Copper-catalyzed: N -alkylation of indoles by N -tosylhydrazones

Article abstract of DOI:10.1039/c7ra03765a

An efficient method for the direct N-alkylation of indoles via copper-catalyzed reductive cross coupling between N-tosylhydrazones and indole reagents has been developed. The reaction was performed in the presence of copper iodide and potassium hydroxide by utilization of tri(p-tolyl)phosphine as a ligand. A wide variety of N-alkylated indoles were obtained in moderate to good yields. The application of the current method to the synthesis of biologically active N-alkylated indole derivatives has also been demonstrated.

Full text of DOI:10.1039/c7ra03765a

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Copper-catalyzed N-alkylation of indoles by N-
tosylhydrazones†
Cite this: RSC Adv., 2017, 7, 27974
ab
abc
Jing Cao,a Jianfeng Huab and Hao Zhang
*
Li Ling,
An efficient method for the direct N-alkylation of indoles via copper-catalyzed reductive cross coupling
between N-tosylhydrazones and indole reagents has been developed. The reaction was performed in
the presence of copper iodide and potassium hydroxide by utilization of tri(p-tolyl)phosphine as a ligand.
A wide variety of N-alkylated indoles were obtained in moderate to good yields. The application of the
current method to the synthesis of biologically active N-alkylated indole derivatives has also been
demonstrated.
Received 1st April 2017
Accepted 17th May 2017
DOI: 10.1039/c7ra03765a
rsc.li/rsc-advances
for the safe generation of diazo compounds and carbenes.7 They
have emerged as a new type of cross-coupling partner in C–C(X)
bond formation, including in reactions with aryl halides,8
Introduction
The indole core is one of the most prevalent architectures found
in a myriad of biologically active natural and synthesized
compounds.1 For over 100 years, substituted indoles have
remained preferred structures in the creation of new potential
drugs, due to their high affinity to bind with many biological
targets.2 Hence, enormous efforts have been devoted to the
preparation and direct functionalization of indoles.3 However,
the direct N-alkylation of indoles remains challenging due to
the inertness of the indole nitrogen atom toward electrophilic
reagents, despite the structural novelties and attractive biolog-
ical activities of N-alkylated indoles. Some biologically active N-
alkylated indole derivatives are shown in Fig. 1.
Fig.
1 Representative biologically active N-alkylated indole
derivatives.
One of the common methods for alkylation of indoles is
a Mitsunobu reaction of indole derivatives with alcohol
(Scheme 1).4 However, electron withdrawing substituents at
position 2 or position 3 are needed to increase NH acidity in this
reaction. Chen et al. reported the use of Morita–Baylis–Hillman
carbonates in asymmetric N-allylic alkylation of indoles.5 Trost
et al. and Hartwig et al. developed palladium-catalyzed and
iridium-catalyzed N-allylic alkylation of indoles, respectively.6
Nevertheless, only N-allylation products were obtained through
these methods. Therefore, it would be highly desirable to
develop a new method for the mild and efficient direct intro-
duction of alkyl substituents at the nitrogen atoms of indoles.
On the other hand, N-tosylhydrazones, which are readily
prepared from carbonyl compounds, have been used as a source
aCollege of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot
010021, P. R. China. E-mail: haozhang@imu.edu.cn
bInner Mongolia Key Laboratory of Fine Organic Synthesis, Hohhot 010021, P. R.
China
cState Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of
Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
† Electronic supplementary information (ESI) available: Spectroscopic data for all
compounds. See DOI: 10.1039/c7ra03765a
Scheme 1 Synthesis of N-alkylated indoles.
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arylsulfonates,9 alkynes,10 H-phosphonates,11 azoles,12 arylbor-
onic acids,13 benzylic halides,14 and amines.15
Under the above optimized reaction conditions, we next
examined the scope of this reaction (Table 2). N-Alkylation of
Herein, N-alkylated indoles were synthesized through the indole proceeded with a wide range of N-tosylhydrazones in
Cu-catalyzed reductive cross coupling of N-tosylhydrazones with good yields. Electron-donating groups at the ortho, meta or para
indoles using potassium hydroxide as a base. Various N- position on the phenyl ring of acetyl benzene-derived N-tosyl-
branched alkylated and N-benzylated indoles were obtained hydrazones led to increased yields (3b to 3f), while strong
through this method.
electron withdrawing groups decreased the reaction efficiency
to some extent (3j and 3k). Halogen groups and heteroaryl
groups were well tolerated (3g to 3j, 3p), generating product in
58–80% yields. Benzophenone-derived N-tosylhydrazones with
methyl or chloro substituents reacted with indoles to give N-
alkylation products in good yield (3m to 3o). More importantly,
alkyl ketone-derived N-tosylhydrazones could be effective
alkylation substrates (3q to 3s). Alkylation of indoles with
benzaldehyde-derived N-tosylhydrazone was examined (3t and
3u), giving products in 82–86% yield. Substituted indoles with
an electron-donating group at the 5-position increased the
product yield to 85% (3w) and electron withdrawing group at
the 5-position caused a small decrease in production yield to
64% (3v). Finally, pyrrole and carbazole also reacted well with N-
tosylhydrazones giving products (3x to 3z, 3aa) in 41–78% yield.
The synthetic value of our method was demonstrated by the
synthesis of N-alkylated indole derivative 6, which has been
shown to have activity in treatment of Alzheimer's disease
(Scheme 2).16 The reaction of 2-phenylbenz[e]indole 4 with 3-
Results and discussion
We selected alkylation of indole with acetyl benzene-derived
tosylhydrazone 1a as the model reaction for optimization
(Table 1). Initial screening of Cu catalysts revealed that CuI
provided the best activity, with 31% yield of 3a (Table 1, entry 7).
Several phosphine ligands, including triphenylphosphine, tri(p-
tolyl)phosphine, tris(4-methoxyphenyl)phosphine and tricyclo-
hexylphosphine were examined. Tri(p-tolyl)phosphine and
tris(4-methoxyphenyl)phosphine were shown to be the most
efficient ligands in terms of reactivity, giving the product 3a in
30–31% yield (Table 1, entries 7 and 10). The best result was
obtained with KOH as the base, giving 3a in 68% yield (Table 1,
entry 12). Further screening of solvents did not improve the
results (Table 1, entries 14–16). In the control experiment, 42%
yield of product 3a was detected under conditions in which the
phosphine ligand was absent (Table 1, entry 17). Thus, opti-
mized reaction conditions were obtained as follows: 10 mol% of
CuI, 10 mol% of tri(p-tolyl)phosphine, 2.5-equivalent of KOH, in
dioxane at 100 ꢀC under argon (Table 1, entry 12).
(methoxycarbonyl)cyclohexanone-derived tosylhydrazone
5
under the current conditions proceeded smoothly to give N-
alkylated product in 71% yield. Following hydrolysis of the ester
Table 1 Optimization of reaction conditionsa
Entry
Catalyst (10 mol%)
Ligand (10 mol%)
Solvent
Base (2.5 equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(acac)2
Cu(OTf)2
Cu(OAc)2
CuBr
CuCl
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
PPh3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toulene
CH3CN
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
LiOtBu
KOH
Trace
18
Trace
20
19
10
31
28
30
21
9
P(p-OMePh)3
PCy3
10
11
12
13
14
15
16
17
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
P(p-tolyl)3
25
68
LiOH
KOH
KOH
KOH
Trace
Trace
Trace
Trace
42
Dioxane
KOH
a
Reactions were carried out with 0.33 mmol of 1a and 0.50 mmol of 2 in the presence of 10 mol% of catalyst, 10 mol% of ligand, 2.5 equiv. of base
b
and 2 mL solvent under an argon atmosphere for 12 h. Isolated yield.
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Table 2 Cu-catalyzed N-alkylation of indoles with tosylhydrazonesa,b
Scheme 2 Application of current method to synthesis of biologically
active N-alkylated indole derivative.
Scheme 3 Proposed reaction mechanism.
group, the biologically active indole derivative 6 was obtained in
70% yield over two steps.
A plausible mechanism for this Cu-catalyzed reductive
coupling is proposed on the basis of transition metal-catalyzed
cross-coupling reactions of N-tosylhydrazones in the literature
(Scheme 3).7b,17 First, the diazo compound B is formed by
decomposition of the tosylhydrazone A in the presence of base.
Subsequently, reaction of copper salt and diazo compound B
leads to the copper-carbene species C. Then, deprotonation of
indole in basic conditions followed by coordination with Cu(I)
generates the intermediate D. Next, migratory insertion of the
indole group gives Cu(I) species E. Finally, protonation of
intermediate E affords the product and regenerates the Cu(I)
catalyst.
Conclusions
In conclusion, we have described a new procedure for the direct
N-alkylation of indoles by reductive coupling of N-tosylhy-
drazones with indoles in the presence of KOH and a catalytic
amount of CuI and tri(p-tolyl)phosphine. Various N-branched
alkylated and N-benzylated indoles could be obtained in
moderate to good yield. Notably, the starting materials in this
method are readily available, since N-tosylhydrazones are easily
prepared from the corresponding aldehydes or ketones. Addi-
tionally, the reaction procedure has functional group compati-
bility and operational simplicity, and may have potential use in
the synthesis of biologically important N-alkylated indoles.
a
Reactions were carried out with 0.33 mmol of 1 and 0.50 mmol of 2 in
the presence of 10 mol% of CuI, 10 mol% of P(p-tolyl)3, 0.83 mmol of
KOH and 2 mL of dioxane at 100 ꢀC under an argon atmosphere for
12 h. b Isolated yield aer chromatography.
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d 8.51 (d, J ¼ 20.3 Hz, 2H), 8.24 (d, J ¼ 8.2 Hz, 1H), 8.02–7.79 (m,
1H), 7.36 (dd, J ¼ 6.8, 5.2 Hz, 1H), 4.85 (s, 2H), 4.37 (s, 2H), 4.13
(s, 5H). 13C NMR (126 MHz, CDCl3) d 139.7, 137.1, 136.1, 129.4,
128.8, 125.9, 124.9, 121.5, 120.9, 119.5, 110.1, 101.4, 54.6, 21.8,
21.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H17N 236.1439;
found: 236.1442.
Experimental section
General experimental methods
All reactions were carried out in oven dried glassware under
argon unless otherwise specied. All NMR experiments were
carried out on a Bruker AVANCE 500 MHz nuclear magnetic
resonance spectrometer using CDCl3 or DMSO-d6 as the solvent
with tetramethylsilane as the internal standard. Chemical shi
values (d) are given in parts per million. HRMS data were ob-
tained on a Bruker QTOF mass spectrometer. The melting
points were determined on an X-4 binocular microscope
melting point apparatus and uncorrected. Dioxane, toluene,
DMF and acetonitrile were dried according to literature
techniques.
1-(1-(2-Methoxyphenyl)ethyl)-1H-indole (3e). Yellow oil,
1
51.4 mg (65% yield); Rf (petroleum ether) ¼ 0.4. H NMR (500
MHz, CDCl3) d 7.61 (d, J ¼ 7.7 Hz, 1H), 7.38 (d, J ¼ 3.2 Hz, 1H),
7.22 (d, J ¼ 8.0 Hz, 1H), 7.16 (s, 1H), 7.13–7.00 (m, 2H), 6.84 (d, J
¼ 8.1 Hz, 1H), 6.76 (d, J ¼ 6.6 Hz, 2H), 6.54 (d, J ¼ 3.1 Hz, 1H),
6.03 (q, J ¼ 7.0 Hz, 1H), 3.83 (s, 3H), 1.84 (d, J ¼ 7.0 Hz, 3H). 13
C
NMR (126 MHz, CDCl3) d 156.2, 136.1, 131.3, 128.7, 128.5, 126.0,
125.1, 121.3, 120.8, 119.4, 110.5, 110.3, 101.0, 55.5, 49.2, 20.5.
HRMS (ESI-TOF) m/z: [M]+ calcd for C17H17NO 251.1310; found:
251.1305.
General procedure for preparation of N-alkylindoles
1-(1-(4-Methoxyphenyl)ethyl)-1H-indole (3f). Yellow oil,
1
The indoles (0.50 mmol, 1.5 equiv.), N-tosylhydrazones 64.1 mg (81% yield); Rf (petroleum ether) ¼ 0.4. H NMR (500
(0.33 mmol, 1.0 equiv.), potassium hydroxide (0.83 mmol, 2.5 MHz, CDCl3) d 7.69 (d, J ¼ 7.5 Hz, 1H), 7.30 (t, J ¼ 6.4 Hz, 2H),
equiv.), copper iodide (0.03 mmol, 10 mol%), P(p-tolyl)3 7.19 (t, J ¼ 7.5 Hz, 1H), 7.13 (d, J ¼ 15.2, 7.8 Hz, 3H), 6.86 (d, J ¼
(0.03 mmol, 10 mol%) and 2 mL dioxane were mixed in a dry 8.7 Hz, 2H), 6.60 (d, J ¼ 3.2 Hz, 1H), 5.68 (q, J ¼ 7.0 Hz, 1H), 3.80
reaction tube. The mixture was stirred at 100 ꢀC under an argon (s, 3H), 1.93 (d, J ¼ 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
atmosphere for 12 hours. When the reaction was completed, the d 158.9, 136.0, 134.7, 128.8, 127.2, 124.9, 121.4, 120.9, 119.5,
crude reaction mixture was allowed to reach room temperature, 114.0, 110.1, 101.4, 55.3, 54.3, 21.7. HRMS (ESI-TOF) m/z: [M]+
and the solvent was eliminated. Then ethyl acetate and calcd for C17H17NO 251.1310; found: 251.1305.
ammonia were added and the layers were separated. The
1-(1-(2-Chlorophenyl)ethyl)-1H-indole (3g). Yellow oil,
1
aqueous phase was extracted three times with ethyl acetate. The 49.8 mg (63% yield); Rf (petroleum ether) ¼ 0.5. H NMR (500
combined organic layers were washed with water and then dried MHz, CDCl3) d 7.67–7.56 (m, 1H), 7.36 (dd, J ¼ 18.9, 5.6 Hz, 2H),
over MgSO4 and ltered. The solvents were evaporated under 7.16–7.05 (m, 4H), 7.02 (d, J ¼ 14.8, 7.4 Hz, 1H), 6.74 (d, J ¼
reduced pressure and the residue was puried by ash chro- 7.8 Hz, 1H), 6.58 (d, J ¼ 3.2 Hz, 1H), 6.02 (q, J ¼ 7.0 Hz, 1H), 1.86
matography on silica gel.
(d, J ¼ 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 140.7, 136.1,
1-(1-Phenylethyl)-1H-indole (3a).18 Yellow oil, 52.2 mg (68% 132.1, 129.7, 128.9, 128.7, 127.6, 126.5, 124.7, 121.7, 120.9,
yield); Rf (petroleum ether) ¼ 0.6. H NMR (500 MHz, CDCl3) 119.8, 110.1, 101.6, 52.1, 20.5. HRMS (ESI-TOF) m/z: [M]+ calcd
1
d 7.71 (d, J ¼ 7.3 Hz, 1H), 7.32 (d, J ¼ 17.5, 11.8, 6.3 Hz, 5H), for C16H14NCl 255.0815; found: 255.0809.
7.25–7.13 (m, 4H), 6.65 (t, J ¼ 4.3 Hz, 1H), 5.73 (d, J ¼ 13.8,
1-(1-(3-Chlorophenyl)ethyl)-1H-indole (3h). Yellow oil,
1
6.8 Hz, 1H), 1.98 (t, J ¼ 6.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) 57.7 mg (73% yield); Rf (petroleum ether) ¼ 0.5. H NMR (500
d 149.2, 148.5, 147.5, 139.1, 123.4, 115.8, 113.8, 69.7, 69.0, 66.9. MHz, CDCl3) d 7.63 (d, J ¼ 7.4 Hz, 1H), 7.17 (d, J ¼ 9.1, 7.9 Hz,
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H15N 222.1283; 3H), 7.12 (d, J ¼ 25.6, 11.7, 4.2 Hz, 4H), 6.92 (d, J ¼ 7.2, 1.1 Hz,
found: 222.1283.
1H), 6.57 (s, 1H), 5.59 (t, J ¼ 6.9 Hz, 1H), 1.86 (d, J ¼ 7.1, 1.6 Hz,
1-(1-(o-Tolyl)ethyl)-1H-indole (3b). Yellow oil, 55.2 mg (71% 3H). 13C NMR (126 MHz, CDCl3) d 145.0, 136.0, 134.7, 130.1,
1
yield); Rf (petroleum ether) ¼ 0.6. H NMR (500 MHz, CDCl3) 128.9, 127.7, 126.1, 124.7, 124.3, 121.1, 121.1, 120.0, 110.0,
d 7.62 (d, J ¼ 7.8 Hz, 1H), 7.21–7.14 (m, 4H), 7.13–7.06 (m, 4H), 102.0, 54.4, 21.8. HRMS (ESI-TOF) m/z: [M]+ calcd for C16H14NCl
6.50 (d, J ¼ 3.0 Hz, 1H), 5.78 (q, J ¼ 6.9 Hz, 1H), 2.24 (s, 3H), 1.84 255.0815; found: 255.0812.
(d, J ¼ 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 140.1, 136.0,
1-(1-(4-Chlorophenyl)ethyl)-1H-indole (3i). Yellow oil,
1
135.7, 130.8, 128.8, 127.7, 126.6, 125.4, 125.1, 121.5, 121.0, 65.7 mg (83% yield); Rf (petroleum ether) ¼ 0.5. H NMR (500
119.6, 109.7, 101.3, 51.8, 20.5, 19.1. HRMS (ESI-TOF) m/z: [M]+ MHz, CDCl3) d 7.63 (d, J ¼ 7.1 Hz, 1H), 7.23 (d, J ¼ 15.1, 5.9 Hz,
calcd for C17H17N 235.1361; found: 235.1356.
3H), 7.19–7.04 (m, 3H), 7.01 (d, J ¼ 8.4 Hz, 2H), 6.57 (d, J ¼
1-(1-(m-Tolyl)ethyl)-1H-indole (3c). Yellow oil, 60.5 mg (78% 3.2 Hz, 1H), 5.60 (q, J ¼ 7.1 Hz, 1H), 1.87 (d, J ¼ 7.1 Hz, 3H). 13
C
1
yield); Rf (petroleum ether) ¼ 0.5. H NMR (500 MHz, CDCl3) NMR (126 MHz, CDCl3) d 141.4, 136.0, 133.2, 128.9, 127.3, 124.7,
d 8.51 (d, J ¼ 20.3 Hz, 2H), 8.24 (d, J ¼ 8.2 Hz, 1H), 8.02–7.79 (m, 121.7, 121.1, 119.8, 110.0, 101.8, 54.3, 21.7. HRMS (ESI-TOF) m/
1H), 7.36 (d, J ¼ 6.8, 5.2 Hz, 1H), 4.85 (s, 2H), 4.37 (s, 2H), 4.13 (s, z: [M]+ calcd for C16H14NCl 255.0815; found: 255.0809.
5H). 13C NMR (126 MHz, CDCl3) d 142.7, 138.4, 136.2, 128.8,
1-(1-(4-Fluorophenyl)ethyl)-1H-indole (3J). White solid,
ꢀ
128.6, 128.3, 126.7, 125.0, 123.1, 121.5, 120.9, 119.6, 110.1, 61.7 mg (79% yield); mp 72–73 C; Rf (petroleum ether) ¼ 0.4.
101.4, 54.8, 21.9, 21.6. HRMS (ESI-TOF) m/z: [M]+ calcd for 1H NMR (500 MHz, CDCl3) d 7.63 (d, J ¼ 7.3 Hz, 1H), 7.22 (d, J ¼
C
17H17N 235.1361; found: 235.1358.
3.0 Hz, 1H), 7.17 (d, J ¼ 7.7 Hz, 1H), 7.14–7.06 (m, 2H), 7.03 (d, J
1-(1-(p-Tolyl)ethyl)-1H-indole (3d). Yellow oil, 62.9 mg (81% ¼ 8.3, 5.5 Hz, 2H), 6.95–6.88 (m, 2H), 6.55 (d, J ¼ 3.1 Hz, 1H),
yield); Rf (petroleum ether) ¼ 0.5. H NMR (500 MHz, CDCl3) 5.59 (q, J ¼ 7.0 Hz, 1H), 1.84 (d, J ¼ 7.1 Hz, 3H). 13C NMR (126
1
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MHz, CDCl3) d 163.0, 161.0, 138.5, 138.5, 136.0, 128.9, 127.6,
127.6, 124.7, 121.6, 121.0, 119.7, 115.7, 115.5, 110.0, 101.7, 54.2,
21.8. HRMS (ESI-TOF) m/z: [M]+ calcd for C16H14NF 239.1110;
found: 239.1105.
1-(Pentan-3-yl)-1H-indole (3q). Yellow oil, 59.5 mg (81%
yield); Rf (petroleum ether) ¼ 0.6. H NMR (500 MHz, CDCl3)
1
d 7.63 (d, J ¼ 7.8 Hz, 1H), 7.37 (d, J ¼ 8.3 Hz, 1H), 7.18 (d, J ¼
13.7, 5.6 Hz, 1H), 7.12 (d, J ¼ 3.2 Hz, 1H), 7.08 (t, J ¼ 7.1 Hz, 1H),
6.54 (d, J ¼ 3.0 Hz, 1H), 4.17–4.04 (m, 1H), 1.91–1.82 (m, 4H),
0.75 (t, J ¼ 7.4 Hz, 6H). 13C NMR (126 MHz, CDCl3) d 136.9,
128.4, 124.4, 121.1, 120.9, 119.1, 109.7, 101.4, 59.7, 29.8, 28.6,
11.0. HRMS (ESI-TOF) m/z: [M]+ calcd for C13H17N 187.1361;
found: 187.1356.
1-(1-(4-(Triuoromethyl)phenyl)ethyl)-1H-indole (3k). White
1
oil, 26.7 mg (33% yield); Rf (petroleum ether) ¼ 0.4. H NMR
(500 MHz, CDCl3) d 7.66 (d, J ¼ 6.8, 2.0 Hz, 1H), 7.54 (d, J ¼
8.2 Hz, 2H), 7.32 (d, J ¼ 3.3 Hz, 1H), 7.20 (d, J ¼ 8.4 Hz, 2H),
7.18–7.09 (m, 3H), 6.62 (d, J ¼ 3.2 Hz, 1H), 5.72 (q, J ¼ 7.1 Hz,
1H), 1.96 (d, J ¼ 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 136.0,
128.9, 126.2, 125.8, 124.6, 121.8, 121.2, 119.9, 110.0, 102.1,
100.1, 54.6, 21.8. HRMS (ESI-TOF) m/z: [M]+ calcd for C17H14NF3
239.1110; found: 239.1105.
1-(4-Phenylbutan-2-yl)-1H-indole (3r). Yellow oil, 38.5 mg
(49% yield); Rf (petroleum ether) ¼ 0.5. 1H NMR (500 MHz,
CDCl3) d 7.64 (d, J ¼ 7.8 Hz, 1H), 7.30–7.25 (m, 2H), 7.20 (d, J ¼
12.6, 5.2 Hz, 3H), 7.08 (t, J ¼ 7.0 Hz, 3H), 6.56 (d, J ¼ 2.8 Hz, 1H),
4.48 (d, J ¼ 14.3, 6.8 Hz, 1H), 2.50 (d, J ¼ 8.2 Hz, 2H), 2.32–2.22
(m, 1H), 2.19–2.08 (m, 1H), 1.51 (d, J ¼ 6.8 Hz, 3H). 13C NMR
(126 MHz, CDCl3) d 141.3, 136.0, 128.4, 126.1, 124.0, 121.3,
121.0, 119.3, 109.6, 101.8, 509, 38.7, 32.6, 21.5. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H19N 250.1596; found: 250.1570.
1-Cyclohexyl-1H-indole (3s). Yellow oil, 27.6 mg (37% yield);
Rf (petroleum ether) ¼ 0.7. 1H NMR (500 MHz, CDCl3) d 7.61 (t, J
¼ 6.7 Hz, 1H), 7.36 (d, J ¼ 8.3 Hz, 1H), 7.17 (d, J ¼ 8.0, 5.3 Hz,
2H), 7.11–7.04 (m, 1H), 6.49 (d, J ¼ 3.2 Hz, 1H), 4.18 (t, J ¼ 11.9,
3.7 Hz, 1H), 2.12 (d, J ¼ 1.7 Hz, 2H), 1.90 (d, J ¼ 13.6 Hz, 2H),
1.70–1.61 (m, 2H), 1.47 (t, J ¼ 13.2, 6.6 Hz, 2H), 1.35–1.16 (m,
2H). 13C NMR (126 MHz, CDCl3) d 135.9, 135.6, 128.8, 128.5,
126.7, 124.1, 121.6, 121.0, 119.7, 119.2, 111.1, 109.5, 102.0,
101.0, 55.1, 33.6, 29.8, 28.9, 26.0, 25.7, 24.6, 23.0, 22.0. HRMS
(ESI-TOF) m/z: [M]+ calcd for C14H17N 199.1361; found:
199.1356.
1-(1-Phenylpropyl)-1H-indole (3l). Yellow oil, 63.7 mg (82%
1
yield); Rf (petroleum ether) ¼ 0.6. H NMR (500 MHz, CDCl3)
d 7.62 (d, J ¼ 7.8 Hz, 1H), 7.29 (d, J ¼ 3.1 Hz, 2H), 7.25–7.10 (m,
6H), 7.07 (t, J ¼ 7.6 Hz, 1H), 6.56 (d, J ¼ 3.2 Hz, 1H), 5.32 (d, J ¼
8.7, 6.7 Hz, 1H), 2.36–2.24 (m, 2H), 0.94 (t, J ¼ 7.3 Hz, 3H). 13
C
NMR (126 MHz, CDCl3) d 141.7, 136.5, 128.7, 128.7, 127.5, 126.5,
125.0, 121.5, 121.0, 119.5, 110.0, 101.7, 61.4, 28.5, 11.6. HRMS
(ESI-TOF) m/z: [M]+ calcd for C17H17N 235.1361; found:
235.1362.
1-(Diphenylmethyl)-1H-indole (3m).19 White solid, 60.7 mg
1
ꢀ
(75% yield); mp 91–92 C; Rf (petroleum ether) ¼ 0.5. H NMR
(500 MHz, CDCl3) d 7.63 (d, J ¼ 5.8, 2.9 Hz, 1H), 7.35–7.16 (m,
7H), 7.11 (d, J ¼ 14.5, 11.7, 7.9 Hz, 7H), 6.85–6.78 (m, 2H), 6.48
(d, J ¼ 3.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) d 139.9, 136.6,
129.0, 128.7, 128.6, 128.5, 128.2, 128.0, 127.0, 125.9, 121.7,
121.0, 119.9, 110.3, 101.5, 63.7. HRMS (ESI-TOF) m/z: [M]+ calcd
for C21H17N 283.1361; found: 283.1356.
1-Benzyl-1H-indole (3t).21 Yellow oil, 61.9 mg (82% yield); Rf
(petroleum ether) ¼ 0.4. 1H NMR (500 MHz, CDCl3) d 7.68 (d, J ¼
7.8 Hz, 1H), 7.34–7.27 (m, 4H), 7.22–7.17 (m, 1H), 7.17–7.12 (m,
4H), 6.58 (d, J ¼ 3.1, 0.6 Hz, 1H), 5.35 (s, 2H). 13C NMR (126
MHz, CDCl3) d 137.6, 136.4, 128.8, 128.8, 128.3, 127.7, 126.8,
121.8, 121.0, 119.6, 109.8, 101.8, 50.1. HRMS (ESI-TOF) m/z: [M]+
calcd for C15H13N 207.1048; found: 207.1043.
1-(Di-p-tolylmethyl)-1H-indole (3n). White solid, 69.0 mg
(84% yield); mp 111–113 ꢀC; Rf (petroleum ether) ¼ 0.6. 1H NMR
(500 MHz, CDCl3) d 7.72 (d, J ¼ 6.2, 2.4 Hz, 1H), 7.31 (d, J ¼
7.2 Hz, 1H), 7.18 (t, J ¼ 6.3 Hz, 6H), 7.06 (d, J ¼ 8.0 Hz, 4H), 6.92
(d, J ¼ 3.3 Hz, 1H), 6.84 (s, 1H), 6.56 (d, J ¼ 3.1 Hz, 1H), 2.40 (s,
6H). 13C NMR (126 MHz, CDCl3) d 137.6, 137.2, 136.6, 129.4,
129.0, 128.3, 127.0, 121.5, 120.9, 119.7, 110.3, 101.2, 63.2, 21.2.
HRMS (ESI-TOF) m/z: [M]+ calcd for C23H21N 311.1674; found:
311.1669.
1-(4-Methylbenzyl)-1H-indole (3u).22 Yellow oil, 65.9 mg (86%
1
yield); Rf (petroleum ether) ¼ 0.4. H NMR (500 MHz, CDCl3)
d 7.63 (d, J ¼ 7.8 Hz, 1H), 7.18–6.96 (m, 8H), 6.52 (d, J ¼ 3.1 Hz,
1H), 5.23 (s, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 137.3, 136.3, 134.5, 129.5, 128.8, 128.3, 126.9, 121.7, 121.0,
119.5, 109.8, 101.6, 49.9, 21.1. HRMS(ESI-TOF) m/z: [M]+ calcd
for C15H13N 221.1204; found: 221.1199.
1-((4-Chlorophenyl) (phenyl)methyl)-1H-indole (3o). Yellow
1
oil, 68.4 mg (83% yield); Rf (petroleum ether) ¼ 0.5. H NMR
(500 MHz, CDCl3) d 7.77–7.70 (m, 1H), 7.40 (d, J ¼ 6.2 Hz, 3H),
7.36 (d, J ¼ 8.3 Hz, 2H), 7.29 (d, J ¼ 6.4 Hz, 1H), 7.22 (d, J ¼ 9.4,
5.7 Hz, 2H), 7.19–7.15 (m, 2H), 7.08 (d, J ¼ 8.4 Hz, 2H), 6.91–6.84
(m, 2H), 6.60 (d, J ¼ 3.1 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d 139.3, 138.5, 136.5, 133.8, 129.7, 129.0, 128.9, 128.9, 128.5,
128.2, 126.7, 121.8, 121.1, 120.0, 110.1, 101.8, 63.0. HRMS (ESI-
TOF) m/z: [M]+ calcd for C21H16NCl 317.0971; found: 317.0970.
1-(1-(Thiophen-2-yl)ethyl)-1H-indole (3p).20 Yellow oil,
5-Fluoro-1-(pentan-3-yl)-1H-indole (3v). Yellow oil, 43.4 mg
(64% yield); Rf (petroleum ether) ¼ 0.4. 1H NMR (500 MHz,
CDCl3) d 7.30–7.26 (m, 1H), 7.25–7.23 (m, 1H), 7.22–7.20 (m,
1H), 6.96–6.90 (m, 1H), 6.47 (d, J ¼ 3.1 Hz, 1H), 4.59–4.32 (m,
1H), 1.93–1.70 (m, 4H), 0.88 (t, J ¼ 7.4 Hz, 6H). 13C NMR (126
MHz, CDCl3) d 157.8 (d, J ¼ 233.6 Hz), 132.7, 128.6 (d, J ¼ 10.1
Hz), 125.7, 110.1 (d, J ¼ 9.7 Hz), 109.7 (d, J ¼ 26.3 Hz), 105.6 (d, J
¼ 23.1 Hz), 101.4 (d, J ¼ 4.7 Hz), 51.8, 39.5, 14.0. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C13H16FN 228.1164; found:
228.1165.
1
44.8 mg (58% yield); Rf (petroleum ether) ¼ 0.5. H NMR (500
MHz, CDCl3) d 7.66 (d, J ¼ 7.9 Hz, 1H), 7.40 (d, J ¼ 8.3 Hz, 1H),
7.22 (t, J ¼ 3.7 Hz, 3H), 7.14 (t, J ¼ 7.4 Hz, 1H), 6.98–6.86 (m, 2H),
6.57 (d, J ¼ 3.2 Hz, 1H), 5.93 (q, J ¼ 7.0 Hz, 1H), 1.99 (d, J ¼
7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 146.1, 135.8, 128.8,
126.8, 124.8, 124.5, 121.6, 121.2, 119.7, 109.7, 102.1, 50.8, 22.3.
HRMS (ESI-TOF) m/z: [M]+ calcd for C14H13NS 227.0769; found:
227.0763.
5-Methoxy-1-(pentan-3-yl)-1H-indole (3w). Colorless oil,
1
61.0 mg (85% yield); Rf (petroleum ether) ¼ 0.4. H NMR (500
MHz, CDCl3) d 7.28–7.25 (m, 1H), 7.15 (d, J ¼ 3.1 Hz, 1H), 7.09
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(d, J ¼ 2.4 Hz, 1H), 6.88–6.83 (m, 1H), 6.44 (d, J ¼ 3.1 Hz, 1H),
4.49–4.33 (m, 1H), 3.85 (s, 3H), 2.02–1.62 (m, 4H), 0.87 (t, J ¼
7.4 Hz, 6H). 13C NMR (126 MHz, CDCl3) d 153.9, 131.4, 128.8,
124.7, 111.7, 110.3, 102.6, 100.9, 56.0, 51.6, 29.9, 14.0. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H19NO 218.1545; found:
218.1551.
Notes and references
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M. Ishikura and K. Yamada, Nat. Prod. Rep., 2009, 26, 803–
852; (c) M. Somei and F. Yamada, Nat. Prod. Rep., 2005, 22,
73–103.
1-Benzhydryl-1H-pyrrole (3x). Colorless oil, 42.3 mg (55%
2 (a) B. Evans, K. Rittle, M. Bock, R. DiPardo, R. Freidinger,
W. Whitter, G. Lundell, D. Veber, P. Anderson and
R. Chang, J. Med. Chem., 1988, 31, 2235–2246; (b)
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1
yield); Rf (petroleum ether) ¼ 0.5. H NMR (500 MHz, CDCl3)
d 7.35–6.99 (m, 10H), 6.76 (t, J ¼ 2.1 Hz, 2H), 6.19 (t, J ¼ 2.1 Hz,
2H), 5.33–5.24 (m, 1H). 13C NMR (126 MHz, CDCl3) d 143.7,
133.4, 129.6, 128.8, 128.5, 127.6, 127.5, 127.2, 126.0, 119.7,
108.2, 58.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H15N
234.1283; found: 234.1281.
1-(1-Ferrocenylethyl)-1H-pyrrole (3y). Yellow oil, 70.0 mg
(76% yield); Rf (petroleum ether) ¼ 0.5. 1H NMR (500 MHz,
CDCl3) d 6.76–6.60 (m, 2H), 6.20–5.96 (m, 2H), 5.07 (d, J ¼
7.0 Hz, 1H), 4.20–4.18 (m, 1H), 4.17–4.10 (m, 7H), 4.10–4.06 (m,
1H), 1.78 (d, J ¼ 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 119.1,
107.6, 90.8, 69.0, 68.3, 67.8, 67.8, 66.2, 54.5, 22.5. HRMS (ESI-
TOF) m/z: [M]+ calcd for C16H17FeN 279.0710; found: 279.0723.
9-(4-Phenylbutan-2-yl)-9H-carbazole (3z). Yellow oil, 38.7 mg
(41% yield); Rf (petroleum ether : ethyl acetate ¼ 100 : 1) ¼ 0.4.
1H NMR (500 MHz, CDCl3) d 7.68 (d, J ¼ 7.8 Hz, 1H), 7.30 (d, J ¼
8.0 Hz, 3H), 7.22 (d, J ¼ 8.5 Hz, 3H), 7.12 (t, J ¼ 7.7 Hz, 3H), 6.59
(d, J ¼ 2.9 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 2.54 (d, J ¼ 5.9 Hz,
2H), 2.30 (d, J ¼ 6.2 Hz, 1H), 2.16 (d, J ¼ 6.0 Hz, 1H), 1.54 (d, J ¼
6.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 141.2, 128.5, 126.0,
125.5, 120.4, 118.7, 50.6, 36.6, 33.0, 19.3. HRMS (ESI-TOF) m/z:
[M]+ calcd for C22H21N 299.1674; found: 299.1670.
9-Benzhydryl-9H-carbazole (3aa). White solid, 74.1 mg (78%
yield); mp 170–173 ꢀC; Rf (petroleum ether : ethyl acetate ¼
100 : 1) ¼ 0.6. 1H NMR (500 MHz, CDCl3) d 8.22 (d, J ¼ 7.6 Hz,
2H), 7.38 (d, J ¼ 3.7 Hz, 7H), 7.36–7.27 (m, 8H), 7.18 (d, J ¼
8.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) d 140.7, 138.9, 128.7,
128.4, 127.9, 125.6, 123.6, 120.2, 119.3, 110.8, 62.3. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C25H19N 356.1415; found:
356.1406.
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´
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0.7. H NMR (500 MHz, CDCl3) d 8.30–8.25 (m, 1H), 8.10–8.05
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(m, 2H), 7.84–7.88 (m, 2H), 7.55–7.44 (m, 6H), 7.02–6.98 (m,
1H), 4.54–4.31 (m, 1H), 2.94–1.51 (m, 9H). 13C NMR (126 MHz,
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127.5, 126.5, 126.4, 126.1, 124.9, 120.5, 110.7, 95.0, 43.1, 38.0,
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´
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C
25H23NO2 370.1729; found: 370.1739.
Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (Grant No. 21364005), Natural Science Foundation
of Inner Mongolia (2017MS0206) and Grassland Talent Innovative
Teams of Inner Mongolia Autonomous Region. The project was
supported by Open Research Fund of State Key Laboratory of
Polymer Physics and Chemistry, Changchun Institute of Applied
Chemistry, Chinese Academy of Sciences.
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