Enantioselective N-propargylation of indoles via Cu-catalyzed propargylic alkylation/dehydrogenation of indolines

Article abstract of DOI:10.1016/S1872-2067(14)60230-8

The synthesis of optically active N-propargylindoles has been accomplished via the Cu-catalyzed asymmetric propargylic alkylation of indolines with propargylic esters, followed by the dehydrogenation of the resulting N-substituted indolines with 2,3-dichl

Full text of DOI:10.1016/S1872-2067(14)60230-8

Chinese Journal of Catalysis 36 (2015) 86–92
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e /c h n j c
Article (Special Issue on Catalysis in Organic Synthesis)
Enantioselective N‐propargylation of indoles via Cu‐catalyzed
propargylic alkylation/dehydrogenation of indolines
Fulin Zhua,b, Xiangping Hua,*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
b University of Chinese Academy of Sciences, Beijing 100049, China
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of optically active N‐propargylindoles has been accomplished via the Cu‐catalyzed
asymmetric propargylic alkylation of indolines with propargylic esters, followed by the dehydro‐
genation of the resulting N‐substituted indolines with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone.
The reaction proceeded in good yield with high enantioselectivity under mild conditions using a
bulky and structurally rigid tridentate ketimine P,N,N‐ligand, and exhibited a broad substrate scope.
© 2015, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Received 30 August 2014
Accepted 19 September 2014
Published 20 January 2015
Keywords:
Asymmetric synthesis
Copper
Published by Elsevier B.V. All rights reserved.
Propargylic substitution
Dehydrogenation
N‐propargylindole
1. Introduction
However, the propargylation reaction in this particular case
occurred at the C3‐position of the indole instead of the
Following of the pioneering works of Hattori et al. [1] and
Detz et al. [2] in 2008, there has been significant progress to‐
wards the development of Cu‐catalyzed asymmetric propar‐
gylic substitution reactions [3,4], with numerous N‐ and
C‐based nucleophiles, including primary and secondary amines,
enamines and enolates, being identified as suitable reaction
partners [5–21]. Despite these advances, several challenging
issues still need to be addressed in the Cu‐catalyzed asymmet‐
ric propargylic substitution reaction. One of the biggest issues
with this transformation is the enantioselective N‐propargyla‐
tion of indole, in that the direct N‐propargylation of indole with
propargylic esters is effectively impossible because of the
weakly acidic nature of the N–H group of the indole. Indeed,
Detz et al. [9] reported the development of a highly enantiose‐
lective Cu‐catalyzed propargylation of indole with propargylic
acetates that used a copper‐pybox complex as the catalyst.
N1‐position. This result was consistent with the observation
that the C3‐position of indole is more reactive than its N1 and
C2 positions towards the Friedel‐Crafts alkylation reaction [22].
The development of an alternative strategy for the construction
of optically active N‐propargylindoles is therefore highly de‐
sirable.
In 2003, Corey’s group [23] reported a strategy for the con‐
struction of N‐propargylindole via the sequential N‐propar‐
gylation and dehydrogenation of the corresponding indoline in
their total synthesis of okaramines, which are a family of bio‐
logically active tryptophan‐derived heptacyclic and octacyclic
alkaloids that are produced by the fungus Penicillium simplicis‐
sum [24]. Although an asymmetric version of this reaction has
never been reported, this strategy provided a platform for the
enantioselective construction of optically active N‐propar‐
gylindole. Employing a similar strategy, Liu et al. [25] recently
*Corresponding author. Tel: +86‐411‐84379276; Fax: +86‐411‐84684746; E‐mail: xiangping@dicp.ac.cn
This work was supported by Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
DOI: 10.1016/S1872‐2067(14)60230‐8 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 36, No. 1, January 2015

Fulin Zhu et al. / Chinese Journal of Catalysis 36 (2015) 86–92
87
Scheme 1. The enantioselective synthesis of N‐propargylindoles via a sequential propargylic alkylation and dehydrogenation strategy.
developed a general process for the synthesis of N‐allylindoles
via the Ir‐catalyzed allylic alkylation of indolines followed by an
oxidation reaction. Compared with the Ir‐catalyst used in this
reaction, Cu salts are much cheaper and easier to handle, as
well as being much less toxic. Herein, we wish to report the
development of a highly enantioselective reaction for the
Cu‐catalyzed propargylic alkylation of indolines with propar‐
gylic esters, followed by dehydrogenation of the resulting
N‐substituted indolines with 2,3‐dichloro‐5,6‐dicyano‐1,4‐
benzoquinone (DDQ) (Scheme 1). This method can be used to
provide facile and efficient access to optically active N‐substi‐
tuted indoles, which are privileged structural motifs found in
numerous natural products and biologically active compounds
[26].
0.0165 mmol) were added to anhydrous methanol (1 mL), and
the resulting mixture was stirred at room temperature under
N2 atmosphere for 1 h. The solution was then cooled to 0 °C and
treated with a solution of indoline 1 (0.33 mmol), propargylic
ester 2 (0.3 mmol) and i‐Pr2NEt (62 μL, 0.36 mmol) in anhy‐
drous methanol (2 mL). The resulting mixture was stirred at 0
°C for 5 h before being warmed to room temperature and
passed over a short pad of silica. The silica pad was eluted with
a mixture of hexanes and ethyl acetate to give the crude
N‐propargylindoline product, which was treated with a solu‐
tion of DDQ (0.33 mmol) in CH2Cl2 (3 mL) at room temperature
for 5 min to give the oxidized product as a crude mixture. The
desired N‐propargylindole product 3 was purified by FCC over
silica gel eluting with a mixture of hexanes and ethyl acetate.
(R)‐1‐(1‐Phenylprop‐2‐yn‐1‐yl)‐1H‐indole (3aa). Obtained
as a colorless oil in 90% yield following purification by FCC
over silica gel eluting with a mixture of hexanes and ethyl ace‐
tate (V/V = 100/1); 92% ee was determined by chiral HPLC
(Chiralcel OJ‐H, n‐hexane/i‐PrOH = 50/50, 0.8 mL/min, detec‐
tion at 230 nm, column temperature 40 °C): tR (major) = 25.4
2. Experimental
2.1. General
All reactions were carried out under N2 atmosphere. All of
the solvents were purified by standard procedures before be‐
ing used. Commercial reagents were used as supplied without
further purification. Flash column chromatography (FCC) was
performed over silica gel 60 (40–63 μm; Qingdao Makall Group
Co., LTD, Qingdao, China). Thin layer chromatography (TLC)
was performed on glass plates coated with silica gel 60 with an
F254 indicator (Yantai Jiangyou Silica Gel Development Co.,
LTD, Yantai, China). Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a Bruker 400 MHz spectrome‐
ter (Bruker, Switzerland). The chemical shifts (δ) of the protons
have been reported in parts per million (ppm) downfield of
tetramethylsilane, which was used as a reference together with
the residual proton of the deuterated NMR solvent (i.e., CHCl3 =
δ 7.28). 13C NMR spectra were recorded on a Bruker 101 MHz
spectrometer. The chemical shifts (δ) for carbon signals have
been reported in ppm downfield from tetramethylsilane, which
was used as a reference together with the carbon resonances of
the deuterated solvent (i.e., CDCl3 = δ 77.07). NMR data have
been presented as follows: chemical shift, multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multi‐
plet), coupling constants (J) in Hz and integration. Enantio‐
meric ratios were determined by chiral HPLC using n‐hexane
and i‐PrOH as the mobile phases. Optical rotations were rec‐
orded on a JASCO P‐1020 polarimeter (JASCO Corporation,
Tokyo, Japan).
29
1
min, tR (minor) = 19.9 min; [α]D = 121.3 (c 0.48, CH2Cl2); H
NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 1H), 7.35–7.25 (m,
7H), 7.18–7.09 (m, 2H), 6.55 (dd, J = 3.3, 0.6 Hz, 1H), 6.39 (d, J =
2.4 Hz, 1H), 2.67 (d, J = 2.5 Hz, 1H); 13C NMR (101 MHz, CDCl3):
δ = 137.5, 135.6, 129.2, 128.9, 128.5, 126.7, 126.5, 121.9, 121.2,
120.0, 110.0, 102.5, 80.1, 75.5, 51.6; HRMS calculated for
C17H13N [M+H]+, Mr = 232.1126, found Mr = 232.1128.
(R)‐1‐(1‐(2‐Chlorophenyl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ab).
Obtained as a colorless oil in 79% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 70/1); 85% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
8.4 min, tR (minor) = 7.7 min; [α]D29 = 1.31 (c 0.48, CH2Cl2); 1H
NMR (400 MHz, CDCl3): δ = 7.63–7.61 (m, 1H), 7.41–7.09 (m,
8H), 6.73 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 3.3 Hz, 1H), 2.67 (d, J =
2.5 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ = 135.5, 135.2, 133.1,
130.0, 130.0, 129.2, 128.5, 127.5, 126.2, 122.0, 121.2, 120.2,
109.8, 102.4, 79.1, 75.8, 49.0; HRMS calculated for C17H12ClN
[M+H]+, Mr = 266.0737, found Mr = 266.0735.
(R)‐1‐(1‐(3‐Chlorophenyl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ac).
Obtained as a colorless oil in 88% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 93% ee was determined by chiral
HPLC (Chiralcel OJ‐H, n‐hexane/i‐PrOH = 50/50, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
17.3 min, tR (minor) = 14.2 min; [α]D29 = 145.9 (c 0.48, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.65–7.63 (m, 1H), 7.40 (d, J =
1.4 Hz, 1H), 7.30–7.10 (m, 7H), 6.58 (dd, J = 2.6, 2.2Hz, 1H), 6.35
(d, J = 1.9 Hz, 1H), 2.71 (dd, J = 2.5, 0.9 Hz, 1H); 13C NMR (101
MHz, CDCl3): δ = 139.6, 135.5, 134.9, 130.1, 129.2, 128.7, 126.9,
2.2. General procedure for the synthesis of optically active
N‐propargylindoles via a one‐pot propargylation/
dehydrogenation process
.
Cu(OAc)2 H2O (3.0 mg, 0.015 mmol) and (S)‐L5 (7.8 mg,

88
Fulin Zhu et al. / Chinese Journal of Catalysis 36 (2015) 86–92
126.3, 124.8, 122.1, 121.3, 120.2, 109.8, 102.9, 79.4, 76.1, 51.1;
HRMS calculated for C17H12ClN [M+H]+, Mr = 266.0737, found
Mr = 266.0733.
(R)‐1‐(1‐(4‐Methoxyphenyl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ah).
Obtained as a colorless oil in 85% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 70/1); 83% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
11.7 min, tR (minor) = 19.9 min; [α]D29 = 134.5 (c 0.25, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.63–7.61 (m, 1H), 7.36–7.09 (m,
6H), 6.86–6.84 (m, 2H), 6.54 (d, J = 3.2 Hz, 1H), 6.36 (d, J = 2.2
Hz, 1H), 3.77 (s, 3H), 2.67 (d, J = 2.5 Hz, 1H); 13C NMR (101
MHz, CDCl3): δ = 159.7, 135.5, 129.5, 129.2, 128.1, 126.3, 121.8,
121.2, 119.9, 114.2, 110.0, 102.3, 80.3, 75.2, 55.3, 51.1; HRMS
calculated for C18H15NO [M+H]+, Mr = 262.1232, found Mr =
262.1229.
(R)‐1‐(1‐(Naphthalen‐2‐yl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ai).
Obtained as a colorless oil in 88% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 70/1); 87% ee was determined by chiral
HPLC (Chiralcel OJ‐H, n‐hexane/i‐PrOH = 50/50, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
36.3 min, tR (minor) = 26.9 min; [α]D29 = 205.4 (c 0.46, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.90–7.63 (m, 5H), 7.48–7.09 (m,
7H), 6.57–6.54 (m, 2H), 2.73 (dd, J = 2.4, 1.0 Hz, 1H); 13C NMR
(101 MHz, CDCl3): δ = 135.7, 134.7, 133.2, 133.2, 129.3, 128.9,
128.3, 127.7, 126.6, 126.6, 126.5, 125.9, 124.4, 122.0, 121.2,
120.1, 110.0, 102.6, 80.0, 75.9, 51.8; HRMS calculated for
C21H15N [M+H]+, Mr = 282.1283, found Mr = 282.1280.
(R)‐1‐(1‐(Thiophen‐2‐yl)prop‐2‐yn‐1‐yl)‐1H‐indole (3aj).
Obtained as a colorless oil in 89% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 91% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
11.3 min, tR (minor) = 19.4 min; [α]D29 = 162.6 (c 0.14, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 7.8 Hz, 1H), 7.42 (d, J
= 8.1 Hz, 1H), 7.29–7.08 (m, 5H), 6.90 (dd, J = 5.1, 3.6 Hz, 1H),
6.56–6.54 (m, 2H), 2.67 (d, J = 2.5 Hz, 1H); 13C NMR (101 MHz,
CDCl3): δ = 141.0, 135.4, 129.3, 126.9, 126.4, 126.2, 126.0,
122.0, 121.3, 120.2, 109.9, 102.9, 79.6, 74.9, 47.5; HRMS calcu‐
lated for C15H11NS [M+H]+, Mr = 238.0690, found Mr = 238.0689.
(R)‐3‐Methyl‐1‐(1‐phenylprop‐2‐yn‐1‐yl)‐1H‐indole (3ba).
Obtained as a colorless oil in 89% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 94% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
10.1 min, tR (minor) = 12.7 min; [α]D29 = 116.4 (c 0.46, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.57–7.55 (m, 1H), 7.36–7.09 (m,
8H), 7.03 (s, 1H), 6.34 (s, 1H), 2.64 (dd, J = 2.4, 0.9 Hz, 1H),
2.32–2.31 (m, 3H); 13C NMR (101 MHz, CDCl3): δ = 137.7, 136.0,
129.5, 128.8, 128.4, 126.8, 123.9, 121.9, 119.4, 119.3, 111.8,
109.7, 80.4, 75.2, 51.3, 9.7; HRMS calculated for C18H15N
[M+H]+, Mr = 246.1283, found Mr = 246.1281.
(R)‐1‐(1‐(4‐Chlorophenyl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ad).
Obtained as a colorless oil in 91% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 91% ee was determined by chiral
HPLC (Chiralcel OJ‐H, n‐hexane/i‐PrOH = 90/10, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
21.9 min, tR (minor) = 20.3 min; [α]D29 = 161.7 (c 0.58, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 1H), 7.28–7.09 (m,
8H), 6.56–6.55 (m, 1H), 6.34 (d, J = 2.4 Hz, 1H), 2.68 (d, J = 2.5
Hz, 1H); 13C NMR (101 MHz, CDCl3): δ = 136.1, 135.5, 134.4,
129.3, 129.1, 128.1, 126.4, 122.1, 121.3, 120.2, 109.9, 102.8,
79.6, 75.9, 51.1; HRMS calculated for C17H12ClN [M+H]+, Mr =
266.0737, found Mr = 266.0733.
(R)‐1‐(1‐(4‐Bromophenyl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ae).
Obtained as a colorless oil in 92% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 89% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
10.5 min, tR (minor) = 17.0 min; [α]D29 = 138.0 (c 0.70, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 1H), 7.42 (d, J =
8.3 Hz, 2H), 7.27–7.11 (m, 6H), 6.56 (dd, J = 2.2, 1.0 Hz, 1H),
6.32 (d, J = 2.3 Hz, 1H), 2.68 (dd, J = 2.5, 0.9 Hz, 1H); 13C NMR
(101 MHz, CDCl3): δ = 136.6, 135.5, 132.0, 129.3, 128.4, 126.4,
122.6, 122.1, 121.3, 120.2, 109.9, 102.8, 79.5, 76.0, 51.1; HRMS
calculated for C17H12BrN [M+H]+, Mr = 310.0231, found Mr =
310.0231.
(R)‐1‐(1‐(4‐(Trifluoromethyl)phenyl)prop‐2‐yn‐1‐yl)‐1H‐
indole (3af). Obtained as a colorless oil in 86% yield following
purification by FCC over silica gel eluting with a mixture of
hexanes and ethyl acetate (V/V = 100/1); 90% ee was deter‐
mined by chiral HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH =
95/5, 0.8 mL/min, detection at 230 nm, column temperature
40 °C): tR (major) = 9.8 min, tR (minor) = 14.2 min; [α]D29 = 97.8
1
(c 0.56, CH2Cl2); H NMR (400 MHz, CDCl3): δ = 7.66–7.56 (m,
3H), 7.42–7.11 (m, 6H), 6.60 (d, J = 3.3 Hz, 1H), 6.43 (d, J = 2.3
Hz, 1H), 2.73 (d, J = 2.5 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ =
141.5, 135.4, 130.8 (q, J = 32.5 Hz), 129.3, 127.0, 126.3, 125.9
(q, J = 3.7 Hz), 123.9 (q, J = 272.1 Hz), 122.1, 121.4, 120.3, 109.8,
103.0, 79.2, 76.3, 51.3; HRMS calculated for C18H12F3N [M+H]+,
Mr = 300.1000, found Mr = 300.1003.
(R)‐1‐(1‐(p‐Tolyl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ag). Obtained
as a colorless oil in 87% yield following purification by FCC
over silica gel eluting with a mixture of hexanes and ethyl ace‐
tate (V/V = 100/1); 90% ee was determined by chiral HPLC
(Chiralcel OJ‐H, n‐hexane/i‐PrOH = 50/50, 0.8 mL/min, detec‐
tion at 230 nm, column temperature 40 °C): tR (major) = 25.6
29
1
min, tR (minor) = 17.0 min; [α]D = 81.7 (c 0.45, CH2Cl2); H
NMR (400 MHz, CDCl3): δ = 7.63–7.61 (m, 1H), 7.35–7.09 (m,
8H), 6.54 (d, J = 3.3 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 2.66 (dd, J =
2.5, 0.9 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3): δ =
138.3, 135.6, 134.5, 129.5, 129.2, 126.7, 126.4, 121.8, 121.1,
119.9, 110.0, 102.3, 80.3, 75.3, 51.4, 21.1; HRMS calculated for
C18H15N [M+H]+, Mr = 246.1283, found Mr = 246.1281.
(R)‐2‐Methyl‐1‐(1‐phenylprop‐2‐yn‐1‐yl)‐1H‐indole (3ca).
Obtained as a yellow solid in 90% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); m.p. = 53–55 °C; 89% ee was de‐

Fulin Zhu et al. / Chinese Journal of Catalysis 36 (2015) 86–92
89
termined by chiral HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH =
95/5, 0.8 mL/min, detection at 230 nm, column temperature
40 °C): tR (major) = 7.8 min, tR (minor) = 9.5 min; [α]D29 = 208.5
MeOH solvent gave the crude N‐propargylindoline as a residue,
which was treated with a solution of DDQ in CH2Cl2 at room
temperature to give the corresponding dehydrogenated prod‐
uct in only 5 min. The desired 1‐(1‐phenylprop‐2‐yn‐1‐yl)‐1H‐
indole (3aa) was obtained in good yield in all cases, although it
is noteworthy that the structure of the ligand was found to have
a significant impact on the enantioselectivity of the reaction
(Table 1, entries 1–5). For example, BINAP (L1) and the
P,N,N‐ligands L3 and L4 gave moderate enantioselectivity (Ta‐
ble 1, entries 1, 3, and 4), whereas the tridentate N‐ligand L2
gave a low enantioselectivity (Table 1, entry 2). The bulky and
structurally rigid chiral tridentate ketimine P,N,N‐ligand (S)‐L5,
which was developed in our group, gave the best result of all of
the ligands screened in this reaction in terms of its reactivity
1
(c 0.76, CH2Cl2); H NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m,
1H), 7.28–7.24 (m, 6H), 7.07–7.03 (m, 2H), 6.51 (s, 1H), 6.32 (s,
1H), 2.64 (dd, J = 2.4, 2.0 Hz, 1H), 2.38–2.37 (m, 1H); 13C NMR
(101 MHz, CDCl3): δ = 137.2, 136.5, 136.3, 128.7, 128.6, 128.1,
126.3, 126.3, 120.8, 119.9, 110.6, 101.9, 79.7, 75.2, 48.9, 13.5;
HRMS calculated for C18H15N [M+H]+, Mr = 246.1283, found Mr
= 246.1279.
(R)‐4‐Methyl‐1‐(1‐phenylprop‐2‐yn‐1‐yl)‐1H‐indole (3da).
Obtained as a colorless oil in 86% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 88% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
8.5 min, tR (minor) = 10.4 min; [α]D29 = 98.9 (c 0.50, CH2Cl2); 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.28 (m, 6H), 7.20–7.05 (m,
2H), 6.92–6.90 (m, 1H), 6.58–6.57 (m, 1H), 6.38 (s, 1H), 2.66
(dd, J = 2.4, 2.0 Hz, 1H), 2.54 (d, J = 2.2 Hz, 3H); 13C NMR (101
MHz, CDCl3): δ = 137.5, 135.4, 130.7, 129.0, 128.9, 128.4, 126.7,
125.8, 122.1, 120.3, 107.6, 101.0, 80.2, 75.5, 51.7, 18.7; HRMS
calculated for C18H15N [M+H]+, Mr = 246.1283, found Mr =
246.1282.
(R)‐6‐Fluoro‐1‐(1‐phenylprop‐2‐yn‐1‐yl)‐1H‐indole (3ea).
Obtained as a colorless oil in 91% yield following purification
by FCC over silica gel eluting with a mixture of hexanes and
ethyl acetate (V/V = 100/1); 90% ee was determined by chiral
HPLC (Chiralcel OD‐H, n‐hexane/i‐PrOH = 95/5, 0.8 mL/min,
detection at 230 nm, column temperature 40 °C): tR (major) =
8.3 min, tR (minor) = 9.2 min. [α]D29 = 94.7 (c 0.80, CH2Cl2); 1H
NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m, 1H), 7.33–7.23 (m,
6H), 7.01 (d, J = 9.9 Hz, 1H), 6.89–6.84 (m, 1H), 6.52 (d, J = 3.3
Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 2.70 (d, J = 2.5 Hz, 1H); 13C NMR
(101 MHz, CDCl3): δ = 159.7 (d, J = 237.9 Hz), 137.0, 135.5 (d, J
= 12.2 Hz), 128.9, 128.6, 127.0 (d, J = 3.7 Hz), 126.7, 125.6,
121.8 (d, J = 10.2 Hz), 108.8 (d, J = 24.6 Hz), 102.5, 96.8 (d, J =
26.8 Hz), 79.6, 75.9, 52.0; HRMS calculated for C17H12FN
[M+H]+, Mr = 250.1032, found Mr = 250.1026.
Table 1
Screening the reaction condition.
Yield a ee b
Entry
[Cu]
L
Base
Solvent
(%)
87
87
85
89
90
89
81
82
87
65
88
45
88
—
—
—
—
—
(%)
72 (R)
38 (S)
79 (S)
76 (R)
92 (R)
92 (R)
87 (R)
83 (R)
91 (R)
76 (R)
92 (R)
25 (R)
89 (R)
—
1
2
3
4
5
6
7
8
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OTf)2
L1 i‐Pr2NEt
L2 i‐Pr2NEt
L3 i‐Pr2NEt
L4 i‐Pr2NEt
L5 i‐Pr2NEt
L5 i‐Pr2NEt
L5 i‐Pr2NEt
L5 i‐Pr2NEt
L5 i‐Pr2NEt
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CuCl
CuI
9
Cu(CH3CN)4BF4
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
10
11
12
13
14
15
16
17
18
19
L5
L5
L5
L5
DBU
Et3N
—
K2CO3
L5 i‐Pr2NEt
L5 i‐Pr2NEt Toluene
L5 i‐Pr2NEt
L5 i‐Pr2NEt
L5 i‐Pr2NEt
L5 i‐Pr2NEt
—
—
—
—
THF
DMF
DMSO
MeOH
35 92 (R)c
Reaction conditions: (1) 1a (0.33 mmol), 2a (0.3 mmol), [Cu] (0.015
mmol, 5 mol%), L (0.0165 mmol, 5.5 mol%) and base (0.36 mmol) in
solvent (3 mL) at 0 °C for 5 h; (2) DDQ (0.33 mmol) in CH2Cl2 (3 mL) at
r.t. for 5 min.
3. Results and discussion
The optically active N‐propargylindoles were prepared ac‐
cording to the strategy reported by Corey et al. [23] via an
N‐propargylation/dehydrogenation sequence (Scheme 1). The
optical purity of the N‐propargylindole products was found to
be determined during the propargylic alkylation step. With this
in mind, we screened a variety of chiral ligands in this reaction
that have been proven to be performed effectively as ligands in
various other Cu‐catalyzed asymmetric propargylic substitu‐
tion reactions [1,2,12,16]. Indoline (1a) and 1‐phenylprop‐2‐
yn‐1‐yl acetate (2a) were selected as model substrates for this
reaction, which was performed in the presence of 5 mol% Cu
a Isolated yield.
b Determined by chiral HPLC analysis.
c A solution of DDQ in CH2Cl2 (3 mL) was added directly to the reaction
mixture following the removal of MeOH under reduced pressure.
N
N
PPh2
PPh2
O
O
N
PPh2
N
N
Fe
Ph
Ph
Ph-pybox (L2)
(S)-BINAP (L1)
(Rc,Sp)-L3
Ph
.
catalyst (prepared in situ from 5 mol% Cu(OAc)2 H2O and 5.5
N
N
mol% chiral ligand) and 1.2 equiv of i‐Pr2NEt in MeOH (3 mL)
at 0 °C for 5 h. Upon completion of the propargylation reaction,
the Cu catalyst was removed by filtration. Evaporation of the
N
N
PPh2
PPh2
(S)-L4
(S)-L5

90
Fulin Zhu et al. / Chinese Journal of Catalysis 36 (2015) 86–92
and enantioselectivity, and was selected as the optimum ligand
for further evaluation (Table 1, entry 5).
A variety of different Cu sources were also screened in this
model reaction, but the results revealed that the type of Cu salts
used in the transformation had no discernible impact on the
reactivity or enantioselectivity of the reaction (Table 1, entries
5–9). These results demonstrated that Cu(OAc)2·H2O was the
best source of Cu for the reaction (Table 1, entry 5). The addi‐
tion of a base was determined to be critical to the success of
this reaction, with the product being formed in a very low yield
and enantioselectivity when the reaction was performed in the
absence of base (Table 1, entry 12). The addition of a stronger
base, such as 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), had a
detrimental impact on the yield and enantioselectivity of the
reaction (Table 1, entry 10), whereas the use of Et3N provided
similar good result to that of i‐Pr2NEt (Table 1, entry 11). In‐
terestingly, the inorganic base K2CO3 also performed efficiently
in the reaction, with the desired product being formed in good
yield and enantioselectivity (Table 1, entry 13). The effect of
the solvent on the outcome of the model reaction was also in‐
vestigated, and the results revealed a significant solvent de‐
pendency. For example, MeOH was found to be the only one of
the six different solvents tested to be suitable for the transfor‐
mation, with very little product being observed when the reac‐
tion was conducted in CH2Cl2, toluene, tetrahydrofuran,
N,N‐dimethylformamide or dimethyl sulfoxide (Table 1, entries
14–18). These results were found to be consistent with those
observed in other Cu‐catalyzed asymmetric propargylic sub‐
stitution reactions [1,2]. Pleasingly, a one‐pot version of this
reaction also worked well, with 1.1 equivalents of DDQ being
added directly to the reaction mixture upon the completion of
F
N
N
N
N
3ba
89% yield,
94% ee
3ca
90% yield,
89% ee
3da
86% yield,
88% ee
3ea
91% yield,
90% ee
Fig. 1. Scope of indolines.
Cu‐catalyzed propargylic amination step. Disappointingly,
however, this process gave a much lower yield of the desired
product, albeit with a high enantioselectivity (Table 1, entry
19). This result suggested that the Cu salt had an adverse im‐
pact on the DDQ‐mediated dehydrogenation process.
With optimized conditions in hand, we proceeded to inves‐
tigate the scope of the reaction using a variety of different pro‐
pargylic esters (Table 2). The results of the reactions indicated
that the substitution pattern of the phenyl ring had an impact
on the outcome of the reaction (Table 2, entries 2–4). For ex‐
ample, the 3‐ and 4‐Cl substituted substrates (2c and 2d, re‐
spectively) provided the corresponding indole products in
good yields and high enantioselectivities (Table 2, entries 3 and
4), whereas the 2‐Cl substituted substrate 2b gave the corre‐
sponding product with a decreased yield and lower enantiose‐
lectivity (Table 2, entry 2). The electronic properties of the
substituent at the para position of the phenyl ring also had a
significant impact on the performance of the reaction. In most
cases, the reaction gave good results, although the 4‐MeO‐sub‐
stituted substrate 2h gave a slight decrease in the enantioselec‐
tivity of the product to 83% ee (Table 2, entry 8). The 2‐naph‐
thyl substrate 2i reacted smoothly to give 1‐(1‐(naphtha‐
len‐2‐yl)prop‐2‐yn‐1‐yl)‐1H‐indole (3ai) in 88% yield and 87%
ee (Table 2, entry 9). The 2‐thienyl substrate 2j also performed
well in the reaction, with the corresponding N‐propargylindole
product 3aj being formed in 89% yield and 91% ee (Table 2,
entry 10).
Table 2
Cu‐catalyzed propargylation/dehydrogenation of indoline (1a) with
propargylic esters (2).
The scope of the indolines was also evaluated (Fig. 1), and
the results revealed that the optimized reaction could be suc‐
cessfully applied to a variety of substituted indolines. For ex‐
ample, 2‐, 3‐ and 4‐methyl indolines all reacted smoothly under
the optimized conditions to give the corresponding N‐propar‐
gylated indoles 3ba, 3ca, and 3da, respectively, in good yields
and high enantioselectivities. Electron‐withdrawing substitu‐
ents were also well tolerated on the indoline ring with
6‐fluoroindoline reacting smoothly to give the N‐propargylated
fluoroindole product 3ea in a high yield and enantioselectivity.
Entry
2 (R1)
3
Yield a (%)
ee b (%)
92 (R) c
85
93
91
89
90
90
83
1
2
3
4
5
6
7
8
9
10
2a: R1 = Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
90
79
88
91
92
86
87
85
88
89
2b: R1 = 2‐ClC6H4
2c: R1 = 3‐ClC6H4
2d: R1 = 4‐ClC6H4
2e: R1 = 4‐BrC6H4
2f: R1 = 4‐CF3C6H4
2g: R1 = 4‐MeC6H4
2h: R1 = 4‐MeOC6H4
2i: R1 = 2‐naphthyl
2j: R1 = 2‐thienyl
87
91
4. Conclusions
Reaction conditions: (1) 1a (0.33 mmol), 2 (0.3 mmol), Cu(OAc)2·H2O
(0.015 mmol, 5 mol%), (S)‐L5 (0.0165 mmol, 5.5 mol%) and i‐Pr2NEt
(0.36 mmol) in MeOH (3 mL) at 0 °C for 5 h; (2) DDQ (0.33 mmol) in
CH2Cl2 (3 mL) at r.t. for 5 min.
a Isolated yields.
b Determined by chiral HPLC analysis.
c The absolute configuration was determined by comparing the specific
rotation of the corresponding 1‐(1‐phenylprop‐2‐yn‐1‐yl)indoline
compound with the data reported in Ref. [8].
We have developed an efficient and highly enantioselective
process for the construction of optically active N‐propargylin‐
doles via the Cu‐catalyzed asymmetric propargylic amination of
indolines with propargylic esters followed by the dehydro‐
genation of the resulting N‐substituted indolines with DDQ.
This reaction can be performed under mild conditions using a

Fulin Zhu et al. / Chinese Journal of Catalysis 36 (2015) 86–92
91
Graphical Abstract
Chin. J. Catal., 2015, 36: 86–92 doi: 10.1016/S1872‐2067(14)60230‐8
Enantioselective N‐propargylation of indoles via Cu‐catalyzed propargylic alkylation/dehydrogenation of indolines
Fulin Zhu, Xiangping Hu*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences; University of Chinese Academy of Sciences
A new strategy has been developed for the sequential Cu‐catalyzed asymmetric propargylic alkylation and DDQ‐mediated dehydrogena‐
tion of indolines using a bulky and structurally rigid ketimine P,N,N‐ligand. This reaction allowed for the enantioselective synthesis of
optically active N‐propargylindoles.
[14] Mino T, Taguchi H, Hashimoto M, Sakamoto M. Tetrahedron:
Asymmetry, 2013, 24: 1520
[15] Han F Z, Zhu F L, Wang Y H, Zou Y, Hu X H, Chen S, Hu X P. Org Lett,
2014, 16: 588
[16] Zhu F L, Zou Y, Zhang D Y, Wang Y H, Hu X H, Chen S, Xu J, Hu X P.
Angew Chem Int Ed, 2014, 53: 1410
broad range of different substrates, with the resulting chiral
N‐propargylindole products being formed in good yields and
high enantioselectivities. Further work towards the develop‐
ment and application of this reaction is currently underway in
our laboratory.
[17] Zou Y, Zhu F L, Duan Z C, Wang Y H, Zhang D Y, Cao Z, Zheng Z, Hu
X P. Tetrahedron Lett, 2014, 55: 2033
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