Download PDF
Synthesis 2023; 55(09): 1460-1466
DOI: 10.1055/a-2003-3207
paper

Ruthenium-Catalyzed Regioselective Synthesis of C3-Alkylated Indoles Following Transfer Hydrogenation or Borrowing Hydrogen Strategy

Xia Chen
a   School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui 553004, P. R. of China
b   Guizhou Key Laboratory of Coal Clean Utilization, Liupanshui 553004, P. R. of China
,
Xiao-Yu Zhou∗
a   School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui 553004, P. R. of China
b   Guizhou Key Laboratory of Coal Clean Utilization, Liupanshui 553004, P. R. of China
› Author Affiliations

The authors are grateful to National Natural Science Foundation of China (Nos. 22062012 and 22262019) and Scientific Research Projects of Liupanshui Normal University (LPSSYZDZK202201) for their financial support. This work was also supported by Guizhou Key Laboratory of Coal Clean Utilization (qiankehepingtairencai [2020]2001).
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

By employing either borrowing hydrogen or transfer hydrogenation strategy, two straightforward [Ru(p-cymene)Cl2]2-catalyzed methods for regioselective synthesis of C3-alkylated indoles have been developed, utilizing alcohols as H atom donors or alkylating agents. The developed catalytic system could accommodate a broad substrate scope including primary/secondary aliphatic alcohols and substituted indoles, and in most cases providing good yields. Notable features of the developed system include high-activity, easy operation, and air atmosphere.


#

Key words

transfer hydrogenation - borrowing hydrogen - alkylation - indoles - alcohols

The indole moiety is a privileged structural framework in a wide range of natural products as well as biologically, physiologically, and pharmaceutically active molecules.[1] Owing to the obvious interest in indoles, an impressive number of practical and atom-economic methods have been developed for the synthesis of indole-containing compounds and related functionalization. Among the many known natural products or bioactive molecules containing indole moiety, C3-alkylated indoles as common pharmacophores have attracted much attention because of their bioactivity.[2] The most straightforward and classical method to prepare C3-alkylated indoles is C3-alkylation of indoles via Friedel–Crafts reaction using both alkyl halides and Lewis acid catalysts[3] (Scheme [1a]). In general, Friedel–Crafts alkylation primarily relies on stoichiometric use of Lewis acids, therefore leading to low atom-efficiency, functional group tolerance, and poor regioselectivity. Also, halides used in the reaction are usually prepared from alcohols, which generates toxic and hazardous wastes. From the perspective of environmentally benign chemistry, the development of more efficient and greener catalytic alkylation methods is gaining increasingly importance. In particular, replacing alkyl halides with alcohols as alkylating reagents, while using transition metals as catalysts to avoid the waste of large amounts of metal salts, seem to be reasonable and advantageous choices.

Zoom Image
Scheme 1 Methods for the alkylation of indoles

Borrowing hydrogen (BH) strategy, combining the advantages of transfer hydrogenation (TH) with additional in situ transformations, is a more sustainable alternative to the conventional alkylation process as nontoxic or nonhazardous alcohols are applied as alkylating reagents.[4] Due to safety and ubiquity of nonderivatized alcohols, they are interesting electrophiles for functional group interconversion; in addition, water is the sole stoichiometric by-product. According to an accepted mechanism, BH strategy mainly consists of three steps: i) dehydrogenation of alcohol in the presence of a transition metal catalyst [M] to generate a carbonyl intermediate and a metal hydride species [MH2]; ii) condensation of the nucleophile such as indoles to form an α,β-unsaturated imine derivative; and iii) hydrogenation to liberate the alkylated compound such as C-3 alkylated indole (Scheme [1b]).

Table 1 Optimization Conditions for Ru-Catalyzed TH Reactiona

Entry

Catalyst (mol%)

Base

Solvent

Yield (%)b

 1

[Ru(p-cymene)Cl2]2 (2.5)

K2CO3

EtOH

60

 2

[Ru(p-cymene)Cl2]2 (2.5)

Na2CO3

EtOH

trace

 3

[Ru(p-cymene)Cl2]2 (2.5)

Cs2CO3

EtOH

73

 4

[Ru(p-cymene)Cl2]2 (2.5)

DBU

EtOH

trace

 5

[Ru(p-cymene)Cl2]2 (2.5)

NaOAc

EtOH

61

 6

[Ru(p-cymene)Cl2]2 (2.5)

HCOONa·2H2O

EtOH

72

 7

[Ru(p-cymene)Cl2]2 (2.5)

KOH

EtOH

99

 8

Ru(cod)Cl2 (5.0)

KOH

EtOH

trace

 9

Ru(PPh3)3Cl2 (5.0)

KOH

EtOH

trace

10

Ru/C (1.0)

KOH

EtOH

trace

11

Pd/C (0.9)

KOH

EtOH

NR

12

Pd(OAc)2 (5.0)

KOH

EtOH

NR

13

PdCl2 (5.0)

KOH

EtOH

NR

14

CuCl (10.0)

KOH

EtOH

NR

15

CuCl2 (10.0)

KOH

EtOH

NR

16

Fe(OAc)2 (10.0)

KOH

EtOH

NR

17

[Ru(p-cymene)Cl2]2 (2.5)

KOH

MeOH

87

18

[Ru(p-cymene)Cl2]2 (2.5)

KOH

n PrOH

78

19

[Ru(p-cymene)Cl2]2 (2.5)

KOH

i PrOH

30

20

[Ru(p-cymene)Cl2]2 (2.5)

KOH

n BuOH

63

21

[Ru(p-cymene)Cl2]2 (2.5)

KOH

t BuOH

NR

22c

[Ru(p-cymene)Cl2]2 (2.5)

KOH

EtOH

81

23d

[Ru(p-cymene)Cl2]2 (2.5)

KOH

EtOH

90

a Reaction conditions: 1a (73 mg, 0.50 mmol), catalyst (2.5–10.0 mol%), base (2.0 equiv), solvent (3.0 mL), 100 °C, 24 h.

b Isolated yield. NR: No reaction.

c KOH (28.0 mg, 0.50 mmol, 1.0 equiv) was added.

d Conducted at 80 °C.

The first example of C3-alkylation of indoles with benzyl alcohols following the BH concept was reported in 2007. Grigg and collaborators[5] used an iridium catalyst and KOH at 110 °C under essentially solvent-free conditions, affording the corresponding C3-alkylated indoles in moderate to high yields. Afterwards, a variety of transition metal catalysts including Pd,[6] Pt,[7] Ir,[5] [8] Fe,[9] Co,[10] Ni,[11] Cu,[12] and Mn[13] have been proved to be useful in C3-alkylation of indoles with alcohols in succession. Ruthenium catalysts[14] – surprisingly only two examples – showed high catalytic activities for this transformation as well. The first example was reported by Ohta and co-workers[14a] in 2013 using RuCl2(PPh3)3/DPEphos in the presence of K3PO4 at 165 °C under argon. The other example was reported by Srimani and co-workers[14b] in 2020 employing a ruthenium pincer complex in the presence of KOH at 135 °C. Moreover, the direct C3-alkylation of indoles using KOH and alcohols at 150 °C without transition metal catalyst was achieved.[15] However, this reaction system was mainly suitable for aromatic alcohols. Aliphatic alcohols seemed to be more problematic than aromatic alcohols due to their higher enthalpy of dehydrogenation. Indeed, based on the methods developed, the direct alkylation of indoles with alcohols in accordance with BH strategy generally adopted >100 °C, even up to 160 °C.[5] , [7] [8] [9] [10] [11] [12] [13] [14]

Direct hydrogenation and TH are two parallel strategies for reduction reactions.[16] The catalytic hydrogenation generally employs hydrogen gas as hydrogen source; in contrast, TH appeals to many chemists due to the avoidance of a flammable gas. To date, various H atom donors including alcohols, especially isopropyl alcohol ( i PrOH), are available for use in both homo- and heterogeneous catalytic TH reactions.[16] Compared to i PrOH and methanol (MeOH), ethanol (EtOH) as a well-known renewable platform chemical[17] is a more available and greener H atom donors because it is already produced on a large scale via fermentation using lignocellulose as raw material.[18] We are committed to developing a convenient method for the synthesis of C3-alkylated indoles via TH of 3-acylindoles using EtOH as H atom donors under an air atmosphere, which can be successfully performed at 100 °C or lower.

Initially, the reaction of indole-3-carbaldehyde (1a) was performed as a model to optimize the reaction parameters in EtOH at 100 °C under an air atmosphere. The results are summarized in Table [1]. Utilizing commercially available [Ru(p-cymene)Cl2]2 (2.5 mol%) and K2CO3 (2.0 equiv) as the catalyst and base, the reaction provided 3-methylindole (2) in 60% yield (Table [1], entry 1). The influence of bases on the TH was investigated. Among the examined bases [Na2CO3, Cs2CO3, DBU, NaOAc, HCO2Na·2H2O, and KOH (flakes)] (entries 2–7), KOH proved to be the better base, providing 99% yield. Two homogeneous ruthenium complexes including Ru(cod)Cl2 (cod = 1,5-cyclooctadiene) and RuCl2(PPh3)3 (entries 8 vs 9) cannot catalyze this transformation, and the substrates were recovered. When using heterogeneous Ru/C as catalyst, the reaction cannot proceed also (entry 10). Other transition metal catalysts such as Pd/C, Pd(OAc)2, PdCl2, CuCl, CuCl2 and Fe(OAc)2 showed almost no catalytic activity for this reaction (entries 11–16). The results of solvent screening exhibited that, even though the yield of 2 was decreased, MeOH (entry 17), n-propyl alcohol (entry 18), and n-butanol (entry 20) proved to be effective in the reaction as both H atom donor and solvent. Unexpectedly, the most common TH reagent i PrOH did not enable the reaction to proceed smoothly (entry 19). The relatively low yield was obtained when decreasing the amount of KOH (entry 22). Furthermore, the reaction took place at 80 °C, but the yield of 2 was diminished to 90% (entry 23). Therefore, the optimal conditions are: [Ru(p-cymene)Cl2]2 (2.5 mol%)/KOH (2.0 equiv)/EtOH/100 °C.

Subsequently, 1-(1H-indol-3-yl)ethan-1-one (1b) was subjected to the [Ru(p-cymene)Cl2]2-catalyzed TH reaction under the optimal conditions, as shown in Scheme [2]. The corresponding C3-alkylated indole 3a was obtained in 99% yield. Though the developed catalytic system has advantages such as good catalytic activity and excellent yield, strictly speaking, it is not a perfect method to obtain C3-alkylated indoles because of the limitation of substrates.

Zoom Image
Scheme 2 Ru-catalyzed TH reaction of 1-(1H-indol-3-yl)ethan-1-one

BH strategy enables TH to combine seamlessly with additional in situ transformations.[4] Inspired by this, the catalytic system was directly applied to selective synthesis of C3-alkylated indoles using alcohols as alkylating reagents; thus, the application range of the catalytic system is extended effectively, meanwhile breaking the limitation of substrates. In accordance with our expectation, when the Ru-catalyzed C3-alkylation of indole 1b was performed under the optimal conditions, the expected C3-alkylated indole 3a was achieved with 95% yield. For comparison on the catalytic activity of the transition metal catalyst, [Ru(p-cymene)Cl2]2 was found to be the most effective although homogeneous ruthenium catalysts including [Ru(p-cymene)I2]2, Ru(COD)Cl2, and Ru(PPh3)3Cl2 were also effective. Furthermore, when the reaction was carried out at 80 °C, 3a was obtained only in 52% yield. Indeed, even when the catalyst loading was reduced to 1 mol%, 90% yield of 3a was also obtained. Therefore, the optimal conditions for the ruthenium-catalyzed regioselective synthesis of C3-alkylated indoles are: [Ru(p-cymene)Cl2]2 (2.5 mol%)/ KOH (2.0 equiv)/ EtOH/100 °C (for details, see the Supporting Information).

Given the optimized reaction conditions, the scope and limitation of this reaction were explored, and the results are summarized in Table [2]. By using this protocol, the indoles bearing electron-donating substituents as well as electron-withdrawing substituents at the C-5 or C-6 position can undergo C3-ethylation to give moderate-to-excellent yields of the C3-ethylated indoles (Table [2], entries 2–9, 74–>99% yield). However, the presence of groups at the C-2, C-4, or C-7 position, with significant steric hindrance, severely hamper the reaction, and only trace amounts of the expected products 3 were obtained (entries 10–13). No product was detected when N-methylindole was utilized as substrate (entry 14), implicating the formation of indole anion in the alkylation, which is consistent with BH strategy. Then, we investigated other aliphatic alcohols in the alkylation reaction. MeOH showed good reactivity and gave the corresponding product 2 in 92% yield (entry 15). It is worth mentioning that the secondary alcohol i PrOH also afforded the isopropylated product 5 in good yield (entry 16, 86%). To the best of our knowledge, i PrOH is difficult to use in this transformation and the yield is often too low.[11b] The alkylation reaction employing other aliphatic alcohols such as 1-pentanol, 3-methyl-1-butanol, 2-methyl-1-butanol, 2-methyl-1-propanol, 1-butanol, and 1-propanol as alkylating agents could not proceed smoothly, and only trace amounts of the corresponding products were detected; moreover, the same results were obtained even when the reactions were carried out at 120 C, and in most cases the substrates were recovered. Alcohols containing nitrogen or sulfur including 2-dimethylaminoethanol (entry 17) and 2-(methylthio)ethanol (entry 18) under the optimal conditions cannot also undergo C3-alkylation of indole. Compared with MeOH, EtOH, and i PrOH, the alcohols mentioned above are significantly less active possibly due to their higher enthalpy of dehydrogenation.

Table 2 Scope of Indoles and Alcoholsa

Entry

4

2, 3, 5

Yield (%)b

 1

4a

3a

95

 2

4b

3b

82

 3

4c

3c

74

 4

4d

3d

80

 5

4e

3e

83

 6

4f

3f

>99

 7

4g

3g

88

 8

4h

3h

83

 9

4i

3i

80

10

4j

3j

trace

11

4k

3k

trace

12

4l

3l

trace

13

4m

3m

trace

14

4n

3n

NR

15c

4a

2

92

16d

4a

5

86

17e

4a

6

NR

18f

4a

7

NR

a Reaction conditions: 1 (0.50 mmol), [Ru(p-cymene)Cl2]2 (7.7 mg, 0.0125 mmol, 2.5 mol%), KOH (56 mg, 1.0 mmol, 2.0 equiv), EtOH (3.0 mL), 100 °C, 24 h.

b Isolated yield. NR: No reaction.

c MeOH (3.0 mL) was used.

d i PrOH (3.0 mL) was used.

e 2-Dimethylaminoethanol (3.0 mL) was used.

f 2-(Methylthio)ethanol (3.0 mL) was used.

In conclusion, a ruthenium-catalyzed system using EtOH as H atom donor under an air atmosphere was developed for the synthesis of C3-alkylated indoles via TH reactions of 3-acylindoles. The commercially available [Ru(p-cymene)Cl2]2 was utilized as the catalyst. Unlike the most TH process of ketones, the catalytic system enables the complete reduction of 3-acylindoles to afford methylenes instead of alcohols. On the other hand, compared to the common TH reagents such as i PrOH and MeOH, the renewable EtOH is a more readily available and interesting H atom donor. Inspired by BH strategy, the catalytic system was successfully applied to selective C3-alkylation of indoles, thus expanding its application and breaking the limitation of the substrates. The system is highly efficient with NH indoles bearing either electron-donating or electron-withdrawing moieties, in most cases providing good yields. Moreover, the primary/secondary aliphatic alcohols including EtOH, MeOH, and i PrOH can be used as the alkylating reagents to afford their corresponding C3-alkylated indoles. Aliphatic alcohols, after all, seemed to be more problematic than aromatic alcohols due to their higher enthalpy of dehydrogenation. Work continues on the development and application of this methodology in our laboratory.

All reagents and solvents were of pure analytical grade. TLC was performed on HSGF254 silica gel, pre-coated on glass-backed plates coated with 0.2 mm silica gel and revealed with a UV lamp (λmax = 254 nm). The products were purified by flash column chromatography on silica gel (200–300 mesh). 1H and 13C NMR spectra were recorded on a 600 MHz spectrometer (1H 600 MHz, 13C 151 MHz) using CDCl3 as the solvent with TMS as the internal standard at rt. Chemical shifts are in δ (ppm) relative to TMS. The coupling constants (J) are in hertz (Hz).

C-3 Alkylated Indoles 2, 3, and 5; General Procedure

A mixture of indole 4 (0.50 mmol), [Ru(p-cymene)Cl2]2 (7.7 mg, 0.0125 mmol, 2.5 mol%), and KOH (56 mg, 1.0 mmol, 2.0 equiv) in EtOH (3 mL) was added to a Schlenk flask (25 mL) and stirred at 100 °C. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (PE/EtOAc 20:1 to 10:1) to provide the product 2, 3, or 5 (Table [2]).


#

3-Methyl-1H-indole (2)

Yield: 60.5 mg (92%); white solid; mp 50–52 °C; Rf = 0.51 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.89 (br s, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 7.26–7.20 (m, 1 H), 7.20–7.12 (m, 1 H), 7.00 (d, J = 0.9 Hz, 1 H), 2.38 (d, J = 1.0 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 136.3, 128.3, 121.9, 121.6, 119.1, 118.8, 111.7, 111.0, 9.7.

HRMS (ESI): m/z [M + H]+ calcd for C9H10N: 132.0813; found: 132.0806.


#

3-Ethoxy-1H-indole (3a)

Yield: 69.0 mg (95%); colorless oil; Rf = 0.42 (hexanes/EtOAc 10:1).

1H NMR (400 MHz, CDCl3): δ = 7.88 (br s, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H), 7.23 (t, J = 7.4 Hz, 1 H), 7.04 (s, 1 H), 2.90 (q, J = 7.5 Hz, 2 H), 1.45 (t, J = 7.5 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.5, 127.5, 122.0, 120.5, 119.1, 119.0, 118.9, 111.1, 18.4, 14.6.

HRMS (ESI): m/z [M + H]+ calcd for C10H12N: 146.0970; found: 146.0965.


#

3-Ethoxy-5-methyl-1H-indole (3b)

Yield: 66.0 mg (82%); white solid; mp 55–57 °C; Rf = 0.42 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.74 (br s, 1 H), 7.49 (d, J = 0.7 Hz, 1 H), 7.33–7.25 (m, 1 H), 7.11 (dd, J = 8.2, 1.0 Hz, 1 H), 7.00–6.94 (m, 1 H), 2.85 (q, J = 7.5 Hz, 2 H), 2.56 (s, 3 H), 1.42 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 134.8, 128.3, 127.7, 123.5, 120.7, 118.7, 118.3, 110.8, 21.6, 18.4, 14.6.

HRMS (ESI): m/z [M + H]+ calcd for C11H14N: 160.1126; found: 160.1125.


#

3-Ethoxy-5-methoxy-1H-indole (3c)

Yield: 65.1 mg (74%); colorless oil; Rf = 0.46 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3) δ = 7.89 (br s, 1 H), 7.26 (d, J = 8.7 Hz, 1 H), 7.12 (d, J = 2.4 Hz, 1 H), 7.01–6.96 (m, 1 H), 6.92 (dd, J = 8.7, 2.4 Hz, 1 H), 3.94 (s, 3 H), 2.84–2.80 (m, 2 H), 1.39 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3) δ = 153.8, 131.7, 127.8, 121.5, 118.4, 112.0, 111.9, 100.9, 56.0, 18.4, 14.4.

HRMS (ESI): m/z [M + H]+ calcd for C11H14NO: 176.1075; found: 176.1073.


#

5-(Benzyloxy)-3-ethoxy-1H-indole (3d)

Yield: 100.5 mg (80%); colorless oil; Rf = 0.42 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.81 (br s, 1 H), 7.60–7.55 (m, 2 H), 7.48–7.45 (m, 2 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 1 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.01 (dd, J = 8.7, 2.4 Hz, 1 H), 6.99–6.95 (m, 1 H), 5.19 (s, 2 H), 2.82 (q, J = 7.5 Hz, 2 H), 1.39 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 153.0, 137.8, 131.9, 128.6, 127.9, 127.84, 127.75, 121.5, 118.5, 112.7, 111.8, 102.7, 71.2, 18.4, 14.4.

HRMS (ESI): m/z [M + H]+ calcd for C17H18NO: 252.1388; found: 252.1382.


#

5-Chloro-3-ethoxy-1H-indole (3e)

Yield: 75.0 mg (83%); colorless oil; Rf = 0.37 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.91 (br s, 1 H), 7.62 (d, J = 1.9 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.18 (dd, J = 8.6, 2.0 Hz, 1 H), 7.04–6.98 (m, 1 H), 2.78 (q, J = 7.5 Hz, 2 H), 1.36 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 134.8, 128.6, 124.8, 122.2, 122.0, 118.6, 118.5, 112.1, 18.2, 14.4.

HRMS (ESI): m/z [M + H]+ calcd for C10H11ClN: 180.0580; found: 180.0571.


#

3-Ethoxy-6-methyl-1H-indole (3f)

Yield: 80.0 mg (>99%); colorless oil; Rf = 0.42 (hexanes/EtOAc 10:1).

1H NMR (400 MHz, CDCl3): δ = 7.77 (br s, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 7.20 (s, 1 H), 7.04 (d, J = 8.1 Hz, 1 H), 6.96 (s, 1 H), 2.85 (q, J = 7.5 Hz, 2 H), 2.55 (s, 3 H), 1.41 (t, J = 7.5 Hz, 3 H).

13C NMR (101 MHz, CDCl3): δ = 136.9, 131.7, 125.4, 120.9, 119.8, 118.7, 118.7, 111.1, 21.8, 18.5, 14.6.

HRMS (ESI): m/z [M + H]+ calcd for C11H14N: 160.1126; found: 160.1119.


#

3-Ethoxy-6-methoxy-1H-indole (3g)

Yield: 77.7 mg (88%); white solid; mp 86–88 °C; Rf = 0.41 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.78 (br s, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 6.97–6.74 (m, 3 H), 3.89 (s, 3 H), 2.82 (q, J = 7.5 Hz, 2 H), 1.39 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 156.5, 137.2, 122.0, 119.6, 119.3, 118.7, 109.1, 94.8, 55.7, 18.5, 14.5.

HRMS (ESI): m/z [M + H]+ calcd for C11H14NO: 176.1075; found: 176.1074.


#

6-(Benzyloxy)-3-ethoxy-1H-indole (3h)

Yield: 104.9 mg (83%); white solid; mp 114–116 °C, Rf = 0.38 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.74 (br s, 1 H), 7.55–7.51 (m, 3 H), 7.45–7.42 (m, 2 H), 7.37 (t, J = 7.3 Hz, 1 H), 6.94–6.92 (m, 2 H), 6.90–6.85 (m, 1 H), 5.14 (s, 2 H), 2.80 (q, J = 7.5 Hz, 2 H), 1.37 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 155.6, 137.6, 137.1, 128.6, 127.9, 127.6, 122.2, 119.6, 119.4, 118.8, 109.8, 96.2, 70.7, 18.4, 14.5.

HRMS (ESI): m/z [M + H]+ calcd for C17H18NO: 252.1388; found: 252.1381.


#

6-Chloro-3-ethoxy-1H-indole (3i)

Yield: 71.1 mg (80%); white solid; mp 87–89 °C; Rf = 0.49 (hexanes/EtOAc 10:1).

1H NMR (600 MHz, CDCl3): δ = 7.86 (s, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 1.7 Hz, 1 H), 7.13 (dd, J = 8.4, 1.8 Hz, 1 H), 7.01–6.95 (m, 1 H), 2.80 (q, J = 7.5 Hz, 2 H), 1.36 (t, J = 7.5 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 136.7, 127.8, 126.1, 121.1, 119.83, 119.81, 119.0, 111.0, 18.2, 14.4.

HRMS (ESI): m/z [M + H]+ calcd for C10H11ClN: 180.0580; found: 180.0577.


#

3-Isopropyl-1H-indole (5)

Yield: 68.2 mg (86%); white solid; mp 38–40 °C.

1H NMR (400 MHz, CDCl3): δ = 7.88 (br s, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.31–7.27 (m, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.02 (s, 1 H), 3.35–3.29 (m, 1 H), 1.47 (d, J = 6.9 Hz, 6 H).

13C NMR (101 MHz, CDCl3): δ = 136.6, 126.8, 124.1, 121.9, 119.5, 119.3, 119.1, 111.2, 25.5, 23.4.

HRMS (ESI): m/z [M + H]+ calcd for C11H14N: 160.0026; found: 160.0018.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2003-3207.
  • Supporting Information

Corresponding Author

Xiao-Yu Zhou
School of Chemistry and Materials Engineering, Liupanshui Normal University
Liupanshui 553004
P. R. of China   

Publication History

Received: 01 December 2022

Accepted after revision: 22 December 2022

Accepted Manuscript online:
22 December 2022

Article published online:
12 January 2023

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Methods for the alkylation of indoles
Zoom Image
Scheme 2 Ru-catalyzed TH reaction of 1-(1H-indol-3-yl)ethan-1-one