Copper-Catalyzed Regioselective sp3 C-H Azidation of Alkyl

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Copper-Catalyzed Regioselective sp3 C-H Azidation of Alkyl Substituents of Indoles and Tetrahydrocarbazoles Liwu Huang, Xudong Xun, Man Zhao, Jianzhong Xue, Guofeng Li, and Liang Hong J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01742 • Publication Date (Web): 30 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019

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The Journal of Organic Chemistry

Copper-Catalyzed Regioselective sp3 C-H Azidation of Alkyl Substituents of Indoles and Tetrahydrocarbazoles Liwu Huang, Xudong Xun, Man Zhao, Jianzhong Xue, Guofeng Li* and Liang Hong* Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yatsen University, Guangzhou 510006, P.R. China Supporting Information Placeholder R2 R1

N R3

R2

H

N3 I O

+

CuBr (10 mol %) EA, r.t.

R1

O

N R3

N3

ABSTRACT: An efficient regioselective sp3 C-H azidation is developed using CuBr as the catalyst and Zhdankin azidoiodinane as the “N3” source. Under a simple and mild reaction conditions, the azido group could be successfully incorporated into the sp3 C-H alkyl substituents of indoles and tetrahydrocarbazoles.

INTRODUCTION Since the discovery of “click chemistry”, the organic azides have found broad application in chemical biology, drug discovery, and materials science.1 Their vast utilities has driven the development of numerous methods, among which the direct C−H azidation has received particular attention as it could introduce the azide group into the organic molecules in a single step. Great progress has been made in the direct aryl sp2 C−H azidation using transitionmetal catalysis.2 In contrast, the azidation of aliphatic sp3 C−H has been less developed due to the low reactivity of aliphatic C–H bonds. The successful examples are restricted to the unactivated sp3 C−H bonds,3 sp3 C−H bonds in allylic or benzylic positions4 and α-positions of β-keto esters.5 However, the direct azidation of the sp3 C−H bonds in the side chains of the heteroaromatic compounds still continues to be a challenge. The heteroaromatic indoles are potential intermediates for many alkaloids and are privileged frameworks found in a variety of biologically and medicinally active compounds. Among them, 2-aminoalkyl indoles constitute an important core structure found in many biologically relevant compounds. Their derivatives are expected to have the potential activities for IDO1 inhibitor, anti-HIV and anti-HPV (Scheme 1).6 Thus, it is highly desirable to develop an efficient method to access 2-aminoalkyl indoles. In this regard, the direct azidation of the side chains of indoles will provide an efficient approach for the construction of C–N bond (Scheme 1).

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Due to the inherent electronic properties of indoles, the reported methods focused on the selective azidation of sp2 C-H bonds of indole derivatives at the C2-, C3-, and C7-positions. For example, Prabhu et al. developed a copper-catalyzed azidation of indoles at the C-2 position (Scheme 2a)7. Suna and Sudalai’s group reported the regioselective azidation at the C-3 position (Scheme 2b).8 Jiao and our group found tryptophols and tryptamines could undergo C-3 azidation followed by cyclization cascade (Scheme 2c).9 Recently, Chang et al. developed the C-7 amidation of indoles with organic azides (Scheme 2d).10 However, little attention has been paid to the sp3 C-H bond azidation of the alkyl side chains of indole derivatives. Therefore, the development of an efficient method for the regioselective sp3 C-H α-azidation of alkyl substituents of indoles is of great interest. Scheme 1. Bioactive 2-Aminoalkyl Indoles. OMe Me O N

O HN N

Et

Cl

NH

anti-HIV

MT2 antagonist Cl F

Br N H

N

Ph

OH

N H

N IDO1 inhibitor

anti-HPV

R2

R1 N H

NH2

core structure

HN

R1 N H

R2

?

N3

direct azidation

R2

R1 N H

H

Recently, Hartwig et al. developed an elegant azidation of tertiary and benzylic sp3 C−H bonds using an azidoiodinane reagent11. Inspired by this study and our previous work on functionalization of indoles, we were curious if a direct sp3 C−H azidation of the side chains of indoles would be possible. Herein, we reported a mild and simple method for the direct α-azidation of alkyl substituents of indoles (Scheme 2e). Scheme 2. Functionalization of Indoles.


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The Journal of Organic Chemistry a) azidation at C-2 position CO2Alkyl R1

H

TMSN3

+

N R2

CO2Alkyl

CuBr (5 mol %) TBHP (1.0 eq.)

R1

CH3CN

N3

N R2

b) azidation at C-3 position H R1

N R2

N3

PhI(OAc)2 CO2Et

+

TsOH

NaN3

R1

CH3CN

N R2

CO2Et

c) azidation-cyclization N3 I O

XH R1

+ N H

N3 Cu-catalyst

X

R1

N H

O

d) amidatio at C-7 position IrCp*(OAc)2 1

R

+

N H

O

TsN3

R1

AgNTf 2 ClCH2CH2Cl

Ts

R2

N NH

O

R2

e) This work: α-azidation of alkyl substituents R2 1

R

N H

H

+

"N3"

?

R2 1

R

N H

N3

At the outset of our study, indole 1a was used as a model substrate in our beginning investigation (Table 1). The initial investigation focused on the reaction of indole 1a with various “N3” source by the catalysis of CuBr in ethyl acetate (EA) at room temperature. The use of TMSN3 or NaN3 failed to give the azidation product (Table 1, entries 1 and 2), while the azidoiodinane reagent (I)12 or (II) could deliver the desired product in 88% and 50% yield respectively (Table 1, entries 3 and 4). We then evaluated the solvent effect on the reaction. Among the tested solvents, all of them could promote the reaction, but none of them gave better yield than ethyl acetate (Table 1, entries 5-9). Besides CuBr catalyst, other copper catalysts were also found to be reactive for this reaction, albeit with lower yield (Table 1, entries 10-14).

RESULTS AND DISCUSSION



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Table 1. Optimization of the Reaction Conditions.a

Me

Me Me N H

H

1a

solvent

N H

O

N3

2a

N3 I O

N3 I O (I)

Me

Cu-catalyst

"N3"

+

(II)

entry

Cu-catalyst

“N3”

solvent

yield (%)b

1

CuBr

TMSN3

EA

-

2

CuBr

NaN3

EA

-

3

CuBr

(I)

EA

88

4

CuBr

(II)

EA

50

5

CuBr

(I)

EtOH

74

6

CuBr

(I)

THF

58

7

CuBr

(I)

DCM

64

8

CuBr

(I)

MeOH

49

9

CuBr

(I)

CH3CN

56

10

CuCl

(I)

EA

78

11

CuI

(I)

EA

63

12

CuCl2

(I)

EA

77

13

Cu(OAc)2

(I)

EA

78

14 CuBr2 (I) EA 76 aUnless otherwise noted, the reaction was carried out on a 0.2 mmol scale in 1.0 mL of solvent at room temperature with the ratio of 1a : catalyst : “N3” = 1.0 : 0.1 : 1.2. bIsolated yield. EA = ethyl acetate; MeCN = acetonitrile; EtOH = ethyl alcohol; MeOH = methyl alcohol; DCM = dichloromethane; THF = Tetrahydrofuran.

With the optimal conditions identified for the direct α-azidation of alkyl substituents, the scope of the reaction was subsequently examined by examining various indoles (Table 2). A wide range of 2,3-alkyl indoles could delivered the azidation products 2 in moderate to good yields. For example, 2-alky-3-methyl indoles and 2-benzyl-3-methyl indoles gave the corresponding products 2a2d in good yields ranging from 50-88% (Table 2, entries 1-4). Indoles bearing methyl, fluoro, chloro, bromo and cyano groups at C5- or C4, C6-positions reacted smoothly to result in yields from 58-74% (Table 2, entries 5-11). The protecting group on the nitrogen had distinct effects on the reaction. The yields were reduced remarkably when the nitrogen was protected with Et and CH2CO2Me (Table 2, entries 12-13). Table 2. Scope of the Reaction.a


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The Journal of Organic Chemistry R2

N3 I O

3

R 1

R

1

N R4

+

H

R2 CuBr (10 mol %)

R3

1

R

EA, r.t.

O

N R4 2

N3

entry

R1

R2

R3

R4

2, yield (%)

1

H

Me

Me

H

2a, 88

2

H

Me

H

H

2b, 74

3

H

Et

H

H

2c, 68

4

H

Bn

H

H

2d, 50

5

5-Me

Me

Me

H

2e, 58

6

5-F

Me

Me

H

2f, 74

7

5-Cl

Me

Me

H

2g, 74

8

5-Br

Me

Me

H

2h, 70

9

5-CN

Me

Me

H

2i, 65

10

4,6-F2

Me

Me

H

2j, 68

11

4,6-Cl2

Me

Me

H

2k, 64

12

H

Me

Me

Et

2l, 34

13

H

Me

Me

CH2CO2Me

2m, 18

aUnless otherwise noted, the reaction was carried out on 0.2 mmol scale in 1 mL ethyl acetate at room temperature with the ratio of 1a : CuBr : I = 1.0 : 0.1 : 1.2. bIsolated yield.

Because α-benzylamino tetrahydrocarbazoles could be used as a potential anti-HPV agents, we sought to expand the substrate indoles described above to tetrahydrocarbazoles 3a and 3b. Under the same reaction conditions, both tetrahydrocarbazoles could deliver the desired α-azide tetrahydrocarbazoles 4a and 4b in 69% and 70% yield respectively (Scheme 3). It should be noted that, in this case, the presence of N-protecting group had little effect on the reaction. Scheme 3. α-Azidation of Tetrahydrocarbazoles.

N H 3a

H

+


N3 N H 4a, 69% yield

O

Me N

N3 I O

H CO2Me

+

N3 I O


O

Me N3

N

CO2Me 4b, 70% yield

3b

To demonstrate the utility of this method, we conducted some transformations of the azido group. For example, the azido group could be converted to the amino group easily by the treatment of LiAlH4 in THF to give 5 in 82% yield.13 When reacted with phenyl acetylene, the click reaction afforded the triazole product 6 in 60% yield (Scheme 4).14



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Scheme 4. Transformations of the Azido Group.

Me

Cl

Cl

N H

Me

LiAlH4

N3

THF

Me

Cl

Me N H

Cl 5, 82% yield

2k

Cl

Me

Cl

Me + Cl

N H

N3

NH2

Ph

Me Me

CuSO4 (5 mol %) t

BuOH/H2O

Cl

2k

N H

N N N 6, 60% yield

Ph

In summary, we have developed an efficient regioselective sp3 C-H azidation. Under a simple and mild reaction conditions, the azido group could be successfully incorporated into the alkyl substituents of indoles and tetrahydrocarbazoles. The synthetic utility was highlighted by the transformations of the azido group to amino and triazole groups.

EXPERIMENTAL SECTION General Information. Unless stated otherwise, all reactions were carried out in flame dried glassware. All solvents were purified and dried according to standard methods prior to use. 1H and 13C NMR spectra were recorded on a Varian instrument (400 MHz or 500 MHz and 100 MHz or 125 MHz, respectively) and internally referenced to tetramethylsilane signal or residual protio solvent signals. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet or unresolved, coupling constant (s) in Hz, integration). Data for

13C

NMR are reported in terms of

chemical shift (δ, ppm). IR spectra were recorded on a FT-IR spectrometer and only major peaks were reported in cm-1. High resolution mass spectra (HRMS) were obtained by the ESI-TOF ionization sources.

General Procedure for the Preparation of 4-Aminobiaryls (1). Take the synthesis of 1e as an example. Following a reported procedure,14 The suspension of substituted m-tolylhydrazine hydrochloride (1.58 g, 10 mmol) in AcOH (10 mL) was heated in an oil bath at 50 ℃ for 30 min, the pentan-3-one (1.72 g, 20 mmol, 2 equiv) was added in one portion and the reaction mixture was refluxed for 3 h. After this time, EtOAc (60 mL) was added, the organic phase was washed with brine (2 × 50 mL) and with a saturated solution of NaHCO3 (50 mL) and dried over Na2SO4, and the solvent was removed by distillation under reduced pressure affording gray residue, which was purified by flash chromatography (petroleum ether/AcOEt 30:1) to afford the 2,3-disubstituted indoles.


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The Journal of Organic Chemistry 2-ethyl-3,5-dimethyl-1H-indole (1e). 1H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 7.26 (d, J = 0.6 Hz, 1H), 7.15 (d, J = 8.2 Hz,

1H), 6.93 (dd, J = 8.2, 1.3 Hz, 1H), 2.78 – 2.68 (m, 2H), 2.43 (d, J = 8.3 Hz, 3H), 2.20 (s, 3H), 1.25 (q, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 136.6, 133.4, 129.7, 128.2, 122.4, 117.9, 109.8, 105.7, 21.5, 19.4, 14.0, 8.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H16N+ 174.1277, Found 174.1277. 2-ethyl-5-fluoro-3-methyl-1H-indole (1f). 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1H), 7.16 (dd, J = 8.6, 4.3 Hz, 1H), 7.11 (d, J = 9.6 Hz, 1H), 6.84 (t, J = 9.0 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 157.8 (d, J = 233.4 Hz), 138.5, 131.5, 129.9 (d, J = 9.8 Hz), 110.6 (d, J = 9.8 Hz), 108.9 (d, J = 26.2 Hz), 106.6 (d, J = 4.5 Hz), 103.1 (d, J = 23.2 Hz), 19.5 , 13.9 , 8.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H13NF+ 178.1027, Found 178.1035. 5-chloro-2-ethyl-3-methyl-1H-indole (1g). 1H NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.1, 133.4, 130.6, 124.7, 121.0, 117.6, 111.1, 106.2, 19.4, 13.9, 8.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H13NCl+ 194.0731, Found 194.0732. 5-bromo-2-ethyl-3-methyl-1H-indole (1h). 1H NMR (500 MHz, CDCl3): δ 7.71 (d, J = 26.2 Hz, 1H), 7.61 (d, J = 13.8 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.27 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 138.0, 133.8, 131.4, 123.7, 120.9, 112.4, 111.7, 106.2, 19.5, 14.0, 8.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H13NBr+ 238.0226, Found 238.0212. 2-ethyl-3-methyl-1H-indole-5-carbonitrile (1i). 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.81 (s, 1H), 7.32 (dd, J = 17.8, 8.3 Hz, 2H), 2.78 (q, J = 7.6 Hz, 2H), 2.23 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 138.9, 136.9, 129.4, 124.1, 123.6, 121.2, 110.9, 107.2, 101.9, 19.4, 13.8, 8.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H13N2+ 185.1073, Found 185.1075. 2-ethyl-4,6-difluoro-3-methyl-1H-indole (1j). 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 6.75 (dd, J = 9.1, 2.0 Hz, 1H), 6.59 6.46 (m, 1H), 2.70 (q, J = 7.6 Hz, 2H), 2.33 (s, 3H), 1.26 (dd, J = 9.5, 5.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.8 (d, J = 11.9 Hz), 157.5 (dd, J = 13.5, 7.2 Hz), 155.0 (d, J = 14.5 Hz), 136.8, 136.6, 136.4, 104.8, 95.0, 94.7 (d, J = 4.2 Hz), 94.4, 93.0 (d, J = 4.3 Hz), 92.8 (d, J = 4.4 Hz), 19.0, 13.9, 9.8 (d, J = 2.3 Hz); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12NF2+ 196.0932, Found 196.0928. 4,6-dichloro-2-ethyl-3-methyl-1H-indole (1k). 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 2.71 (q, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.25 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.3, 136.4, 126.3, 126.2, 124.7, 120.4, 109.0, 107.1, 19.2, 13.8, 10.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H12NCl2+ 228.0341, Found 228.0343.



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1,2-diethyl-3-methyl-1H-indole (1l). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.17 - 7.11 (m, 1H), 7.09 - 7.04 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.77 (q, J = 7.6 Hz, 2H), 2.26 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3): δ 137.7, 135.3, 128.7, 120.5, 118.5, 118.1, 108.7, 105.8, 37.7, 17.7, 15.7, 14.7, 8.6; HRMS

(ESI-TOF) m/z: [M + H]+ Calcd for C13H18N+ 188.1434, Found 188.1451. methyl 2-(2-ethyl-3-methyl-1H-indol-1-yl)acetate (1m). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 7.6 Hz, 1H), 7.18 - 7.07 (m, 3H), 4.81 (s, 2H), 3.72 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.8, 137.9, 136.5, 129.0, 121.3, 119.5, 118.5, 108.4, 107.2, 52.6, 44.9, 17.8, 14.5, 8.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H18NO2+ 232.1332, Found 232.1328. methyl 2-(6-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetate (3b). 1H NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 6.99 (d, J = 26.0 Hz, 2H), 4.59 (s, 2H), 3.62 (s, 3H), 2.59 (t, J = 37.9 Hz, 4H), 2.43 (s, 3H), 1.93 (t, J = 37.2 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.7, 135.5, 135.0, 128.5, 127.9, 122.5, 118.0, 110.0, 107.9, 52.5, 44.5, 23.2, 23.2, 21.9, 21.5, 21.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H20NO2+ 258.1489, Found 258.146. General Procedure for the Preparation of (2). Take the synthesis of 2a as an example. Indole 1a (31.8 mg, 0.2 mmol), azidoiodinane reagent (I) (69.4 mg, 0.24 mmol) and CuBr (2.88 mg, 0.02 mmol) were added to ethyl acetate (1.0 ml) in a 10 ml tube under air. The formed mixture was stirred at room temperature under air for 6 h. The solution was concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether/AcOEt 100:1) to afford the yellow oil product 2a (35.2 mg, yield: 88 %).

1 g scale for the synthesis of 2a. Indole 1a (954 mg, 6 mmol), azidoiodinane reagent (I) (2.08 g, 7.2 mmol) and CuBr (86.4 mg, 0.6 mmol) were added to ethyl acetate (15.0 ml) in a 50 ml tube under air. The formed mixture was stirred at room temperature under air for 6 h. The solution was concentrated in vacuo to afford a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether/AcOEt 100:1) to afford the product 2a (888 mg, yield: 74 %). 2-(1-azidoethyl)-3-methyl-1H-indole (2a). Yellow oil (35.2 mg, yield: 88 %); 1H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.23 – 7.17 (m, 1H), 7.16 – 7.09 (m, 1H), 5.04 (q, J = 6.9 Hz, 1H), 2.31 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 135.6, 132.5, 128.9, 122.6, 119.6, 119.1, 111.0, 108.9, 53.7, 20.7, 8.6; IR (KBr): 3459, 3369, 2115, 1620, 1515, 1381, 810 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H13N4+ 201.1135, Found 201.1134. 2-(azidomethyl)-3-methyl-1H-indole (2b). Yellow oil (27.5 mg, yield: 74 %); 1H NMR (400 MHz, CDCl3): δ 8.09 - 7.81 (m, 1H), 7.57 (dd, J = 18.9, 6.8 Hz, 1H), 7.40 – 7.32 (m, 1H), 7.26 (dd, J = 13.6, 6.4 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 4.54 (s, 2H), 2.35 (d, J


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= 12.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 135.9, 128.6, 127.7, 122.8, 119.6, 119.2, 110.9, 110.9, 46.2, 8.5; IR (KBr): 3382, 2920, 2078, 1457, 1333, 758 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C10H9N4–185.08327, Found 185.0835. 2-(azidomethyl)-3-ethyl-1H-indole (2c). Yellow oil (27.2 mg, yield: 68 %); 1H NMR (500 MHz, CDCl3): δ 7.95 (d, J = 51.8 Hz, 1H), 7.69 (dd, J = 20.6, 7.9 Hz, 1H), 7.42 – 7.33 (m, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.23 – 7.15 (m, 1H), 4.52 (s, 2H), 2.84 (q, J = 7.4 Hz, 2H), 1.37 – 1.28 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 136.1, 127.7, 127.1, 122.7, 119.6, 119.4, 117.9, 111.0, 46.1, 17.4, 16.3; IR (KBr): 3398, 2965, 2091, 1455, 1231, 739 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H13N4+ 201.1135, Found 201.1135. 2-(azidomethyl)-3-benzyl-1H-indole (2d). Yellow oil (26.2 mg, yield: 50 %); 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.34 – 7.19 (m, 6H), 7.12 (t, J = 7.5 Hz, 1H), 4.51 (s, 2H), 4.19 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 140.8, 136.0, 128.8, 128.5, 128.4, 128.3, 128.2, 126.1, 122.9, 119.9, 119.6, 113.8, 111.0, 46.22 30.0; IR: (KBr) 3400, 2921, 2080, 1457, 1240, 742 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15N4+ 263.1291, Found 263.1295. 2-(1-azidoethyl)-3,5-dimethyl-1H-indole (2e). Yellow oil (24.8 mg, yield: 58 %); 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.36 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.05 (dd, J = 8.3, 1.2 Hz, 1H), 5.05 (q, J = 6.9 Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 1.59 (d, J = 13.0, 6.9 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ 133.8, 132.5, 129.0, 128.8, 124.1, 118.7, 110.6, 108.4, 53.7, 21.5, 20.5, 8.5;

IR (KBr): 3333, 2976, 2102, 1517, 1257, 818 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H15N4+ 215.1291, Found 215.1291. 2-(1-azidoethyl)-5-fluoro-3-methyl-1H-indole (2f). Yellow oil (32.3 mg, yield: 74 %); 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 7.27 - 7.22 (m, 1H), 7.19 (dd, J = 9.5, 2.3 Hz, 1H), 6.95 (td, J = 9.1, 2.5 Hz, 1H), 5.04 (q, J = 6.9 Hz, 1H), 2.28 (s, 3H), 1.59 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.0, 156.7, 134.4, 131.9, 129.3 (d, J = 9.5 Hz), 111.5 (d, J = 9.6 Hz), 110.9, 110.6, 108.8 (d, J = 4.7 Hz), 104.0, 103.8, 77.4, 77.1, 76.7, 53.6, 20.5, 8.5; IR (KBr): 3337, 2981, 2102, 1487, 1229, 796 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C11H10N4F– 217.0895, Found 217.0896. 2-(1-azidoethyl)-5-chloro-3-methyl-1H-indole (2g). Yellow oil (34.6 mg, yield: 74 %); 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 8.6, 2.0 Hz, 1H), 5.03 (q, J = 6.9 Hz, 1H), 2.27 (s, 3H), 1.58 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 134.0, 133.8, 130.0, 125.2, 122.7, 118.5, 111.9, 108.4, 53.5, 20.5, 8.4; IR (KBr): 3384, 2080, 1457, 1333, 1224, 7748 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C11H10N4Cl– 233.0600, Found 233.0602. 2-(1-azidoethyl)-5-bromo-3-methyl-1H-indole (2h). Yellow oil (38.9 mg, yield: 70 %); 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 7.67 (d, J = 1.4 Hz, 1H), 7.28 (dd, J = 8.6, 1.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 5.03 (q, J = 6.9 Hz, 1H), 2.27 (s, 3H), 1.58 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 134.0, 133.9, 130.6, 125.3, 121.6, 112.7, 112.4, 108.3, 53.5, 20.5, 8.4; IR



Page 10 of 14

(KBr): 3427, 2921, 2100, 1467, 1302, 1236, 739 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C11H10N4Br– 277.0094, Found 277.0095. 2-(1-azidoethyl)-3-methyl-1H-indole-5-carbonitrile (2i). Yellow oil (29.3 mg, yield: 65 %); 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H), 7.88 (s, 1H), 7.41 (dd, J = 4.6, 2.0 Hz, 2H), 5.15 – 4.98 (m, 1H), 2.32 (s, 3H), 1.67 – 1.53 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 137.2, 135.1, 128.7, 125.3, 124.6, 120.9, 111.8, 109.2, 102.4, 53.3, 20.4, 8.3; IR (KBr): 3305, 2223, 2101, 1457, 1232, 809 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H12N5+ 226.1087, Found 226.1087. 2-(1-azidoethyl)-4,6-difluoro-3-methyl-1H-indole (2j). Yellow oil (32.1 mg, yield: 68 %); 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.56 (t, J = 10.5 Hz, 1H), 5.00 (q, J = 6.9 Hz, 1H), 2.41 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 160.8 (d, J = 11.9 Hz), 158.56 – 158.02 (m), 155.8 (d, J = 14.8 Hz), 137.1 (t, J = 14.1 Hz), 132.7, 114.2 (d, J = 18.8 Hz), 107.5, 95.7, 95.5 (d, J = 4.7 Hz), 95.2, 93.7 (d, J = 4.4 Hz), 93.5 (d, J = 4.6 Hz), 53.2, 20.6, 10.0 (d, J = 2.4 Hz); IR (KBr): 3460, 2982, 2103, 1640, 1242, 823 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C11H9N4F2– 235.0801, Found 235.0801. 2-(1-azidoethyl)-4,6-dichloro-3-methyl-1H-indole (2k). Yellow oil (34.3 mg, yield: 64 %); 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 5.04 (q, J = 6.8 Hz, 1H), 2.50 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 136.7, 134.4, 127.9, 127.2, 124.2, 121.0, 109.7, 109.1, 53.1, 20.6, 10.6; IR (KBr): 3297, 2104, 1451, 1228, 833 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C11H9N4Cl2– 267.0209, Found 267.0212. 2-(1-azidoethyl)-1-ethyl-3-methyl-1H-indole (2l). Yellow oil (15.5 mg, yield: 34 %); 1H NMR (500 MHz, CDCl3): δ 7.57 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.12 (dd, J = 11.0, 3.8 Hz, 1H), 5.12 (q, J = 7.1 Hz, 1H), 4.34 - 4.23 (m, 2H), 2.39 (s, 3H), 1.64 (d, J = 7.1 Hz, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 136.1, 132.5, 128.3, 122.2, 119.1, 119.1, 109.3, 109.1, 53.8, 38.8, 20.6, 15.4, 9.0; IR (KBr): 2979, 2097, 1462, 1343, 1239, 738 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H17N4+ 229.1448, Found 229.1447. methyl 2-(2-(1-azidoethyl)-3-methyl-1H-indol-1-yl)acetate (2m). Yellow oil (9.8 mg, yield: 18 %); 1H NMR (500 MHz, CDCl3): δ 7.60 - 7.52 (m, 1H), 7.24 (dd, J = 7.1, 1.1 Hz, 1H), 7.17 – 7.12 (m, 2H), 5.14 – 5.03 (m, 2H), 4.95 (d, J = 18.1 Hz, 1H), 3.78 – 3.69 (m, 3H), 2.37 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.5, 137.4, 132.7, 128.3, 123.0, 119.9, 119.3, 110.3, 108.6, 53.8, 52.6, 45.8, 20.6, 9.0; IR (KBr): 2985, 2100, 1740, 1466, 1206, 737 cm-1; HRMS (ESI-TOF) m/z: [M +Na]+ Calcd for C14H16N4O2Na+ 295.1165, Found 295.1164. 1-azido-2,3,4,9-tetrahydro-1H-carbazole (4a). Yellow oil (29.3 mg, yield: 69 %); 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.31 – 7.21 (m, 1H), 7.15 (dd, J = 16.6, 9.4 Hz, 1H), 4.65 (t, J = 5.3 Hz, 1H), 2.85 (dt, J = 15.6, 5.8 Hz, 1H), 2.74 (dt, J = 15.7, 6.2 Hz, 1H), 2.30 – 2.19 (m, 1H), 2.11 (dq, J = 8.5, 6.0 Hz, 2H), 2.01 – 1.88 (m, 1H);


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13C{1H}

NMR (125 MHz, CDCl3): δ 136.3, 130.6, 126.9, 122.7, 119.7, 119.0, 113.7, 111.2, 55.1, 29.8, 20.7, 20.6; IR (KBr): 3400,

2929, 2090, 1450, 1235, 738 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C12H11N4– 211.0989, Found 211.0990. HRMS (ESI): C12H12N4 - H, Calc: 2, Found:. methyl 2-(1-azido-6-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetate (4b). Yellow oil (41.7 mg, yield: 70 %); 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 1H), 7.14 (q, J = 8.4 Hz, 2H), 4.93 (q, J = 17.8 Hz, 2H), 4.54 (d, J = 3.7 Hz, 1H), 3.78 (s, 3H), 2.92 (dt, J = 15.8, 4.3 Hz, 1H), 2.78 – 2.65 (m, 1H), 2.50 (s, 3H), 2.40 – 2.29 (m, 1H), 2.26 – 2.16 (m, 1H), 2.12 – 1.97 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.4, 135.8, 130.8, 129.1, 126.8, 124.6, 119.1, 114.3, 108.5, 52.9, 52.5, 44.9, 30.3, 21.4, 20.9, 19.6; IR (KBr): 2916, 2091, 1738, 1440, 1206, 803 cm-1; HRMS (ESI-TOF) m/z: [M +Na]+ Calcd for C16H18N4O2Na+ 321.1322, Found 321.1327. General Procedure for the Preparation of 1-(4,6-dichloro-3-methyl-1H-indol-2-yl)ethan-1-amine (5). Following a reported procedure,12 2-(1-azidoethyl)-4,6-dichloro-3-methyl-1H-indole (2k) (26.8 mg, 0.1 mmol) was dissolved in 1 mL dry THF and the mixture added dropwise over 10 min to a stirred suspension of lithium aluminium hydride (LiAlH4, 11.4 mg, 0.3 mmol) in 1 ml dry THF at 0 ℃ under nitrogen. Upon completion, the reaction was allowed to recover to ambient temperature and stirred. After 48 h, the reaction was placed on an ice bath and cautiously quenched with H2O and approximately 1mL KOH (2 N) solution. Once fully quenched, 100 mL ethyl acetate was added and the resulting slurry gravity filtered and the salts washed heavily three times with ethyl acetate. The organic extractions were pooled, dried over anhydrous sodium sulfate and reduced under vacuum to give the crude primary amine as light yellow oil, which was further purified by silica gelcolumn chromatography (DCM/MeOH 10:1) to offer 39.7 mg (82%) yellow oil product. 1H NMR (500 MHz, CDCl3): δ 8.95 (s, 1H), 7.16 (s, 1H), 6.98 (t, J = 16.6 Hz, 1H), 4.55 (dd, J = 12.9, 6.4 Hz, 1H), 2.43 (s, 3H), 2.25 (s, 2H), 1.39 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 139.9, 136.3, 126.7, 126.6, 124.8, 120.4, 109.7, 106.4, 42.9, 23.8, 10.4; IR (KBr): 3158, 2924, 1553, 1327, 1083, 828 cm-1; HRMS (ESI-TOF) m/z: [M - H]+ Calcd for C11H11N2Cl2– 241.0305, Found 241.0307. General Procedure for the Preparation of 4,6-dichloro-3-methyl-2-(1-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-indole (6). Following a reported procedure,13 In a 10 mL one-neck round bottle, 2-(1-azidoethyl)-4,6-dichloro-3-methyl-1H-indole (2k) (26.8 mg, 0.1 mmol) and phenylethynyl (20.4 mg, 0.2 mmol) were suspended in a 1 : 1.5 mixture of water and tBuOH (1 mL : 1.5 mL). To this was added CuSO4·5H2O (1.25 mg, 0.025 mmol) and sodium ascorbate solution (1 mg, 0.005 mmol). The mixture was stirred over night at room temperature, after the reaction was completed (monitored by TLC). The solvent was distilled, water (2 mL) was added, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with brine (5 mL) and saturation NaHCO3 (5 ml), anhydrous Na2SO4 dried. The solvent was evaporated to afford crude product, which was further purified by silica gelcolumn chromatography (DCM/MeOH 10:1) to offer 22 mg (60 %) yellow oil product. 1H NMR (400 MHz, Acetone): δ 10.67 (s, 1H), 8.40 (s, 1H), 7.86 (d, J = 6.3 Hz, 2H), 7.35 (dd, J = 30.3, 7.7 Hz, 4H), 7.03 (s, 1H), 6.35 (d, J = 6.2 Hz,



Page 12 of 14

1H), 2.58 (s, 3H), 2.11 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (100 MHz, Acetone): δ 147.8, 138.6, 135.8, 132.2, 129.6, 128.7, 127.9, 127.6, 126.2, 124.6, 120.8, 120.5, 111.2, 109.9, 52.8, 20.5, 10.7. IR (KBr): 3140, 2926, 1615, 1312, 1232, 1087, 759, 687 cm-1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H17N4Cl2+ 371.0825, Found 371.0824.

ASSOCIATED CONTENT Supporting Information 1H

and 13C spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected]

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for financial support from the NSFC (21871296, 21907111), Guangdong Natural Science Founds for Distinguished Young Scholars (2017A030306017), and Guangdong Provincial Key Laboratory of Construction Foundation (2017B030314030).

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