ATR: 3057, 2935, 1601, 1467, 1441, 1366, 1339,

1024, 919 cm⁻¹; HRMS (ESI-TOF) m/z: [M + Na]⁺calcd for

C₂₅H₂₃NNa, 360.1723; found, 360.1719.

AUTHOR INFORMATION

Corresponding Author

■

Jaray Jaratjaroonphong − Department of Chemistry and

Center of Excellence for Innovation in Chemistry, Faculty of

Science, Burapha University, Chonburi 20131, Thailand;

Research Unit in Synthetic Compounds and Synthetic

Analogues form Natural Product for Drug Discovery

(RSND), Burapha University, Chonburi 20131, Thailand;

1-Methyl-3-(3-methyl-1-phenylbut-3-en-1-yl)-2-phenyl-1H-in-

dole (8l). Following the general procedure, the product was puriﬁed

by radial chromatography using a gradient of 0−70% EtOAc in

2324

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J. Org. Chem. 2021, 86, 2312−2327

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

ase inhibitory constitutents. J. Nat. Prod. 2014, 77, 650−656.

(b) Porter, J. K.; Bacon, C. W.; Robbins, J. D.; Himmelsbach, D.

S.; Higman, H. C. Indole alkaloids from Balansia epichloe (Weese). J.

Agric. Food Chem. 1977, 25, 88−93. (c) Nawwar, M. A. M.; Hussein,

S. A. M.; Merfort, I. NMR spectral analysis of polyphenols from

Punica granatum . Phytochemistry 1994, 36, 793−798. (d) Garbe, T. R.;

Kobayashi, M.; Shimizu, N.; Takesue, N.; Ozawa, M.; Yukawa, H.

Indolyl carboxylic acids by condensation of indoles with α -keto acids.

J. Nat. Prod. 2000, 63, 596−598.

orcid.org/0000-0003-3170-0133; Email: jaray@

buu.ac.th

Author

Chayamon Chantana − Department of Chemistry and Center

of Excellence for Innovation in Chemistry, Faculty of Science,

Burapha University, Chonburi 20131, Thailand

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02466

(4) Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Bis-

and trisindolylmethanes (BIMs and TIMs). Chem. Rev. 2010, 110,

2250−2293.

Notes

́

(5) (a) Esquivias, J.; Gomez Arrayas, R.; Carretero, J. C. A

copper(II)-catalyzed aza-Friedel-Crafts reaction of N -(2-pyridyl)-

sulfonyl aldimines: synthesis of unsymmetrical diaryl amines and

triaryl methanes. Angew. Chem., Int. Ed. 2006, 45, 629−633. (b) Ji, S.-

J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Facile synthesis of bis(indolyl)-

methanes using catalytic amount of iodine at room temperature under

solvent-free conditions. Tetrahedron 2004, 60, 2051−2055. (c) Naidu,

P. S.; Bhuyan, P. J. Synthesis of some analogues of ( )gelliusine F,

( )gelliusine E, and total synthesis of 2,2-di(6 ′-bromo-3 ′-indolyl)-

ethylamine. Tetrahedron Lett. 2012, 53, 426−428. (d) Mari, M.;

Tassoni, A.; Lucarini, S.; Fanelli, M.; Piersanti, G.; Spadoni, G.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by Thailand Research Fund

(RSA6280069), the Royal Golden Jubilee Ph.D. Program

(grant no. 3.C.BU/60/B.1.N.XX), the Oﬃce of National

Higher Education Science Research and Innovation Policy

Council (NXPO) (grant no. BO5F630030), the Center of

Excellence for Innovation in Chemistry (PERCH-CIC), the

Oﬃce of the Higher Education Commission, and the Research

Unit in Synthetic Compounds and Synthetic Analogues form

Natural Product for Drug Discovery (RSND), Burapha

University. This work was also partially supported by Science

Innovation Facility, Faculty of Science, Burapha University

(SIF-IN-621014). Special thanks to Dr. Ron Beckett, Faculty

of Science, Burapha University for his comments and proof-

reading the English manuscript.

Bro ̷nsted acid catalyzed bisindolization of α -amido acetals: Synthesis

and anticancer activity of bis(indolyl)ethanamino derivatives. Eur. J.

Org. Chem. 2014, 3822−3830.

(6) (a) Palmieri, A.; Petrini, M. Recent advances in the synthesis of

unsymmetrical bisindolylmethane derivatives. Synthesis 2019, 51,

829−841. A-M and references cited therein (b) Guo, X.; Pan, S.; Liu,

J.; Li, Z. One-pot synthesis of symmetric and unsymmetric 1,1-bis-

indolylmethanes via tandem iron-catalyzed C −H bond oxidation and

C −O bond cleavage. J. Org. Chem. 2009, 74, 8848−8851. (c) Frías,

́

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Article Doi

FeCl3·6H2O as a Mild Catalyst for Nucleophilic Substitution of Symmetrical Bis(indoyl)methanes

DOI: 10.1021/acs.joc.0c02466

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