Regioselective mercury(I)/palladium(II)-catalyzed single-step approach for the synthesis of imines and 2-substituted indoles

molecules

Article

Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step

Approach for the Synthesis of Imines and 2-Substituted Indoles

Rsuini U. Gutiérrez ¹, Mayra Hernández-Montes ¹, Aarón Mendieta-Moctezuma ², Francisco Delgado ¹

and Joaquín Tamariz ^1,

*

1

Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional,

Prolongación de Carpio y Plan de Ayala s/n, Mexico City 11340, Mexico; rsuini.uri@gmail.com (R.U.G.);

encb.mayra2020@gmail.com (M.H.-M.); jfdelgador@gmail.com (F.D.)

Centro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional, Carretera Estatal Santa

Inés Tecuexcomac-Tepetitla, Km 1.5, Tlaxcala 90700, Mexico; amendieta@ipn.mx

2

*

Correspondence: jtamarizm@gmail.com or jtamarizm@ipn.mx

Abstract: An efﬁcient synthesis of ketimines was achieved through a regioselective Hg(I)-catalyzed

hydroamination of terminal acetylenes in the presence of anilines. The Pd(II)-catalyzed cycliza-

tion of these imines into the 2-substituted indoles was satisfactorily carried out by a C-H acti-

vation. In a single-step approach, a variety of 2-substituted indoles were also generated via a

Hg(I)/Pd(II)-catalyzed, one-pot, two-step process, starting from anilines and terminal acetylenes.

The arylacetylenes proved to be more effective than the alkyl derivatives.

ꢀꢁꢂꢀꢃꢄꢅꢆꢇ

ꢀꢁꢂꢃꢄꢅꢆ

Keywords: mercury(I)-catalyzed alkyne hydroamination; imines; Pd-catalyzed oxidative cyclization;

Citation: Gutiérrez, R.U.;

one-pot indole synthesis

Hernández-Montes, M.;

Mendieta-Moctezuma, A.; Delgado,

F.; Tamariz, J. Regioselective

Mercury(I)/Palladium(II)-Catalyzed

Single-Step Approach for the

Synthesis of Imines and 2-Substituted

Indoles. Molecules 2021, 26, 4092.

https://doi.org/10.3390/molecules

26134092

1. Introduction

Imines are one of the most versatile functional groups in synthesis. Numerous studies

have focused on their preparation [

ination equilibrium [ ], and use as a precursor for the construction of more complex

structures [ 12]. Due to their versatility, they play an important role in medicinal chem-

1–5], chemical structure and tautomeric or transim-

6–8

9–

istry, serving as urease and protease inhibitors [13] as well as antimalarial, antibacterial, and

antifungal agents [14]. They also exhibit activity against Mycobacterium tuberculosis [15] and

Academic Editor: Lucia Veltri

tumor cells [16–19], and act as suppressors of HIV1-gp120, related to the human immun-

odeﬁciency virus (HIV) [20] (Figure 1). Interestingly, imines are present in phytoplankton

and shellﬁsh as toxins [21].

Received: 4 June 2021

Accepted: 29 June 2021

Published: 5 July 2021

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Licensee MDPI, Basel, Switzerland.

This article is an open access article

distributed under the terms and

conditions of the Creative Commons

Attribution (CC BY) license (https://

creativecommons.org/licenses/by/

4.0/).

Figure 1. Imine- and indole-containing compounds with pharmacological activity.

Likewise, indoles are widely distributed in natural products [22

prominent place as pharmacologically active compounds [25 28], including commercial

therapeutic chemicals and active pharmaceutical ingredients [29 31]. The U.S. Food and

–24]. They occupy a

–

Molecules 2021, 26, 4092. https://doi.org/10.3390/molecules26134092

https://ww w .mdpi.com/journal/molecules

Molecules 2021, 26, 4092

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Drug Administration (FDA) has approved at least 43 indole-containing drugs [32

,33]. For

example, arbidol has shown efﬁcient in vitro activity against the SARS-CoV-2 infections [34

and has been administered to infected patients [35 37] (Figure 1). Hence, the molecular

structures of imines and indoles are of great value for medicinal and synthetic purposes.

Despite the variety of methods for the preparation of imines [ ], their synthesis is

mainly carried out with conventional procedures, such as the acid-catalyzed condensation

of a carbonyl compound with a primary amine [ ]. Among the relevant methodologies

are the reduction of nitriles, oximes, and aliphatic nitro derivatives [38 41], the addition

of an organometallic reagent to nitriles and amides [42 43], and the oxidation of alcohols

and amines [44 45]. These methods are only practical, however, if there is an existing

]

–

1–5

1

–

,

carbon–nitrogen formal bond in the substrate.

Intermolecular imine is usually synthesized by condensation reactions with an azeotropic

agent [

tion arose as an alternative, being an attractive and elegant pathway with complete atom

economy [48 51]. Barluenga et al. described several catalytic and noncatalytic hydroami-

1], a desiccant [46], or a water scavenger [47] to remove water. Alkyne hydroamina-

–

nation methods with terminal acetylenes (e.g., 2a) promoted by Tl(III) or Hg(II) salts [52].

They found that HgCl₂acts through a nucleophilic attack of the aniline (1a) on the inter-

nal acetylene carbon, ﬁrstly forming terminal acetylene-HgCl complex

possible conversion into the aminoalkenylmercurial(II) chloride intermediate

3

followed by its

. The latter

4

regenerates the Hg(II) catalyst by protonolysis to give the enamine, which is converted into

the desired imine 5a (Scheme 1a) [53,54].

Scheme 1.

from imines derived by a condensation reaction and Pd(II)-catalyzed oxidative cyclization. (

catalyzed indole synthesis from imines derived from Hg(I)-catalyzed alkyne hydroamination.

(

a) Imine synthesis by a Hg(II)-promoted alkyne hydroamination. (b) Indole synthesis

c) Pd(II)-

Molecules 2021, 26, 4092

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In contrast, indoles have been elaborated by diverse protocols [55], such as the well-

known Fischer [56,57], Julia [58], Bartoli [59], and Gassman [60] procedures, each of which

include a sigmatropic rearrangement at a high temperature. Other efﬁcient approaches

have involved organometallic reagents, as with the syntheses of indoles described by

Castro [61], Larock [62], Fagnou [63], and Söderberg [64,65]. Most of them demand the use

of ortho-halogenated and ortho-vinylated N-protected anilines or nitrobenzenes to build

the indole A ring. Recently, imine substrates have proven valuable for indole synthesis, as

demonstrated by the groups of Yoshikai [66], Xiao [67], and Zhang [68] (Scheme 1b).

Our group has an ongoing interest in designing and carrying out the novel synthesis of

heterocycles [69–71], and in particular of aza-heterocycles and indoles [72–75]. Accordingly,

the aim of the present study was to assess the feasibility of preparing indoles in a one-pot

process, involving the regioselective Hg(I)-catalyzed hydroamination of terminal alkynes

to produce imines as intermediates, and their subsequent Pd(II)-catalyzed cross-coupling

oxidative cyclization to afford the corresponding C-2-substituted indoles (Scheme 1c).

2. Results and Discussion

2.1. Synthesis of Imines 5a–n by Hg(I)-catalyzed Hydroamination of Alkynes 2a–d with

Anilines 1a–k

The properties of Hg(0) and Hg(II) salts have been examined [76], and these species

have many chemical and industrial applications [77

tions [80 82]. Curiously, the use of Hg(I) in organic synthesis is surprisingly rare and

limited [83 84]. Our group has reported the inclusion of Hg₂Cl₂as the catalyst for the

–79], including chemical transforma-

–

,

solvent-free hydroamination of phenylacetylene (2a) with m-anisidine (1e) to furnish the

corresponding imine 5e in quantitative yield [85]. Following up on that effort, the scope of

the method was herein explored by varying the structure of anilines (1) and acetylenes (2) to

develop an efﬁcient synthesis of imines ( ). Unfortunately, when employing the previously

5

described reaction conditions (room temperature, 24 h), the yields of the resulting imines

depended on the anilines (Table 1). For example, with p-anisidine (1i) and 2a, imine 5i

was furnished in a modest yield (61%, entry 2). The yield was improved by increasing the

reaction time (82%, entry 3) or by raising the temperature to 45

4 h (87%, entry 4).

ºC with a reaction time of

Table 1. Optimization of the preparation of N-arylimines 5e and 5i ^a.

Additive

(mol equiv.)

◦

5 (Yield, %) ^b

Entry

1 (Ar)

Catalyst

T ( C)

T (h)

1

2

3

4

5

1e (C₆H₄-3-OMe)

1i (C₆H₄-4-OMe)

1e (C₆H₄-3-OMe)

1i (C₆H₄-4-OMe)

Hg₂Cl₂

Ag₂CO₃

Hg₂Cl₂

HgCl₂

—-

20

45

20

60

24

48

4

72

2

5e (99) ^c

5i (61) ^d

5i (82) ^d

5i (87) ^d

5e (0) ^d

5i (72)

5i (91)

5i (70)

5i (78)

5i (0)

6

—-

7 ^e

8 ^e

9 ^e

10 ^e

Li₂CO₃(0.2)

(^f)

Li₂CO₃(0.2)

Hg⁰

a

b

c

2a (1.0 mol equiv.), ArNH₂(1.0–1.1 mol equiv.), catalyst (10 mol%), and no solvent. After puriﬁcation by column chromatography.

[85].

d

e

f

Calculated by ¹H NMR of the reaction crude mixture. Catalyst (5.0 mol%). Hydroquinone (0.5 mol equiv.).

Other parameters were evaluated, such as solvent, catalyst, and additive. Although

solvent-free reaction conditions are always recommended for designing an optimal green

Molecules 2021, 26, 4092

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chemistry methodology [86], three chlorinated solvents (chloroform, 1,2-dichloroethane,

and methylene chloride), THF, and DMSO were assessed by heating at 60 ºC for 2–12 h.

Whereas imine 5i was obtained in fairly low yields (21–41%) with either the ﬁrst or the

third solvent, it was not detected with 1,2-dichloroethane, THF, and DMSO. When Ag₂CO₃

(Table 1 , entry 5) and CuCl (not shown) were tested as the catalysts for 1e and 2a, the

outcome was the recovery of the reactants but no trace of imine 5e.

Imines, usually water-sensitive, are converted into ketones by hydrolysis. For example,

acetophenone (7a) can be formed from imines 5e or 5i. Therefore, anhydrous lithium

carbonate was employed as the additive, which greatly improved the yield (Table 1,

entries 6 and 7). Of course, under these optimal reaction conditions, the presence of Hg₂Cl₂

was essential for the transformation to take place. Due to a feasible light-induced Hg–Hg

bond disproportionation [87], the generation of radicals was contemplated. Consequently,

hydroquinone was added as a radical quencher, which did not modify the yield (entry 8)

and thus ruled out this possibility.

In agreement with the ﬁndings of Barluenga et al. [52–54], the process was also

catalyzed with HgCl₂under the same reaction conditions, but a lower yield (78%) was

observed (Table 1, entry 9). This suggests that Hg(I) and Hg(II) are both probably the

catalytic species involved in the process. Considering the feasible generation of Hg(0)

as a secondary product during the decomposition of Hg₂Cl₂under an analogous reac-

tion [53,54], the process was carried out in the presence of Hg(0), but no imine was found

(entry 10). Hence, the participation of Hg(0) as a catalyst is unlikely. Moreover, there was

no visual evidence of a dark-silver mirror residue in the Hg(I) trials. Actually, Hg(0) is a

well-known poisoning catalyst in heterogeneous/homogeneous reactions [88].

To gain insights into the mechanism, 2a was reacted with Hg₂Cl₂to examine its

possible conversion into acetophenone (7a) as an intermediate. After heating at 45 ºC for

1 h, however, only the recovery of 2a was achieved. Taking into account the potential

formation of intermediate 7a in the middle of the reaction, a further trial was performed

under the same reaction conditions (45 ºC for 1 h) and in the presence of 1i and Hg₂Cl₂.

The result was again the recovery of the staring material. Finally, after reacting a mixture

of 1i and Hg₂Cl₂at 45 ºC for 1 h, no N-Hg complex was detected.

Once the reaction conditions were optimized (Table 1, entry 7), evaluation was per-

formed for a series of anilines (1a

–

k) bearing substituents with diverse electron-demand at

the three positions of the benzene ring, utilizing arylalkynes 2a

–

d

as the terminal acetylenes

(Table 2). In general, neither the electron-demand of the substituents nor their position

in the benzene ring of the aniline showed any effect on the efﬁcacy of the process. The

only exception was the use of the halogenated anilines 1f and 1k, which gave rise to the

corresponding imines in modest yields (Table 2, entries 6 and 11).

The high yields afforded by the unsubstituted phenylacetylene (2a) were also obtained

with the terminal para-substituted phenylacetylenes 2b–d (Table 2, entries 9 and 12–14),

supporting the idea that Hg(I) easily interacts with the triple bond regardless of the

electron-demand of its substituent. Furthermore, the reaction was successful with terminal

alkyl- and some aryl-acetylenes, including 4-cyanophenylacetylene (2c), propylacetylene

1

(

2e), cyclopropylacetylene (2f), and cyclohexylacetylene (2g), judging by the H NMR

and MS/GC analyses of the crude mixtures. Nevertheless, the corresponding imines 5m

(as a mixture of 5m/p-cyanoacetophenone (7b) (95:5)) and 5o were not stable enough

–

q

to be isolated under the extraction conditions. Evidence of their formation was found

unambiguously by the synthesis of the indoles (see Scheme 3).

Reactivity signiﬁcantly decreased with the di-substitution of the triple bond. For

instance, neither methylpropylacetylene (2h) nor phenylpropylacetylene (2i) reacted with

p-anisidine (1i), even when the mixture was heated to 80 ºC for 53 h, probably because

both electronic and steric effects impede the addition of the aniline or do not allow for the

formation of the σ-Hg(I)-acetylene complex (see below).

Molecules 2021, 26, 4092

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Table 2. Preparation of the series of N-arylimines 5a

of 2a–d with anilines 1a–k ^a.

–

n

through the Hg(I)-catalyzed hydroamination

5 (Yield, %) ^b

Entry

1

2 (R’)

R

T (h)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1a

1b

1c

1d

1e

1f

1g

1h

1i

1j

1k

1i

2a (H)

2b (Me)

2c (CN)

2d (OMe)

H

4

2

8

2

5a (88)

5b (85)

5c (87)

5d (83)

5e (84)

5f (53)

5g (91)

5h (68)

5i (91)

5j (78)

5k (42)

5l (91)

5m (90) ^c

5n (83)

b

2-Me

2-OMe

3-Me

3-OMe

3-Cl

4-Me

4-NMe₂

4-OMe

4-Cl

2-Br-4-Me

4-OMe

a

2 (1.0 mol equiv.), ArNH₂(1.0–1.1 mol equiv.), Hg₂Cl₂(5 mol%), Li₂CO₃(0.2 mol equiv.), and no solvent. After

puriﬁcation by column chromatography. The yield was estimated from the ¹H NMR spectrum of the crude

reaction mixture, resulting in the ratio products, which were then conﬁrmed by the ratio and molecular ions by

MS/GC analysis. The product was not isolated and used without puriﬁcation in the next step.

c

All the imines prepared by this method were characterized by IR and NMR (1D and

2D), and in some cases, HRMS. The latter technique was performed in case of ﬁnding a

discrepancy between the data reported in the literature and the melting point or physical

state of the compound in the current effort. Imine 5i was crystallized in order to be

subjected to X-ray crystallographic analysis (Figure 2), which demonstrated the expected

E conﬁguration of the double bond. However, the N-anisyl ring was not coplanar to the

imine double bond, instead adopting a quasi-orthogonal conformation (torsion angle,

C(8)-N(1)-C(1)-C(2) = 115.31(17), see Supplementary Materials), which indicates that the

π-system is not conjugated. In contrast, the phenyl ring attached to the imine double

bond displayed a planar conformation (torsion angle, C(11)-C(10)-C(8)-N(1) = –4.7(2), see

Supplementary Materials).

Figure 2. Structure of 5i, as determined by single X-ray diffraction crystallography (ellipsoids at the

30% probability level).

2.2. One-Pot Synthesis of Indoles 6a–p by Subsequent Hg(I)- and Pd(II)-Catalyzed Conversion of

Anilines 1a–g and 1i–k with Alkynes 2a–g

The Pd(II)-catalyzed conversion of imines/enamines into indoles has been performed

by fairly similar methods [89

the intermediate [66 68] (Scheme 1b). In all the approaches, the mechanism seems to start

from the tautomerization of imine to enamine , which undergoes a dehydrogenative

–91], previously forming imine 5 or generating it in situ as

–

5

8

Molecules 2021, 26, 4092

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reaction by the metal to furnish the

σ

-Pd(II) complex

9

(Scheme 2). An aryl C–H activation

affords palladacycle 10, bridging the aryl and the methylene moieties. By accomplishing

the reductive elimination step, the internal oxidative cross-coupling reaction of 10 promotes

the formation of the C-3/C-3a sigma bond of the corresponding indole 6 and Pd(0). The

latter is oxidized back to Pd(II) by the oxidizing agent to renew the catalytic cycle. This

aerobic oxidative cyclization reaction is only modestly efﬁcient and regioselective in a one-

pot reaction beginning from the aniline and the ketone [67]. With an excess of Cu(OAc)₂, on

the other hand, the reaction produces a couple of indoles in moderate yields (41–55%) [66].

Scheme 2. Indole synthesis from imines through a Pd(II)-catalyzed oxidative cross-coupling.

Considering the feasibility of the oxidative cyclization reaction from imines

indoles , a one-pot reaction was explored that started from aniline 1i and phenylacetylene

2a) and progressed by a sequential Hg(I)/Pd(II)-catalyzed process. Diverse reagents were

5 to

6

(

tested under aerobic conditions to ﬁnd the proper oxidizing agent (Table 3 ). The reaction

conditions were standardized and carried out in two steps. The ﬁrst step consisted of

applying the optimal reaction conditions found for the preparation of imines

5, thus ﬁxing

the temperature and reaction time at 40 C and 2 h. The second step involved the addition

º

of Pd(OAc)₂along with the oxidizing agent in DMSO as the solvent, and then stirring at

60 ºC for 4.5 h.

Table 3. Selection of the oxidizing agent and optimization of the reaction conditions for the one-pot conversion of 1i and 2a

into indole 6h ^a.

b

5i/6h (Ratio) ^c(Yield, %) ^d

Entry

Additive (mol equiv.)

Oxidant (mol equiv.)

1

2

3

4

5

6

7

8

Cu(OAc)₂(3.0)

O₂

Cu(OAc)₂/O₂(3.0)

KMnO₄/O₂(3.0)

NMMO/O₂(3.0)

DTBP/O₂(3.0)

Cu(OTf)₂/O₂(3.0)

Cu(OAc)₂/O₂(1.0)

Cu(OAc)₂/O₂(3.0)

Cu(OAc)₂(3.0)

Li₂CO₃(0.2)

—-

78:22

85:15

46:54

56:44

67:33

65:35

100:0

53:47

13:87

6h (45)

6h (50)

6h (46)

6h (52)

6h (80)

9 ^e

10 ^e

11 ^e

12 ^e,f

13 ^e,f

14 ^e

EtCO₂H (0.2)

Li₂CO₃(0.2)

—-

Cu(OAc)₂(3.0)

a

1i (1.05 mol equiv.), 2a (1.0 mol equiv.), Li₂CO₃(0.2 mol equiv.), Hg₂Cl₂(0.05 mol equiv.), Pd(OAc)₂(0.1 mol equiv.), and DMSO

(0.2 M). ^bOxygen gas was used. Calculated by ¹H NMR of the reaction crude mixture. After puriﬁcation by column chromatography.

c

d

e

f

Pd(OAc)₂(0.2 mol equiv.) was employed. The additive was added at the second step. NMMO = N-methylmorpholine N-oxide, DTBP =

di-tert-butyl peroxide.

Molecules 2021, 26, 4092

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The synergic action of Cu(OAc)₂and oxygen turned out to be the best oxidizing agent

(Table 3, entries 8 and 9), although no signiﬁcant conversion was shown when reacting

each separately (entries 1 and 2). The addition of 0.2 mol equivalents of Pd(OAc)₂was

critical for improving the yield (entry 9). Interestingly, mixing all the catalysts with the

oxidant and solvent (DMSO) under similar reaction conditions and as a single step did

not provide any trace of the imine or the indole. A possible explanation is that the Hg(I)

catalyst was inactivated by DMSO. Indeed, the ﬁrst step was always inefﬁcient with the

use of this solvent (Table 1).

With the aim of optimizing the process, the additive was changed to K₂CO₃and

Cs₂CO₃rather than Li₂CO₃, but without success (not shown in Table 3). Hence, the

conversion depicted in Table 3 was carried out with or without the addition of Li₂CO₃

in the second step. The addition of an acid instead of Li₂CO₃(entries 10–12) caused a

non-signiﬁcant decrease in the yield. A similar outcome was found without the presence of

oxygen (entry 13). However, when both the additive and oxygen were removed from the

whole process, the yield sharply increased (entry 14). The reaction temperatures and times

with the best efﬁciency were determined, and the optimized method for the elaboration

of 6h was applied to the entire series, mixing anilines 1a

–g and 1i–k with acetylenes 2a–g,

which gave the corresponding indoles 6a (Scheme 3). Most of the 2-arylindoles were

–

p

obtained in good yields, regardless of the position of the substituent in the benzene ring.

One-pot synthesis of indoles 6a–p from a series of anilines 1a–g and 1i–k, and acetylenes 2a–g ^a.

a

Scheme 3. Yields in square brackets were obtained by conversion of imines 5a and 5i

–

j

into indoles

b

6a and 6h

–

i

(see Experimental Section). Minor isomer 4-methyl-2-phenyl-1H-indole (6d’) was

c

detected (12% ratio) by GC/MS of the crude mixture, but could not be isolated. Minor isomer

4-methoxy-2-phenyl-1H-indole (6e’) was detected (7% ratio) by GC/MS of the crude mixture, but

d

could not be isolated. Minor isomer 4-chloro-2-phenyl-1H-indole (6f’) was detected (19% ratio) by

GC/MS of the crude mixture, but could not be isolated.

Molecules 2021, 26, 4092

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On the other hand, the indoles produced in low yields showed a certain correlation

with the imines afforded in fairly modest yields (Table 2). For example, the in-situ formation

of imine 5k delivered indole 6j in a low yield. The unstable and non-isolated imines

5m and 5o

–

q, generated by acetylenes 2c and 2e

–g respectively, provided low yields of

their corresponding indoles 6l and 6n

–

p. It is likely that the low yield of indole 6l was

due to the low stability of the imine under the two-step reaction conditions, since the

corresponding p-cyanoacetophenone (7b) was isolated in 20% yield. The reaction of aniline

1h and phenylacetylene (2a) resulted in a complex mixture of products. With the use of

meta-substituted anilines 1d

respectively. The 6-substituted indoles 6d

indoles 6d’–f’ the minor ones. The latter could not be isolated (see caption, Scheme 3).

Analogous second-step reaction conditions (Pd(OAc)₂/Cu(OAc)₂, DMSO, 80 C, 24 h)

were evaluated for the preparation of indoles 6a and 6h from imines 5a and 5i , leading

–

f

with 2a, a mixture of regioisomers 6d

–f/6d’–f’ was found,

–f

were the major isomers, and the 4-substituted

º

–i

–j

to lower yields than those obtained from the one-pot procedure (Scheme 3 , square brackets).

This suggests that a possible Hg/Pd transmetalation reaction during the one-pot process

may foster the necessary catalytic activity to promote the oxidative cyclization of the in-situ

formed imine and provide the indole. Actually, there are many examples of satisfactory

palladium-catalyzed cross-coupling reactions involving a transmetalation process with

organomercury substrates [80,92,93].

The series of indoles 6a–p

was characterized by IR, ¹H and ¹³C NMR (the signals were

attributed by HMQC and HMBC experiments), and HRMS. Indoles 6e and 6l were isolated

as colorless and pale reddish crystals respectively, and their structures were determined

by single X-ray diffraction crystallography (Figure 3). Regarding 6e, the C-2-substituted

benzene ring adopted a coplanar conformation in relation to the heterocycle (torsion angle:

N(1)-C(1)-C(10)-C(15) = 1.8(3), see Supplementary Materials). A larger torsion angle can

be appreciated for 6l (torsion angle: C(15)-C(10)-C(1)-N(1) = 32.41(18), see Supplementary

Materials). Thus, it is likely that the π-system of the aromatic rings in 6e is stabilized

by conjugation, despite the possible van der Waals repulsions triggered by the eclipsed

conformation of the ortho C-H protons (C2-H and C11-H). Meanwhile, the coplanarity

between the aromatic rings is lost for 6l, leading to the rotation of the sigma bond C1–C10.

This is probably due to the presence of the cyano group, which compensates for the loss

of stability caused by the conjugation of the aromatic rings. The latter loss is due to the

instability caused by such ortho C-H and N-H repulsions.

(a)

) and 6l

(b)

Figure 3. Structures of 6e

probability level).

(

a

(b

) as determined by single X-ray diffraction crystallography (ellipsoids at the 30%

2.3. Mechanism of the Formation of Indoles 6a–p

Taking into account the aforementioned results as well as the role played by the

catalysts through each step [54

catalytic cycles can be suggested (Scheme 4 ). For the ﬁrst event, the triple bond of 2a would

be activated by a -Hg(I) mercurinium cation complex , and then probably stabilized by

the formation of the alkynylmercury(I) II 83]. The addition of aniline to either of the

two possible complexes ( or II) would generate enamino-vinylmercury(I) III, followed by

,66–68] in the one-pot process for 2a, two consecutive

π

I

[

1

I

Molecules 2021, 26, 4092

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tautomerization to obtain imine IV. The protonolysis of the latter [80] would afford imine

5 along with the regeneration of catalyst Hg₂Cl₂to initiate a new catalytic cycle.

Scheme 4. Possible consecutive Hg(I)/Pd(II) catalytic cycles for the one-pot synthesis of indoles

provides imines 5 (Step 1), and then oxidative cyclization (Step 2) furnishes the indole frame.

6. Firstly, hydroamination

The second step would start with the tautomerization of imine

leading to the -Pd(II) complex VI and the subsequent elimination of AcOH to deliver

-Pd(II) complex VII (Scheme 4) [66 68]. Intramolecular aryl C–H activation would furnish

5 to enamine V,

π

σ

–

palladacycle VIII, which would undergo a coupling reaction to give rise to the new C3-C3a

sigma bond of heterocycle IX. The latter process would be associated with the reductive

elimination of Pd(II) to form Pd(0), which would again be oxidized by the action of

Cu(OAc)₂. A ﬁnal aromatization of IX would complete the synthesis of indoles 6.

Considering the possibility that an Hg/Pd transmetalation reaction takes place to

improve the one-pot process with respect to the conversion of imines

plausible alternative reaction mechanism can be postulated. The Pd(II)-catalyzed trans-

metalation reaction may occur either with the vinylmercurial complex III 92 93] or the

alkylmercurial complex IV to directly produce the -Pd(II) complex VII, which implies a

5 to indoles 6, a

[

,

σ

shortcut capable of improving the process and avoiding the in-situ formation of imines 5.

Since modest efﬁciency of the mixture of the catalyst and oxidant agent Pd(OAc)₂/

Cu(OAc)₂was achieved for the one-pot conversion of anilines and ketones to indoles

in only two cases [66], the Hg(I)-free reaction of aniline 1i with 2a in the presence of

the Pd(OAc)₂/Cu(OAc)₂couple was also tested. However, no indole was found [51].

Indeed, the alkyne was consumed only to generate 1,4-diphenylbuta-1,3-diyne, being the

well-known, palladium-catalyzed, self-coupling product of terminal alkynes [94].

Given that Hg(II) was an active catalyst for promoting the formation of imine 5i

(

Table 1, entry 9), analogous alkynyl- and vinyl-mercury(II) (i.e., species I–III) could

not be discarded as a competitive complex species [54]. Consequently, an assay was

carried out with an HgCl₂-catalyzed reaction of aniline 1i with 2a, followed by the

Pd(OAc)₂/Cu(OAc)₂couple-catalyzed cyclization in DMSO, which led to indole 6h in low

yield (12%). This indicates that the mechanism of the reaction described in Scheme 4 is

mainly driven by Hg(I) intermediates (i.e., species I–IV).

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3. Materials and Methods

3.1. General

Melting points were determined on a Krüss KSP 1N (KRÜSS GmbH, Hamburg, Ger-

many) capillary melting point apparatus. IR spectra were recorded on Perkin-Elmer 2000

(PerkinElmer, Waltham, MA, USA) and Bruker Vertex 70 (ATR-FT) (Bruker Corporation,

Billerica, MA, USA) spectrophotometers. ¹H and ¹³C NMR spectra were captured on

Varian Mercury (300 MHz) (Varian, Inc., Palo Alto, CA, USA), Varian VNMR (500 MHz)

(Varian, Inc., Palo Alto, CA, USA), and Bruker 600 AVANCE III (600 MHz) (Bruker Corpo-

ration, Billerica, MA, USA) instruments, with CDCl₃as the solvent and TMS as the internal

standard. Signal assignments were based on 2D NMR spectra (HMQC, HMBC, and/or

ROESY). Mass spectra (MS) were recorded on Thermo Polaris Q-Trace GC Ultra (Finnigan

Co., Waltham, MA, USA) and Hewlett-Packard 5971 A (Hewlett Packard Co., Houston,

TX, USA) spectrometers. High-resolution mass spectra (HRMS) were obtained (in electron

impact mode) on a Jeol JSM-GCMateII (JEOL, Ltd., Tokyo, Japan) spectrometer. X-Ray crys-

tallographic measurements were collected on an Oxford XcaliburS diffractometer (Rigaku

Co., Tokyo, Japan). Analytical thin-layer chromatography was performed with 0.25 plates

coated with E. Merck (Darmstadt, Germany) silica gel 60 F254 and visualized with a

short/long-wavelength UV lamp. Flash column chromatography was conducted over

Natland International Co. (Morrisville, NC, USA) silica gel (230–400 and 230–400 mesh).

All air moisture-sensitive reactions were conducted under N₂in oven-dried glassware.

DMSO was distilled over CaH₂, and Li₂CO₃and K₂CO₃were dried overnight at 250 ^◦C

prior to use. All other reagents were utilized without further puriﬁcation. Warning: The

hazardous wastes of mercury-containing silica gel and reaction residues were treated

with sulfur and placed in high-density plastic containers for disposal, then handled by an

authorized hazardous waste company.

3.2. General Method A for the Preparation of Imines 5a–n

To a round-bottomed ﬂask (at room temperature and in the dark), the corresponding

arylacetylene 2a

(1.05 mol equiv.), and mercury(I) chloride (0.05 mol equiv.) were successively added. The

mixture was vigorously stirred at 60 C for 2–8 h. The organic layer was extracted with

EtOAc (3 5 mL) and dried with Na₂SO₄. The solvent was removed under vacuum and

–d (1.0 mol equiv.), Li₂CO₃(0.20 mol equiv.), the respective aniline 1a–k

º

×

the residue was puriﬁed by column chromatography over silica gel treated with Et₃N (10%

w/w) (40 g/g crude, hexane/EtOAc, 98:2) to afford imines 5a–n.

3.3. General Method B for the Preparation of Indoles 6a–p

To a round-bottomed ﬂask (at room temperature and in the dark), the corresponding

alkyl and arylacetylenes 2a

equiv.), and mercury(I) chloride (0.05 mol equiv.) were successively added. The mixture

was vigorously stirred at 40–60 C for 2–8 h, and anhydrous DMSO (0.2 M), Cu(OAc)₂

(1.5 mol equiv.), and Pd(OAc)₂(0.20 mol equiv.) were successively added. The mixture

was stirred at 80 C for 24 h, ﬁltered over celite, and washed with EtOAc (4 20 mL). The

–g (1.0 mol equiv.), the respective aniline 1a–g and 1i–k (1.05 mol

º

×

organic layer was washed with brine (40 mL) and dried with Na₂SO₄. The solvent was

removed under vacuum and the residue was puriﬁed by column chromatography over

silica gel (30 g/g crude, hexane/EtOAc, 98:2) to provide indoles 6a–p.

3.4. General Method C for the Preparation of Indoles 6a and 6h–i Starting from Imines 5a and 5i–j

In a round-bottomed ﬂask (at room temperature), the respective imine 5a and 5i

anhydrous DMSO (0.2 M), Cu(OAc)₂(1.5 mol equiv.), and Pd(OAc)₂(0.20 mol equiv.) were

mixed and stirred at 80 C for 24 h. The crude reaction was ﬁltered over celite and washed

with EtOAc (4 20 mL). The organic layer was washed with brine (40 mL) and dried with

Na₂SO₄. The solvent was removed under vacuum and the residue was puriﬁed by column

–j,

º

×

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chromatography over silica gel (50 g/g crude, hexane/EtOAc, 98:2) to obtain indoles 6a

and 6h–i.

3.5. Preparation and Characterization of Imines 5a–n

3.5.1. (E)-N-(1-Phenylethylidene)aniline (5a)

Following general method A, a mixture of 2a (0.094 g, 0.92 mmol), Li₂CO₃(0.014 g,

0.19 mmol), 1a (0.090 g, 0.97 mmol), and Hg₂Cl₂(0.022 g, 0.047 mmol) was reacted for 4 h

to furnish 5a (0.159 g, 88%) as a yellow solid. Rf 0.72 (hexane/EtOAc, 7:3); mp 35–36 ^◦C

(Lit. 37 ^◦C [10]; 42–43 ^◦C [95]). IR (ﬁlm): 3058, 3027, 1638, 1593, 1482, 1447, 1366, 1287,

ῡ

1214, 1072, 1026, 783, 762, 730, 694 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.23 (s, 3H, CH₃-2’),

1

6.78–6.82 (m, 2H, H-2), 7.06–7.11 (m, 1H, H-4), 7.32–7.38 (m, 2H, H-3), 7.41–7.49 (m, 3H,

H-3”, H-4”), 7.95–7.80 (m, 2H, H-2”). ¹³C NMR (125 MHz, CDCl₃):

δ

17.4 (CH₃-2’), 119.3

(C-2), 123.2 (C-4), 127.1 (C-2”), 128.3 (C-3”), 128.9 (C-3), 130.4 (C-4”), 139.5 (C-1”), 151.7

(C-1), 165.4 (C-1⁰). HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₃N: 195.1048; found: 195.1046.

3.5.2. (E)-2-Methyl-N-(1-phenylethylidene)aniline (5b)

Following general method A, a mixture of 2a (0.101 g, 0.99 mmol), Li₂CO₃(0.015 g,

0.20 mmol), 1b (0.111 g, 1.04 mmol), and Hg₂Cl₂(0.023 g, 0.049 mmol) was reacted for 4 h

to give 5b (0.176 g, 85%) as a yellow solid. Rf 0.77 (hexane/EtOAc, 7:3); mp 56–58 ^◦C (Lit.

◦

ῡ

61 C [10]). IR (ﬁlm): 3063, 3016, 1637, 1597, 1578, 1482, 1447, 1366, 1287, 1221, 1114, 1026,

1

787, 765, 737, 692 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ 2.10 (s, 3H, CH₃Ar), 2.16 (s, 3H,

CH₃-2’), 6.65 (br d, J = 7.8 Hz, 2H, H-6), 7.00 (br dd, J = 7.8, 7.2 Hz, 1H, H-4), 7.17 (br dd,

J = 7.8, 7.2 Hz, 1H, H-5), 7.21 (br d, J = 7.2 Hz, 1H, H-3), 7.43–7.49 (m, 3H, H-3”, H-4”),

7.99–8.02 (m, 2H, H-2”). ¹³C NMR (150 MHz, CDCl₃): δ 17.4 (CH₃-2’), 17.8 (CH₃Ar), 118.4

(C-6), 123.2 (C-4), 126.3 (C-5), 127.1 (C-2, C-2”), 128.4 (C-3”), 130.3 (C-3), 130.4 (C-4”), 139.4

(C-1”), 150.3 (C-1), 164.9 (C-1’).

3.5.3. (E)-2-Methoxy-N-(1-phenylethylidene)aniline (5c)

Following general method A, a mixture of 2a (0.107 g, 1.05 mmol), Li₂CO₃(0.015 g,

0.20 mmol), 1c (0.135 g, 1.10 mmol), and Hg₂Cl₂(0.025 g, 0.053 mmol) was reacted for 4 h

ῡ

to afford 5c (0.205 g, 87%) as a yellow oil. Rf 0.70 (hexane/EtOAc, 7:3). IR (ﬁlm): 3059,

3001, 2957, 2834, 1684, 1635, 1590, 1489, 1448, 1366, 1242, 1208, 1180, 1115, 1046, 1026, 765,

1

746, 693 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.18 (s, 3H, CH₃-2’), 3.79 (s, 3H, CH₃O), 6.78

(dd, J = 7.5, 1.7 Hz, 2H, H-6), 6.94 (dd, J = 7.5, 1.5 Hz, 1H, H-3), 6.96 (td, J = 7.5, 1.5 Hz, 1H,

H-5), 7.08 (td, J = 7.5, 1.7 Hz, 1H, H-4), 7.42–7.48 (m, 3H, H-3”, H-4”), 7.97–8.03 (m, 2H,

H-2”). ¹³C NMR (125 MHz, CDCl₃):

δ 17.8 (CH₃-2’), 55.6 (CH₃O), 111.5 (C-3), 120.5 (C-5),

120.8 (C-6), 124.1 (C-4), 127.3 (C-2”), 128.3 (C-3”), 130.4 (C-4”), 139.3 (C-1”), 140.5 (C-1),

148.9 (C-2), 167.1 (C-1’) [96].

3.5.4. (E)-3-Methyl-N-(1-phenylethylidene)aniline (5d)

Following general method A, a mixture of 2a (0.096 g, 0.94 mmol), Li₂CO₃(0.014 g,

0.19 mmol), 1d (0.106 g, 0.99 mmol), and Hg₂Cl₂(0.022 g, 0.047 mmol) was reacted for 4 h

to give 5d (0.163 g, 83%) as a yellow oil. Rf 0.67 (hexane/EtOAc, 7:3); (Lit. mp 34 ^◦C [10]).

ῡ

IR (ﬁlm):

3059, 3001, 2958, 2834, 1684, 1634, 1594, 1485, 1447, 1367, 1313, 1288, 1261,

1

1193, 1148, 1045, 913, 852, 784, 765, 694 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.23 (s, 3H,

CH₃-2’), 2.35 (s, 3H, CH₃Ar), 6.60 (dm, J = 7.5 Hz, 1H, H-6), 6.61–6.64 (m, 1H, H-2), 6.90 (dm,

J = 7.5 Hz, 1H, H-4), 7.23 (t, J = 7.5 Hz, 1H, H-5), 7.41–7.48 (m, 3H, H-3”, H-4”), 7.94–7.98

(m, 2H, H-2”). ¹³C NMR (125 MHz, CDCl₃):

δ 17.3 (CH₃-2’), 21.5 (CH₃Ar), 116.3 (C-6),

120.0 (C-2), 123.9 (C-4), 127.1 (C-2”), 128.3 (C-3”), 128.8 (C-5), 130.4 (C-4”), 138.7 (C-3), 139.5

(C-1”), 151.7 (C-1), 165.2 (C-1’). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₅N: 209.1204; found:

209.1205.

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3.5.5. (E)-3-Methoxy-N-(1-phenylethylidene)aniline (5e)

Following general method A, a mixture of 2a (0.096 g, 0.94 mmol), Li₂CO₃(0.014 g,

0.19 mmol), 1e (0.122 g, 0.99 mmol), and Hg₂Cl₂(0.022 g, 0.047 mmol) was reacted for 4 h

ῡ

to form 5e (0.178 g, 84%) as a yellow oil. Rf 0.70 (hexane/EtOAc, 7:3). IR (ﬁlm): 3452,

1

3369, 2929, 2837, 1602, 1496, 1464, 1292, 1206, 1158, 1038, 835, 764, 688. H NMR (500 MHz,

CDCl₃):

J = 8.0, 2.0, 1.0 Hz, 1H, H-4), 7.25 (t, J = 8.0 Hz, 1H, H-5), 7.42–7.49 (m, 3H, H-3”, H-4”),

7.95–7.98 (m, 2H, H-2”). ¹³C NMR (125 MHz, CDCl₃):

17.4 (CH₃-2’), 55.2 (CH₃O), 105.0

δ 2.25 (s, 3H, CH₃-2’), 3.81 (s, 3H, CH₃O), 6.35–6.40 (m, 2H, H-2, H-6), 6.64 (ddd,

δ

(C-2), 108.8 (C-4), 111.7 (C-6), 127.1 (C-2”), 128.3 (C-3”), 129.8 (C-5), 130.5 (C-4”), 139.4

(C-1”), 153.1 (C-1), 160.3 (C-3), 165.5 (C-1’) [97].

3.5.6. (E)-3-Chloro-N-(1-phenylethylidene)aniline (5f)

Following general method A, a mixture of 2a (0.111 g, 1.09 mmol), Li₂CO₃(0.016 g,

0.22 mmol), 1f (0.145 g, 1.14 mmol), and Hg₂Cl₂(0.026 g, 0.055 mmol) was reacted for

ῡ

4 h to provide 5f (0.132 g, 53%) as a brown oil. Rf 0.76 (hexane/EtOAc, 7:3). IR (ﬁlm):

1

3060, 2920, 1635, 1588, 1470, 1448, 1367, 1288, 1212, 1072, 864, 788, 763, 692 cm⁻¹. H NMR

(600 MHz, CDCl₃):

1H, H-2), 7.07 (dm, J = 8.1 Hz, 1H, H-4), 7.27 (t, J = 8.1 Hz, 1H, H-5), 7.43–7.51 (m, 3H, H-3”,

H-4”), 7.94–7.97 (m, 2H, H-2”). ¹³C NMR (150 MHz, CDCl₃):

17.9 (CH₃-2’), 118.0 (C-6),

δ 2.25 (s, 3H, CH₃-2’), 6.68 (dm, J = 8.1 Hz, 1H, H-6), 6.81 (t, J = 1.8 Hz,

δ

119.8 (C-2), 123.5 (C-4), 127.5 (C-2”), 128.7 (C-3”), 130.4 (C-5), 131.1 (C-4”), 134.8 (C-3), 139.3

(C-1”), 152.2 (C-1), 166.6 (C-1’). HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₂N: 229.0658; found:

209.0652 [13].

3.5.7. (E)-4-Methyl-N-(1-phenylethylidene)aniline (5g)

Following general method A, a mixture of 2a (0.096, 0.94 mmol), Li₂CO₃(0.014 g,

0.19 mmol), 1g (0.105 g, 0.98 mmol), and Hg₂Cl₂(0.022 g, 0.047 mmol) was reacted for 2 h

◦

to afford 5g (0.179 g, 91%) as a yellow oil. Rf 0.76 (hexane/EtOAc, 7:3); (Lit. 62 C [10]). IR

ῡ

(ﬁlm): 3449, 3363, 3023, 2920, 1683, 1633, 1516, 1505, 1447, 1364, 1288, 1266, 1219, 1026,

1

842, 827, 763, 692 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ 2.24 (s, 3H, CH₃-2’), 2.35 (s, 3H,

CH₃Ar), 6.70 (d, J = 7.8 Hz, 2H, H-2), 7.16 (d, J = 7.8 Hz, 2H, H-3), 7.41–7.49 (m, 3H, H-3”,

H-4”), 7.94–7.99 (m, 2H, H-2”). ¹³C NMR (150 MHz, CDCl₃): δ 17.3 (CH₃

-2’), 20.9 (CH₃Ar), 119.4 (C-2), 127.1 (C-2”), 128.3 (C-3”), 129.5 (C-3), 130.3 (C-4”),

132.6 (C-4), 139.7 (C-1”), 149.0 (C-1), 165.5 (C-1’). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₅N:

209.1204; found: 209.1210 [51].

3.5.8. (E)-4-(N,N-dimethylamino)-N-(1-phenylethylidene)aniline (5h)

Following general method A, a mixture of 2a (0.099 g, 0.97 mmol), Li₂CO₃(0.014 g,

0.19 mmol), 1h (0.139 g, 1.02 mmol) and Hg₂Cl₂(0.023 g, 0.049 mmol) was reacted f_◦or 2 h

to obtain 5h (0.158 g, 68%) as a brown solid. Rf 0.53 (hexane/EtOAc, 7:3); mp 90–92 C. IR

1

(ﬁlm): 2918, 2803, 1622, 1510, 1446, 1364, 1222, 830, 760, 690 cm⁻¹. H NMR (500 MHz,

ῡ

CDCl₃):

δ 2.28 (s, 3H, CH₃-2’), 2.95 (s, 6H, (CH₃)₂N), 6.75–6.82 (m, 4H, H-2, H-3), 7.41–7.45

(m, 3H, H-3”, H4”), 7.95–7.97 (m, 2H, H-2”). ¹³C NMR (125 MHz, CDCl₃): δ 17.3 (CH₃-2’),

41.2 ((CH₃)₂N), 113.5 (C-3), 121.0 (C-2), 127.0 (C-2”), 128.3 (C-3”), 130.1 (C-4”), 140.1 (C-1”),

141.7 (C-1), 147.4 (C-4), 165.0 (C-1’). HRMS (EI): m/z [M⁺] calcd for C₁₆H₁₈N₂: 238.1470;

found: 238.1471 [98].

3.5.9. (E)-4-Methoxy-N-(1-phenylethylidene)aniline (5i)

Following general method A, a mixture of 2a (0.125 g, 1.23 mmol), Li₂CO₃(0.018 g,

0.24 mmol), 1i (0.158 g, 1.28 mmol), and Hg₂Cl₂(0.029 g, 0.06 mmol) was reacted for 2 h to

furnish 5i (0.252 g, 91%) as a pale yellow crystalline solid. Rf 0.70 (hexane/EtOAc, 7:3); mp

93–94 ^◦C (Lit. 86 ^◦C [10

,

95]; Lit. 85–86 ^◦C [50]). IR (KBr): 2954, 2929, 1616, 1576, 1510,

ῡ

1

1443, 1365, 1284, 1240, 1210, 1032, 846, 771, 752, 699 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ

2.26 (s, 3H, CH₃-2’), 3.82 (s, 3H, CH₃O), 6.73–6.79 (m, 2H, H-2), 6.89–6.94 (m, 2H, H-3),

7.41–7.49 (m, 3H, H-3”, H-4”), 7.95–7.98 (m, 2H, H-2”). ¹³C NMR (150 MHz, CDCl₃):

δ

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17.3 (C-2’), 55.5 (CH₃O), 114.2 (C-3), 120.7 (C-2), 127.1 (C-2”), 128.3 (C-3”), 130.3 (C-4”),

139.8 (C-1”), 144.8 (C-1), 155.9 (C-4), 165.7 (C-1’). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₅NO:

225.1154; found: 225.1164 [51,99].

3.5.10. (E)-4-Chloro-N-(1-phenylethylidene)aniline (5j)

Following general method A, a mixture of 2a (0.119 g, 1.17 mmol), Li₂CO₃(0.017 g,

0.23 mmol), 1j (0.155 g, 1.22 mmol), and Hg₂Cl₂(0.027 g, 0.057 mmol) was reacted for 2 h

to give 5j (0.209 g, 78%) as a yellow solid. Rf 0.76 (hexane/EtOAc, 7:3); mp 68–70 ^◦C (Lit.

73–74 ^◦C [99]). IR (ﬁlm): 3061, 2955, 2854, 1634, 1579, 1483, 1447, 1367, 1288, 1214, 1091,

ῡ

1

1010, 844, 762, 692, 674 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.23 (s, 3H, CH₃-2’), 6.71–6.76

(m, 2H, H-2), 7.28–7.33 (m, 2H, H-3), 7.42–7.50 (m, 3H, H-3”, H-4”), 7.93–7.98 (m, 2H, H-2”).

¹³C NMR (125 MHz, CDCl₃):

δ

17.4 (CH₃-2’), 120.8 (C-2), 127.2 (C-2”), 128.4 (C-3”), 128.5

(C-4), 129.0 (C-3), 130.7 (C-4”), 139.2 (C-1”), 150.2 (C-1), 166.2 (C-1’) [13,51].

3.5.11. (E)-2-Bromo-4-methoxy-N-(1-phenylethylidene)aniline (5k)

Following general method A, a mixture of 2a (0.093 g, 0.91 mmol), Li₂CO₃(0.013 g,

0.182 mmol), 1k (0.177 g, 0.95 mmol), and Hg₂Cl₂(0.021 g, 0.044 mmol) was reacted for 8 h

ῡ

to produce 5k (0.110 g, 42%) as a yellow oil. Rf 0.73 (hexane/EtOAc, 7:3). IR (ﬁlm): 3057,

1

3026, 2921, 1645, 1634, 1578, 1480, 1447, 1366, 1293, 1221, 1044, 865, 828, 761, 692 cm⁻¹. H

NMR (500 MHz, CDCl₃):

H-6), 7.09 (dd, J = 8.0, 2.0 Hz, 1H, H-5), 6.43 (d, J = 2.0 Hz, 1H, H-3), 7.44–7.50 (m, 3H, H-3”,

H-4”), 7.98–8.02 (m, 2H, H-2’). ¹³C NMR (125 MHz, CDCl₃):

18.0 (CH₃-2’), 20.5 (CH₃Ar),

δ 2.19 (s, 3H, CH₃-2’), 2.33 (s, 3H, CH₃Ar), 6.68 (d, J = 8.0 Hz, 1H,

δ

113.5 (C-2), 120.1 (C-6), 127.4 (C-2”), 128.4 (C-3”), 128.7 (C-5), 130.7 (C-4”), 133.1 (C-3), 134.2

(C-4), 139.1 (C-1”), 147.4 (C-1), 167.6 (C-1’). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₄BrN:

287.0310; found: 287.0318.

3.5.12. (E)-4-Methoxy-N-(1-(p-tolyl)ethylidene)aniline (5l)

Following general method A, a mixture of 2b (0.118 g, 1.02 mmol), Li₂CO₃(0.015 g,

0.20 mmol), 1i (0.132 g, 1.07 mmol), and Hg₂Cl₂(0.024 g, 0.051 mmol) was reacted for 2 h to

◦

generate 5l (0.221 g, 91%) as a yellow solid. Rf 0.73 (hexane/EtOAc, 7:3); mp 78–80 C (Lit.

◦

ῡ

83 C [10]). IR (ﬁlm): 2996, 2954, 2930, 2835, 1621, 1576, 1505, 1445, 1366, 1286, 1242, 1211,

1

1181, 1032, 846, 761, 699 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.22 (s, 3H, CH₃-2’), 2.40 (s,

3H, CH₃Ar), 3.81 (s, 3H, CH₃O), 6.72–6.76 (m, 2H, H-2), 6.88–6.92 (m, 2H, H-3), 7.22–7.25

(m, 2H, H-3”), 7.84–7.87 (m, 2H, H-2”). ¹³C NMR (125 MHz, CDCl₃):

δ

17.2 (CH₃-2’), 21.3

(CH₃Ar), 55.5 (CH₃O), 114.2 (C-3), 120.8 (C-2), 127.1 (C-2”), 129.0 (C-3”), 137.1 (C-1”), 140.5

(C-4”), 145.0 (C-1), 155.8 (C-4), 165.5 (C-1’) [100].

3.5.13. (E)-4-(1-((4-methoxyphenyl)imino)ethyl)benzonitrile (5m)

Following general method A, a mixture of 2c (0.083 g, 0.65 mmol), Li₂CO₃(0.010 g,

0.13 mmol), 1i (0.084 g, 0.68 mmol), and Hg₂Cl₂(0.014 g, 0.03 mmol) was reacted for

2 h, resulting in an inseparable mixture of 5m

/

7b (95:5) as an instable brown solid. The

1

yield of compound 5m (0.147 g, 90%) was estimated by H NMR and GC/MS. Rf 0.48

1

(hexano/AcOEt, 7:3). H NMR (500 MHz, CDCl₃):

δ 2.28 (s, 3H, CH₃-2’), 3.83 (s, 3H, CH₃O),

6.73–6.78 (m, 2H, H-2), 6.91–6.95 (m, 2H, H-3), 7.72–7.75 (m, 2H, H-3”), 8.04–8.09 (m, 2H,

H-2”). Signals attributed to 7b: 2.65 (s, CH₃-2’), 3.74 (s, CH₃O), 7.74–7.80 (m, H-3”) [100].

3.5.14. (E)-4-Methoxy-N-(1-(4-methoxyphenyl)ethylidene)aniline (5n)

Following general method A, a mixture of 2d (0.095 g, 0.72 mmol), Li₂CO₃(0.011 g,

0.15 mmol), 1i (0.093 g, 0.76 mmol), and Hg₂Cl₂(0.017 g, 0.036 mmol) was reacted for 2 h to

form 5n (0.152 g, 83%) as a pale yellow solid. Rf 0.57 (hexane/EtOAc, 7:3); mp 130–132 ^◦C

◦

ῡ

(Lit. 132–134 C [95]). IR (ﬁlm):

2968, 2837, 1626, 1601, 1502, 1379, 1286, 1258, 1239,

1

1207, 1172, 1028, 833 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ

2.22 (s, 3H, CH₃-2’), 3.82 (s, 3H,

CH₃O-4), 3.86 (s, 3H, CH₃O-4”), 6.72–6.76 (m, 2H, H-2), 6.88–6.92 (m, 2H, H-3), 6.93–6.96

(m, 2H, H-3”), 7.91–7.95 (m, 2H, H-2”). ¹³C NMR (150 MHz, CDCl₃):

δ

17.1 (C-2’), 55.4

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(CH₃O-C4”), 55.5 (CH₃O-C4), 113.6 (C-3”), 114.2 (C-3), 120.9 (C-2), 128.7 (C-2”), 132.5 (C-1”),

145.0 (C-1), 155.8 (C-4), 161.4 (C4”), 164.8 (C-1’) [99,100].

3.6. Preparation and Characterization of Indoles 6a–p

3.6.1. 2-Phenyl-1H-indole (6a)

Following general method B, a mixture of 2a (0.080 g, 0._◦79 mmol), 1a (0.077 g,

0.83 mmol), and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 4 h. It was then

reacted with DMSO (3.9 mL), Cu(OAc)₂(0.215 g, 1.18 mmol), and Pd(OAc)₂(0.035 g,

0.16 mmol) to yield 6a (0.120 g, 79%) as a brown solid. Rf 0.77 (hexane/EtOAc, 7:3).

Following general method C, a mixture of 5a (0.088 g, 0.45 mmol), DMSO (2.2 mL),

Cu(OAc)₂(0.123 g, 0.68 mmol), and Pd(OAc)₂(0.020 g, 0.09 mmol) was reacted to yield 6a

(0.054 g, 63%) as a pale brownish solid. Rf 0.77 (hexane/EtOAc, 7:3); mp 189–190 ^◦C (Lit.

ῡ

189–190

º

C [66], 188–189

º

C [101], 187–188

º

C [102]). IR (ATR): 3439, 2919, 2853, 1455,

1

1230, 794, 770, 742, 690 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ

6.83 (dd, J = 2.1, 0.9 Hz, 1H,

H-3), 7.12 (td, J = 7.8, 0.6 Hz, 1H, H-5), 7.19 (td, J = 7.8, 1.2 Hz, 1H, H-6), 7.30–7.33 (m, 1H,

H-4’), 7.39 (dd, J = 7.8, 0.9 Hz, 1H, H-7), 7.41–7.46 (m, 2H, H-3’), 7.63 (dd, J = 7.8, 0.9 Hz,

1H, H-4), 7.64–7.67 (m, 2H, H-2’), 8.32 (br s, 1H, NH). ¹³C NMR (150 MHz, CDCl₃):

δ 100.0

(C-3), 110.9 (C-7), 120.3 (C-5), 120.7 (C-4), 122.4 (C-6), 125.2 (C-2’), 127.7 (C-4’), 129.0 (C-3’),

129.3 (C-3a), 132.4 (C-1’), 136.8 (C-7a), 137.9 (C-2).

3.6.2. 7-Methyl-2-phenyl-1H-indole (6b)

Following general method B, a mixture of 2a (0.077 g, 0._◦57 mmol), 1b (0.085 g,

0.79 mmol), and Hg₂Cl₂(0.018 g, 0.04 mmol) was stirred at 60 C for 4 h. It was then

reacted with DMSO (3.8 mL), Cu(OAc)₂(0.205 g, 1.13 mmol), and Pd(OAc)₂(0.034 g,

0.15 mmol) to provide 6b_◦(0.10 g, 64%) as a brown solid. Rf 0.67 (hexane/EtOAc, 7:3); mp

◦

ῡ

114–116 C (Lit. 112–118 C [103]). IR (ATR): 3450, 1601, 1486, 1449, 1335, 1330, 1299, 804,

1

770, 737, 690 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.52 (s, 3H, CH₃Ar), 6.81 (d, J = 2.5 Hz,

1H, H-3), 6.98 (dm, J = 7.5 Hz, 1H, H-6), 7.04 (t, J = 7.5 Hz, 1H, H-5), 7.30 (tm, J = 7.5 Hz,

1H, H-4’), 7.40–7.44 (m, 2H, H-3’), 7.47 (dm, J = 7.5 Hz, 1H, H-4), 7.64–7.68 (m, 2H, H-2’),

8.15 (br s, 1H, NH). ¹³C NMR (125 MHz, CDCl₃):

δ 16.7 (CH₃Ar), 100.6 (C-3), 118.4 (C-4),

120.0 (C-7), 120.4 (C-5), 122.9 (C-6), 125.2 (C-2’), 127.6 (C-4’), 128.8 (C-3a), 129.0 (C-3’), 132.5

(C-1’), 136.4 (C-7a), 137.6 (C-2).

3.6.3. 7-Methoxy-2-phenyl-1H-indole (6c)

Following general method B, a mixture of 2a (0.086 g, 0.84 mmol), 1c (0.110 g,

◦

0.89 mmol), and Hg₂Cl₂(0.020 g, 0.04 mmol) was stirred at 60 C for 4 h. It was then

reacted with DMSO (4.2 mL), Cu(OAc)₂(0.230 g, 1.27 mmol), and Pd(OAc)₂(0.038 g,

0.17 mmol) to furnish 6c (0.149 g, 79%) as an amber solid. Rf 0.67 (hexane/EtOAc, 7:3); mp

63–64 ^◦C (Lit. 94–95

º

C [66]). IR (ATR): 3429, 1608, 1581, 1505, 1485, 1453, 1401, 1332,

ῡ

1

1316, 1258, 1225, 1097, 798, 772, 753, 730 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ 4.00 (s, 3H,

CH₃O), 6.66 (d, J = 7.8 Hz, 1H, H-6), 6.81 (d, J = 2.4, 1H, H-3), 7.04 (t, J = 7.8 Hz, 1H, H-5),

7.24 (d, J = 7.8 Hz, 1H, H-4), 7.31–7.34 (m, 1H, H-4’), 7.42–7.46 (m, 2H, H-3’), 7.68–7.70 (m,

2H, H-2’), 8.56 (br s, 1H, NH). ¹³C NMR (150 MHz, CDCl₃):

δ 55.3 (CH₃O), 100.2 (C-3),

102.1 (C-6), 113.3 (C-4), 120.5 (C-5), 125.1 (C-2’), 127.3 (C-7a), 127.6 (C-4’), 129.0 (C-3’), 130.4

(C-3a), 132.4 (C-1’), 137.5 (C-2), 145.9 (C-7). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₃NO:

223.0997; found: 223.0994.

3.6.4. 6-Methyl-2-phenyl-1H-indole (6d). 4-Methyl-2-phenyl-1H-indole (6d’)

Following general method B, a mixture of 2a (0.076 g, 0._◦75 mmol), 1d (0.084 g,

0.79 mmol), and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 4 h. It was then

reacted with DMSO (3.7 mL), Cu(OAc)₂(0.204 g, 1.12 mmol), and Pd(OAc)₂(0.034 g,

0.15 mmol) to afford a mixture of 6d

/

6d’ (88:12), which was separated to provide 6d

◦

(0.097 g, 63%) as a pale yellow solid. Rf 0.70 (hexane/EtOAc, 7:3); mp 186–187 C (Lit.

189–190 ^◦C

[

102], 190–192 ^◦C [103]). IR (ATR): 3429, 1454, 1384, 1350, 1232, 814, 760, 741,

ῡ

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1

687 cm⁻¹. H NMR (600 MHz, CDCl₃): δ 2.47 (s, 3H, CH₃Ar), 6.78 (dd, J = 2.4, 0.9 Hz, 1H,

H-3), 6.96 (dd, J = 8.4, 0.9 Hz, 1H, H-5), 7.20 (d, J = 0.9 Hz, 1H, H-7), 7.29–7.32 (m, 1H, H-4’),

7.41–7.45 (m, 2H, H-3’), 7.51 (d, J = 8.4, 1H, H-4), 7.63–7.66 (m, 2H, H-2’), 8.21 (br s, 1H, NH).

¹³C NMR (150 MHz, CDCl₃):

δ 21.8 (CH₃Ar), 99.8 (C-3), 110.8 (C-7), 120.3 (C-4), 122.0 (C-5),

125.0 (C-2’), 127.1 (C-3a), 127.5 (C-4’), 129.0 (C-3’), 132.3 (C-6), 132.6 (C-1’), 137.2 (C-7a),

137.3 (C-2). Data for 6d: MS (70 eV): m/z 207 (M⁺, 100), 206 (60), 178 (5), 130 (7), 77 (18), 44

(15). Data for 6d’: MS (70 eV): m/z 207 (M⁺, 10), 177 (13), 169 (11), 143 (7), 119 (14), 77 (30),

44 (100).

3.6.5. 6-Methoxy-2-phenyl-1H-indole (6e). 4-Methoxy-2-phenyl-1H-indole (6e’)

Following general method B, a mixture of 2a (0.085 g, 0._◦83 mmol), 1e (0.107 g,

0.87 mmol), and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 4 h. It was then

reacted with DMSO (4.4 mL), Cu(OAc)₂(0.225 g, 1.24 mmol), and Pd(OAc)₂(0.038 g,

0.17 mmol), leading to a mixture of 6e/6e’ (93:7) [66], which was separated by column

chromatography over silica gel (30 g/g crude, hexane/EtOAc, 98:2) to give 6e (0.138 g,

75%) as a brown solid. Rf 0.60 (hexane/EtOAc, 7:3); mp 160–161 ^◦C (Lit. 177–178 ^◦C [66];

1

173–176 ^◦C [102]). IR (ATR): 3396, 1625, 1446, 1257, 1200, 1158, 1016, 823, 756 cm⁻¹. H

ῡ

NMR (600 MHz, CDCl₃):

δ 3.86 (s, 3H, CH₃O), 6.76 (d, J = 1.8, 1H, H-3), 6.80 (dd, J = 8.4,

2.4 Hz, 1H, H-5), 6.90 (d, J = 2.4, 1H, H-7), 7.27–7.31 (m, 1H, H-4’), 7.41–7.44 (m, 2H, H-3’),

7.50 (d, J = 8.4, 1H, H-4), 7.60–7.63 (m, 2H, H-2’), 8.24 (br s, 1H, NH). ¹³C NMR (150 MHz,

CDCl₃):

δ 55.6 (CH₃O), 94.4 (C-7), 99.8, (C-3), 110.2 (C-5), 121.3 (C-4), 123.5 (C-3a), 124.7

(C-2’), 127.2 (C-4’), 129.0 (C-3’), 132.5 (C-1’), 136.8 (C-2), 137.6 (C-7a), 156.7 (C-6). Data for

6e: MS (70 eV): m/z 223 (M⁺, 77), 208 (100), 180 (23), 152 (17), 77 (3). Data for 6e’: MS (70 eV):

m/z 223 (M⁺, 100), 208 (87), 180 (17), 127 (15), 89 (23), 77 (13). HRMS (EI): m/z [M⁺] calcd for

C₁₅H₁₃NO: 223.0997; found: 223.0991.

3.6.6. 6-Chloro-2-phenyl-1H-indole (6f). 4-Chloro-2-phenyl-1H-indole (6f’)

Following general method B, a mixture of 2a (0.079 g, 0.77 mmol), 1f (0.103 g, 0.81 mmol),

◦

and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 4 h. It was then reacted with DMSO

(4.3 mL), Cu(OAc)₂(0.211 g, 1.16 mmol), and Pd(OAc)₂(0.034 g, 0.15 mmol), resulting in a

mixture of 6f/6f’ (81:19), which was separated by column chromatography over silica gel

(30 g/g crude, hexane/EtOAc, 98:2) to obtain 6f (_◦0.109 g, 62%) as a_◦yellow solid. Rf 0.70

◦

ῡ

(hexane/EtOAc, 7:3); mp 181–182 C (Lit. 171–173 C [104]; 182–183 C [105]). IR (ATR):

1

3429, 1453, 1310, 1067, 876, 805, 758, 736, 688 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 6.79 (d,

J = 2.0 Hz, 1H, H-3), 7.09 (dd, J = 8.5, 1.5 Hz, 1H, H-5), 7.34 (br t, J = 7.5 Hz, 1H, H-4’), 7.39

(d, J = 1.5 Hz, 1H, H-7), 7.45 (t, J = 7.5 Hz, 2H, H-3’), 7.52 (d, J = 8.5 Hz, 1H, H-4), 7.65 (d,

J = 7.5 Hz, 2H, H-2’), 8.32 (br s, 1H, NH). ¹³C NMR (125 MHz, CDCl₃):

δ 100.0 (C-3), 110.8

(C-7), 121.0 (C-5), 121.5 (C-4), 125.2 (C-2’), 127.8 (C-3a), 128.0 (C-4’), 128.1 (C-6), 129.1 (C-3’),

131.9 (C-1’), 137.1 (C-7a), 138.6 (C-2). Data for 6f: MS (70 eV): m/z 229 (M⁺+2, 37), 227 (M⁺,

100), 190 (8), 165 (23), 114 (5), 89 (13), 77 (3). Data for 6f’: MS (70 eV): m/z 229 (M⁺+2, 30),

227 (M⁺, 100), 190 (8), 165 (17), 89 (15).

3.6.7. 5-Methyl-2-phenyl-1H-indole (6g)

Following general method B, a mixture of 2a (0.083 g, 0._◦81 mmol), 1g (0.092 g,

0.86 mmol), and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 2 h. It was then

reacted with DMSO (4.1 mL), Cu(OAc)₂(0.222 g, 1.22 mmol), and Pd(OAc)₂(0.036 g,

0.16 mmol) to produce 6g (0.103 g, 61%) as a pale-yellow solid. Rf_◦0.70 (hexane/EtOAc,

◦

ῡ

7:3); mp 214–215 C (Lit. 216–218 C [66]; 211–213 C [102]; 218–220 C [103]). IR (ATR):

1

3405, 1603, 1449, 1406, 1299, 1202, 1079, 804, 799, 737, 761, 686 cm⁻¹. H NMR (600 MHz,

CDCl₃):

δ 2.45 (s, 3H, CH₃), 6.75 (dd, J = 2.4, 0.6 Hz, 1H, H-3), 7.02 (dd, J = 8.4, 1.2 Hz,

1H, H-6), 7.28 (d, J = 8.4 Hz, 1H, H-7), 7.29–7.32 (m, 1H, H-4’), 7.41 (dd, J = 1.2, 0.6 Hz,

1H, H-4), 7.41–7.44 (m, 2H, H-3’), 7.63–7.66 (m, 2H, H-2’), 8.23 (br s, 1H, NH). ¹³C NMR

(150 MHz, CDCl₃):

δ 21.5 (CH₃), 99.5 (C-3), 110.5 (C-7), 120.3 (C-4), 124.0 (C-6), 125.0 (C-2’),

127.6 (C-4’), 129.0 (C-3’), 129.46 (C-5), 129.54 (C-3a), 132.5 (C-1’), 135.2 (C-7a), 137.9 (C-2).

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3.6.8. 5-Methoxy-2-phenyl-1H-indole (6h)

Following general method B, a mixture of 2a (0.083 g, 0.82 mmol), 1i (0.106 g, 0.86 mmol),

◦

and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 2 h. It was then reacted with

DMSO (4.1 mL), Cu(OAc)₂(0.222 g, 1.22 mmol), and Pd(OAc)₂(0.036 g, 0.16 mmol) to

generate 6h (0.146 g, 80%) as a yellow solid. Rf 0.60 (hexane/EtOAc, 7:3).

Following general method C, a mixture of 5i (0.060 g, 0.27 mmol), DMSO (1.33 mL),

Cu(OAc)₂(0.073 g, 0.40 mmol), and Pd(OAc)₂(0.012 g, 0.054 mmol) was reacted to afford

6h (0.037 g, 62%) as a pale brownish solid. Rf 0.60 (hexane/EtOAc, 7:3). mp 168–169 ^◦C

(Lit. 169–170 ^◦C [66], 166–169 ^◦C [101], 160–162 ^◦C [102]). IR (KBr): 3415, 1615, 1479,

ῡ

1

1208, 1148, 1030, 765 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ 3.87 (s, 3H, CH₃O), 6.76 (dd,

J = 2.4, 1.2 Hz, 1H, H-3), 6.86 (dd, J = 9.0, 2.4 Hz, 1H, H-6), 7.09 (d, J = 2.4 Hz, 1H, H-4),

7.29 (d, J = 9.0 Hz, 1H, H-7), 7.30–7.33 (m, 1H, H-4’), 7.41–7.46 (m, 2H, H-3’), 7.63–7.66

(m, 2H, H-2’), 8.21 (br s, 1H, NH). ¹³C NMR (150 MHz, CDCl₃):

δ 55.8 (CH₃O), 99.9 (C-3),

102.3 (C-4), 111.6 (C-7), 112.6 (C-6), 125.1 (C-2’), 127.6 (C-4’), 129.0 (C-3’), 129.7 (C-3a), 132.0

(C-7a), 132.5 (C-1’), 138.6 (C-2), 154.5 (C-5).

3.6.9. 5-Chloro-2-phenyl-1H-indole (6i)

Following general method B, a mixture of 2a (0.085 g, 0.83 mmol), 1j (0.111 g, 0.87 mmol),

◦

and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 2 h. It was then reacted with

DMSO (4.1 mL), Cu(OAc)₂(0.225 g, 1.24 mmol), and Pd(OAc)₂(0.037 g, 0.17 mmol) to give

6i (0.134 g, 71%) as a yellow solid. Rf 0.60 (hexane/EtOAc, 7:3).

Following general method C, a mixture of 5j (0.081 g, 0.35 mmol), DMSO (1.77 mL),

Cu(OAc)₂(0.073 g, 0.53 mmol), and Pd(OAc)₂(0.016 g, 0.07 mmol) was reacted to provide

◦

6i (0.046 g, 57%) as a yellow solid. Rf 0.60 (hexane/EtOAc, 7:3); mp 195–196 C (Lit.

196–197 ^◦C [66], 198–200 ^◦C [103]). IR (ATR): 3429, 1452, 1313, 1065, 876, 803, 754, 736,

ῡ

1

687 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ 6.76 (d, J = 1.8 Hz, 1H, H-3), 7.14 (dd, J = 8.4,

1.8 Hz, 1H, H-6), 7.31 (d, J = 8.4 Hz, 1H, H-7), 7.35 (t, J = 7.5 Hz, 1H, H-4’), 7.45 (t, J = 7.5 Hz

2H, H-3’), 7.59 (d, J = 1.8 Hz, 1H, H-4), 7.65 (d, J = 7.5 Hz, 2H, H-2’), 8.35 (br s, 1H, NH).

¹³C NMR (150 MHz, CDCl₃):

99.6 (C-3), 111.8 (C-7), 120.0 (C-4), 122.6 (C-6), 125.2 (C-2’),

,

δ

125.9 (C-5), 128.1 (C-4’), 129.1 (C-3’), 130.3 (C-3a), 131.9 (C-1’), 135.1 (C-7a), 139.3 (C-2).

3.6.10. 7-Bromo-5-methyl-2-phenyl-1H-indole (6j)

Following general method B, a mixture of 2a (0.085 g, 0._◦83 mmol), 1k (0.163 g,

0.88 mmol), and Hg₂Cl₂(0.020 g, 0.04 mmol) was stirred at 60 C for 8 h. It was then

reacted with DMSO (4.2 mL), Cu(OAc)₂(0.227 g, 1.25 mmol), and Pd(OAc)₂(0.037 g,

0.17 mmol) to obtain 6j (0.085 g, 36%) as a brown solid. Rf 0.73 (hexane/EtOAc, 7:3); mp

75–77 ^◦C (Lit. 130–131 ^◦C [106]). IR (ﬁlm): 3446, 3036, 2918, 1605, 1568, 1477, 1449, 1395,

ῡ

1310, 1214, 856, 840, 759, 734, 690 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.42 (s, 3H, CH₃),

1

6.78 (dd, J = 2.5, 0.6 Hz, 1H, H-3), 7.18 (br s, 1H, H-6), 7.32–7.36 (m, 1H, H-4, H-4’), 7.42–7.47

(m, 2H, H-3’), 7.65–7.68 (m, 2H, H-2’), 8.32 (br s, 1H, NH). ¹³C NMR (125 MHz, CDCl₃):

δ

21.2 (CH₃), 100.5 (C-3), 103.9 (C-7), 119.5 (C-4), 125.3 (C-2’), 125.9 (C-6), 128.0 (C-4’), 129.0

(C-3’), 130.4 (C-3a), 131.1 (C-5), 131.9 (C-1’), 133.8 (C-7a), 138.6 (C-2). HRMS (EI): m/z [M⁺]

calcd for C₁₅H₁₂NBr: 285.0153; found: 285.0160.

3.6.11. 5-Methoxy-2-(p-tolyl)-1H-indole (6k)

Following general method B, a mixture of 2b (0.094 g, 0_◦.81 mmol), 1i (0.105 g,

0.85 mmol), and Hg₂Cl₂(0.019 g, 0.04 mmol) was stirred at 60 C for 2 h. It was then

reacted with DMSO (4.1 mL), Cu(OAc)₂(0.222 g, 1.22 mmol), and Pd(OAc)₂(0.036 g,

0.16 mm_◦ol) to give 6k (0.1_◦22 g, 64%) as a yellow solid. Rf 0.70 (hexane/EtOAc, 7:3); mp

ῡ

184–186 C (Lit. 186–187 C [66]). IR (ATR): 3424, 1621, 1543, 1479, 1452, 1301, 1217,

1

1153, 1115, 1029, 823, 789 cm⁻¹. H NMR (500 MHz, CDCl₃):

δ 2.39 (s, 3H, CH₃Ar), 3.86

(s, 3H, CH₃O), 6.71 (dd, J = 2.5, 1.0 Hz, 1H, H-3), 6.84 (dd, J = 8.5, 2.5 Hz, 1H, H-6), 7.08

(d, J = 2.5 Hz, 1H, H-4), 7.21–7.25 (m, 2H, H-3’), 7.26 (d, J = 8.5 Hz, 1H, H-7), 7.51–7.55 (m,

2H, H-2’), 8.17 (br s, 1H, NH). ¹³C NMR (125 MHz, CDCl₃):

δ 21.2 (CH₃Ar), 55.8 (CH₃O),

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99.3 (C-3), 102.2 (C-4), 111.5 (C-7), 112.3 (C-6), 125.0 (C-2’), 129.6 (C-1’ or C-3a), 129.7 (C-3’),

129.8 (C-3a or C-1’), 131.9 (C-7a), 137.6 (C-4’), 138.8 (C-2), 154.5 (C-5).

3.6.12. 2-(4-Cyanophenyl)-5-methoxy-1H-indole (6l)

Following general method B, a mixture of 2c (0.078 g, 0.61 mmol), 1i (0.079 g, 0.64 mmol),

◦

and Hg₂Cl₂(0.014 g, 0.03 mmol) was stirred at 60 C for 2 h. It was then reacted with

DMSO (3.1 mL), Cu(OAc)₂(0.167 g, 0.92 mmol), and Pd(OAc)₂(0.027 g, 0.12 mmol) to

produce 6l (0.050 g, 33%) as yellow crystals. Rf 0.47 (hexane/EtOAc, 7:3); mp 191–192 ^◦C

1

(Lit. 195–196 ^◦C [66]). IR (KBr): 3377, 2219, 1606, 1445, 1209, 1030, 836, 789 cm⁻¹. H

ῡ

NMR (500 MHz, CDCl₃):

(dd, J = 8.7, 2.5 Hz, 1H, H-6), 7.09 (d, J = 2.5 Hz, 1H, H-4), 7.31 (dd, J = 8.7, 0.5 Hz, 1H,

H-7), 7.69–7.73 (m, 4H, H-2’, H-3’), 8.30 (br s, 1H, NH). ¹³C NMR (125 MHz, CDCl₃):

55.8

δ 3.87 (s, 3H, CH₃O), 6.88 (dd, J = 1.5, 0.5 Hz, 1H, H-3), 6.92

δ

(CH₃O) 102.3 (C-4), 102.4 (C-3), 110.5 (C-4’), 112.0 (C-7), 114.3 (C-6), 118.8 (CN), 125.1 (C-2’),

129.4 (C-3a), 132.6 (C-7a), 132.8 (C-3’), 136.1 (C-2), 136.6 (C-1’), 154.8 (C-5). HRMS (EI): m/z

[M⁺] calcd for C₁₆H₁₂N₂O: 248.0950; found: 248.0943.

3.6.13. 5-Methoxy-2-(4-methoxyphenyl)-1H-indole (6m)

Following general method B, a mixture of 2d (0.075 g, 0_◦.57 mmol), 1i (0.074 g,

0.60 mmol), and Hg₂Cl₂(0.014 g, 0.03 mmol) was stirred at 60 C for 2 h. It was then

reacted with DMSO (3.1 mL), Cu(OAc)₂(0.156 g, 0.86 mmol), and Pd(OAc)₂(0.025 g,

0.11 mmol) to generate 6m (0.122 g, 84%) as a colorless crystalline solid. Rf 0.53 (hex-

ane/EtOAc, 7:3); mp 218–219 ^◦C (Lit. 218–219 ^◦C [66]). IR (ATR): 3430, 1543, 1480, 1456,

ῡ

1

1254, 1217, 1155, 1018, 829, 777 cm⁻¹. H NMR (600 MHz, CDCl₃):

δ 3.85 (s, 3H, CH₃O-C4’),

3.86 (s, 3H, CH₃O-C5), 6.64 (d, J = 1.2 Hz, 1H, H-3), 6.83 (dd, J = 8.4, 2.4 Hz, 1H, H-6),

6.96–6.99 (m, 2H, H-3’), 7.10 (d, J = 2.4 Hz, 1H, H-4), 7.27 (d, J = 8.4 Hz, 1H, H-7), 7.56–7.59

(m, 2H, H-2’), 8.13 (br s, 1H, NH). ¹³C NMR (150 MHz, CDCl₃):

δ 55.4 (CH₃O), 55.9 (CH₃O),

98.7 (C-3), 102.2 (C-4), 111.4 (C-7), 112.0 (C-6), 114.5 (C-3’), 125.3 (C-1’), 126.4 (C-2’), 129.9

(C-3a), 131.8 (C-7a), 138.7 (C-2), 154.5 (C-5), 159.3 (C-4’).

3.6.14. 5-Methoxy-2-propyl-1H-indole (6n)

Following general method B, a mixture of 2e (0.088 g, 1.29 mmol), 1i (0.166 g, 1.35 mmol),

◦

and Hg₂Cl₂(0.028 g, 0.06 mmol) was stirred at 60 C for 2 h. It was then reacted with

DMSO (6.5 mL), Cu(OAc)₂(0.352 g, 1.94 mmol), and Pd(OAc)₂(0.058 g, 0.26 mmol) to

form 6n (0.093 g, 38%) as an amber solid. Rf 0.67 (hexane/EtOAc, 7:3); p.f. 55–56 ^◦C (Lit.

−1

.

64–65 ^◦C

[

107]). IR (ATR): 3381, 2961, 1620, 1582, 1478, 1450, 1195, 1166, 1034, 831 cm

ῡ

¹H NMR (500 MHz, CDCl₃):

δ

1.00 (t, J = 7.5 Hz, 3H, H-3’), 1.73 (hex, J = 7.5 Hz, 2H, H-2’),

2.70 (t, J = 7.5 Hz, 2H, H-1’), 3.84 (s, 3H, CH₃O), 6.17 (dd, J = 2.0, 1.0 Hz, 1H, H-3), 6.77 (dd,

J = 8.5, 2.5 Hz, 1H, H-6), 7.00 (d, J = 2.5 Hz, H-4), 7.18 (d, J = 8.5 Hz, 1H, H-7), 7.74 (br s, 1H,

NH). ¹³C NMR (125 MHz, CDCl₃):

δ 13.9 (C-3’), 22.5 (C-2’), 30.4 (C-1’), 55.9 (CH₃O), 99.5

(C-3), 102.0 (C-4), 110.7 (C-6), 110.9 (C-7), 129.3 (C-3a), 130.9 (C-7a), 140.7 (C-2), 154.1 (C-5).

HRMS (EI): m/z [M⁺] calcd for C₁₂H₁₅NO: 189.1154; found: 189.1153.

3.6.15. 2-Cyclopropyl-5-methoxy-1H-indole (6o)

Following general method B, a mixture of 2f (0.097 g, 1.47 mmol), 1i (0.189 g, 1.54 mmol),

◦

and Hg₂Cl₂(0.033 g, 0.07 mmol) was stirred at 40 C for 2 h. It was then reacted with

DMSO (7.3 mL), Cu(OAc)₂(0.401 g, 2.21 mmol), and Pd(OAc)₂(0.065 g, 0.29 mmol) to

provide 6o (0.107 g, 39%) as a yellow solid. Rf 0.67 (hexane/EtOAc, 7:3); mp 57–58 ^◦C.₋IR₁

ῡ

(ATR): 3382, 2914, 1621, 1583, 1482, 1451, 1332, 1214, 1163, 1030, 837, 799, 770, 676 cm

.

¹H NMR (600 MHz, CDCl₃):

δ 0.73–0.76 (m, 2H, CH₂), 0.91–0.95 (m, 2H, CH₂), 1.87–1.93

(m, 1H, H-1’), 6.07 (dd, J = 1.2, 0.6 Hz, 1H, H-3), 6.76 (dd, J = 9.0, 2.4 Hz, 1H, H-6), 6.98 (d,

J = 2.4 Hz, 1H, H-4), 7.13 (d, J = 9.0 Hz, 1H, H-7), 7.83 (br s, 1H, NH). ¹³C NMR (150 MHz,

CDCl₃):

δ 7.3 (2CH₂), 8.9 (C-1’), 55.8 (CH₃O), 97.5 (C-3), 101.9 (C-4), 110.7 (C-6), 110.8 (C-7),

129.1 (C-3a), 130.8 (C-7a), 142.6 (C-2), 154.1 (C-5). HRMS (EI): m/z [M⁺] calcd for C₁₂H₁₃NO:

187.0997; found: 187.0997 [66].

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3.6.16. 2-(Cyclohex-1-en-1-yl)-5-methoxy-1H-indole (6p)

Following general method B, a mixture of 2g (0.096 g, 0.91 mmol), 1i (0.117 g, 0.95 mmol),

◦

and Hg₂Cl₂(0.024 g, 0.05 mmol) was stirred at 40 C for 2 h. It was then reacted with

DMSO (4.5 mL), Cu(OAc)₂(0.247 g, 1.36 mmol), and Pd(OAc)₂(0.040 g, 0.18 mmol) to

yield 6p (0.037 g 18%) as a brown solid. Rf 0.70 (hexane/EtOAc, 7:3); mp 108–110 ^◦C. IR

1

(KBr): 3429, 2929, 1620, 1586, 1483, 1452, 1414, 1210, 1147, 1033, 837, 802, 782 cm⁻¹. H

ῡ

NMR (600 MHz, CDCl₃):

δ 1.66–1.71 (m, 2H, H-4’), 1.76–1.81 (m, 2H, H-5’), 2.21–2.25 (m,

2H, H-3’), 2.42–2.46 (m, 2H, H-6’), 6.09–6.11 (m, 1H, H-2’), 6.37 (d, J = 1.8 Hz, H-3), 6.80

(dd, J = 8.6, 2.4 Hz, 1H, H-6), 7.02 (d, J = 2.4 Hz, 1H, H-4), 7.18 (d, J = 8.6 Hz, 1H, H-7),

7.99 (br s, 1H, NH). ¹³C NMR (150 MHz, CDCl₃): δ 22.2 (C-4’), 22.5 (C-5’), 25.5 (C-3’), 26.0

(C-6’), 55.8 (CH₃O), 98.5 (C-3), 102.2 (C-4), 111.0 (C-7), 111.9 (C-6), 122.5 (C-2’), 129.1 (C-1’),

129.3 (C-3a), 131.3 (C-7a), 140.3 (C-2), 154.1 (C-5). HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₇NO:

227.1310; found: 227.1306.

3.7. Single-Crystal X-ray Crystallography

Compounds 5i (yellow crystals, hexane/EtOAc, 98:2), 6e (colorless crystals, hex-

ane/EtOAc, 98:2), and 6l (pale reddish crystals, hexane/EtOAc, 94:6) were prepared and

mounted on glass ﬁbers. Crystallographic measurements were performed with an area-

detector with Mo Kα diffraction radiation (λ = 71,073 Å; graphite monochromator) at

room temperature (Table 4). Unit cell parameters were obtained from a least-squares

reﬁnement. Intensities were corrected for Lorentz and polarization effects. Multi-scan

absorption correction was applied. Anisotropic temperature factors were introduced for all

non-hydrogen atoms. Hydrogen atoms were placed in accordance with electron density

maps and idealized positions, and their atomic coordinates were reﬁned by utilizing unit

weights. After the structure was solved using SHELXT [108,109], it was implemented

in WinGX [110], reﬁned with SHELXL [111], and then visualized and plotted with the

MERCURY program package [112].

Table 4. Crystal data and structure reﬁnement for 5i, 6e, and 6l.

Structure

5i

6e

6l

CCDC number

Empirical formula

Molecular weight

Temperature

Crystal size

Crystal system

Space group

2082632

C₁₅H₁₅NO

225.28

2082633

C₁₅H₁₃NO

223.26

2082634

C₁₆H₁₂N₂O

248.28

292(2) K

0.79 × 0.47 × 0.27 mm³

0.50 × 0.30 × 0.21 mm³

orthorhombic

P2₁2₁2₁

0.52 × 0.30 × 0.27 mm³

monoclinic

P2₁/n

P2₁/c

a = 10.0110(6) Å, α = 90º

b = 8.7430(5) Å, β = 104.172(7)

ºc = 14.6687(11) Å, γ = 90º

1244.82(14) Å³

4

a = 5.6782(3) Å, α = 90º

b = 8.0462(3) Å, β = 90º

c = 25.5690(16) Å, γ = 90º

1168.19(11) Å³

4

a = 7.0104(3) Å, α = 90º

Unit cell

parameters

b = 14.5242(8) Å,

β = 98.202(4)º

c = 12.5032(7) Å, γ = 90º

1260.06(11) Å³

4

Volume

Z

Density

1.202 mg/m³

1.269 mg/m³

0.080 mm^–1

1.309 mg/m³

−1

Absorption coefﬁcient

Theta range

0.075 mm

0.084 mm

3.655–29.183º

3.187–29.557º

3635

2.936–29.453º

Reﬂections collected

Independent reﬂections

Observed reﬂections

Final R indices

Goodness-of-ﬁt on F²

5094

2839

5405

2909

2352

2017

1999

R₁= 0.0505; wR2 = 0.1110

1.042

2171

R₁= 0.0450; wR2 = 0.1001

1.022

R₁= 0.0387; wR2 = 0.0841

1.056

4. Conclusions

A new Hg(I)-catalyzed hydroamination of terminal acetylenes 2a

anilines 1a generated a series of ketimines 5a . An efﬁcient consecutive Hg(I)/Pd(II)-

catalyzed one-pot process led to the direct conversion of and into a series of 2-substituted

–d in the presence of

–k

–n

1

2

Molecules 2021, 26, 4092

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indoles 6a

–

p. Although good yields were found for most of the 2-arylindoles, the yields

were fairly modest for halogenated, 2-alkyl, and 2-vinyl indoles. The latter limitation was

possibly due to the low stability of the imine intermediate under these reaction condi-

tions. Likewise, the direct Hg(I)-catalyzed preparation of the imines either provided low

yields or made it impossible to avoid decomposition or hydrolysis to their corresponding

acetophenones upon isolation from the reaction mixture. The reaction mechanism of this

transformation was explored, ﬁnding that an Hg(I)–Pd(II) transmetalation step plausibly

connects the consecutive cycles of Hg(I)-catalyzed enamine formation and Pd(II)-catalyzed

oxidative cyclization.

1

Supplementary Materials: The following are available online. H- and ¹³C-NMR spectra are avail-

able online. The CIF ﬁles of crystal structures have been deposited with the CCDC, and the crystal

data and torsion angles for 5i, 6e, and 6l are also provided.

Author Contributions: R.U.G. contributed by developing the method, synthesizing compounds,

performing NMR and HRMS spectra, and writing the experimental section; M.H.-M. carried out

compound synthesis; A.M.-M. performed IR spectra and analyzed the results; F.D. contributed by

doing the literature research, analyzing the results, and reviewing the manuscript; J.T. designed the

project, provided tutorial guidance, discussed the results, acquired the ﬁnancial resources, and wrote

the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: The research was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT,

Mexico) (Grants 178319, A1-S-17131, and 300520) and SIP/IPN (Grants 20170902, 20180198, 20195228,

20200227, and 20210700).

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Acknowledgments: We thank M. Fernanda Ramos and Ailyn N. García and CNMN-IPN for their

help in spectrometric measurements, and Bruce A. Larsen for proofreading. R.U.G. and M.H.-M.

are grateful to CONACYT (SNI) for awarding them graduate and research stay scholarships, and

also thank SIP/IPN (BEIFI) and the Ludwig K. Hellweg Foundation for scholarship complements.

A.M.-M., F.D., and J.T. are fellows of the EDI-IPN and COFAA-IPN programs.

Conﬂicts of Interest: The authors declare no conﬂict of interest.

Sample Availability: Not available.

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Article Doi

Regioselective mercury(I)/palladium(II)-catalyzed single-step approach for the synthesis of imines and 2-substituted indoles

DOI: 10.3390/molecules26134092

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