Synthesis of 2-Indolyltetrahydroquinolines by Zinc(II)-Catalyzed Intramolecular Hydroarylation-Redox Cross-Dehydrogenative Coupling of N-Propargylanilines with Indoles

Article abstract of DOI:10.1002/anie.201602416

An intramolecular hydroarylation-redox cross-dehydrogenative coupling (CDC) of propargylic anilines with indoles proceeded in the presence of zinc(II) catalysts to give 2-indolyltetrahydroquinolines in good to high yields. Three C-H bonds (two sp²and one sp³) are activated in one shot and these hydrogen atoms are trapped by a propargylic triple bond in the molecule.

Full text of DOI:10.1002/anie.201602416

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602416
German Edition: DOI: 10.1002/ange.201602416
À
C H Activation
Synthesis of 2-Indolyltetrahydroquinolines by Zinc(II)-Catalyzed
Intramolecular Hydroarylation-Redox Cross-Dehydrogenative
Coupling of N-Propargylanilines with Indoles
Guangzhe Li and Hiroyuki Nakamura*
Abstract: An intramolecular hydroarylation-redox cross-
dehydrogenative coupling (CDC) of propargylic anilines
with indoles proceeded in the presence of zinc(II) catalysts to
give 2-indolyltetrahydroquinolines in good to high yields.
We previously reported a zinc(II)-catalyzed redox CDC
reaction of propargylic amines with terminal alkynes to give
N-tethered 1,6-enynes.[8] In this reaction, the C C triple bond
À
of the propargylic amine acted as a hydrogen acceptor. Here,
we report a zinc(II)-catalyzed intramolecular hydroarylation-
redox CDC of N-propargylic anilines with indoles for the
2
3
À
Three C H bonds (two sp and one sp ) are activated in one
shot and these hydrogen atoms are trapped by a propargylic
triple bond in the molecule.
synthesis of 2-indolyltetrahydroquinolines (Scheme 1B). In
2
À
the current transformation, three C H bonds (two sp and
T
etrahydroquinolines[1] and tetrahydroisoquinolines[2] are
one sp3) are activated in one shot and these hydrogen atoms
are trapped by a propargylic triple bond in the molecule.
First, the hydroarylation-redox CDC of N-benzyl-N-
(prop-2-ynyl)aniline (1a) with indole (2a) was examined in
the presence of a catalytic amount of ZnBr2 (20 mol%). It
was particularly gratifying that the reaction proceeded
smoothly in 1,2-dichloroethane (DCE) at 1008C as we
envisaged, giving 1-benzyl-2-(1H-indol-3-yl)-1,2,3,4-tetrahy-
droquinoline (3a) in 60% yield along with N-benzyl-1,2,3,4-
tetrahydroquinoline in 15% yield as the by-product (Table 1,
entry 1). The reaction was also carried out in various solvents,
such as toluene, 1,2-dimethoxyethane, THF, and EtOH, in the
presence of ZnBr2 catalyst, and aprotic non-polar solvents,
such as dichloroethane, were found to promote the intra-
molecular hydroarylation-redox CDC (Table S1 in the Sup-
porting Information). Next, the effects of various salts of zinc
and copper were examined in dichloroethane (Table 1,
important structural motifs in pharmaceuticals and agro-
chemicals and hence, the development of simple yet efficient
functionalization protocols is an important requirement for
the discovery of biologically active compounds. The copper-
catalyzed cross-dehydrogenative coupling (CDC) reaction
designed by Li et al. is one of the most efficient protocols for
the direct functionalization at C-1 position of tetrahydroiso-
quinolines (Scheme 1A).[3,4] Although various CDC-type
Table 1: Optimization of reaction conditions.[a]
Scheme 1. Indole insertion: C-1 of tetrahydroisoquinoline vs. C-2 of
tetrahydroquinoline.
Entry
Cat.
Conc. [m]
T [8C]
Yield of
Recovery of
3a [%][b]
1a [%][b]
reactions have been reported for the synthesis of 1-indolyl
tetrahydroquinolines,[5] the functionalization of tetrahydro-
quinolines by methods other than electrolytic transformations
remains to be established.[6] Nishibayashi and co-workers
succeeded in the amination at C-2 position of tetrahydroqui-
nolines with azodicarboxylate esters mediated by visible-light
photoredox catalysts, and the resulting N,N-acetals readily
reacted with indoles to give 2-indolyltetrahydroquinolines.[7]
1
2
3
4
5
6
7
8
ZnBr2
ZnI2
Zn(OAc)2
CuCl
CuBr
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.25
0.5
100
100
100
100
100
100
100
100
100
100
100
120
60
60
3
N.D.
N.D.
97
N.D.
N.D.
40
N.D.
3
90
7
20
16
20
31
9
55
64
82
CuI
CuCl2
Cu(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
9
10
11
12
45
35
13
[*] Dr. G. Li, Prof. Dr. H. Nakamura
1
1
Chemical Resources Laboratory, Tokyo Institute of Technology
Yokohama, Kanagawa 226-8503 (Japan)
E-mail: hiro@res.titech.ac.jp
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol, 3 equiv), and
catalyst (0.05 mmol, 20 mol%) in dichloroethane for 24 h under nitrogen
atmosphere. [b] Yields were determined by 1H NMR measurement.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602416.
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entries 2–8). ZnI2 showed similar catalytic effects to ZnBr2
methoxy (1d), methyl (1e), chloro (1 f), and ethyl ester (1g)
(entry 2). When Zn(OAc)2 was employed, 3a was obtained in
3% yield with the recovery of 1a (97% recovery; entry 3),
suggesting that the generation of by-products was arrested
under Zn(OAc)2 catalyst conditions although the reaction
rate was very low. Various copper salts were also examined,
but the yields of 3a were relatively low in all cases (entries 4–
8). Interestingly, the concentration of the substrate affected
the reaction yield: the yield of 3a was increased from 9% to
64% when the concentration of 1a was increased from 0.125m
to 1m (entries 9–11). Further, the reaction was accelerated at
1208C, giving 3a in 82% yield with 13% recovery of 1a
(entry 12).
groups, also gave corresponding 6-substituted N-benzyl-
1,2,3,4-tetrahydroquinolines 3da–3ga in good yields, indicat-
ing that the intramolecular hydroarylation-redox CDC is
À
applicable to substrates having labile bonds, such as Ar Cl
and ester (entries 4–7). Next, the effect of substituents at the
terminal position (R3) of propargylic anilines was investi-
gated. Interestingly, the intramolecular hydroarylation-redox
CDC of N-benzyl-N-(prop-2-ynyl)anilines having substitu-
ents at R3, such as n-butyl (1h) and phenyl (1i), proceeded
smoothly with 2a and resulting cyclized products, 3ha and
3ia, were obtained in high yields (90% and 95%, respec-
tively). The diastereomeric ratios of both products were
1
With the optimum conditions established, the intramo-
lecular hydroarylation-redox CDC with various propargylic
amines was examined next. The results are summarized in
Table 2. The reaction was performed in the presence of
approximately 6:1 as calculated from H NMR data. Finally,
the effect of substituents at R4 of the indole ring was
examined. Indoles with an electron-donating group, such as
a methoxy (2b) group, or electron-withdrawing groups, such
as bromo (2c) and methyl ester (2d) groups, at R4, and 2-
methylindole (2e) were employed in the reaction to afford
corresponding N-benzyl-1,2,3,4-tetrahydroquinolines 3ab–
3ae in 60–76% yields (entries 10–13).
Table 2: Intramolecular hydroarylation-redox CDC of various N-propar-
gylamines (1a–i) with indoles (2a–e).[a]
A plausible mechanism for the intramolecular hydro-
arylation-redox CDC is shown in Scheme 2. It was reported
that N-phenyl-N-(prop-2-yn-1-yl)anilines 1 underwent intra-
molecular hydroarylation in the presence of various transi-
Scheme 2. Plausible mechanism for the intramolecular hydroarylation-
redox CDC.
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol, 3 equiv), and
Zn(OAc)2 (0.05 mmol, 20 mol%) in dichloroethane (0.25 mL) for 24 h
under nitrogen atmosphere. [b] The reaction was carried out at 1008C.
[c] Dichloroethane (0.50 mL) was used.
tion-metal catalysts, including platinum,[9] gold,[10] and rho-
dium complexes.[11] Therefore, first, N-substituted 1,2-dihy-
droquinoline 5 would be generated from zinc-activated
complex 4 via intramolecular hydroarylation. Then, an
equilibrium would be established among dihydroquinoline
5, dihydroquinoline 5’, and iminium cation 6, and 6 would
undergo nucleophilic addition reaction with indole 2 to afford
the cyclized product 3 through intermediate 7. Indeed,
a deuterium labeling study that used 3-deuteroindole d-2a
revealed that 60% and 28% of deuterium were, respectively
incorporated at C3 and C4 positions of N-benzyl-1,2,3,4-
tetrahydroquinoline 3aa (Scheme 3), suggesting the establish-
ment of an equilibrium among 5, 5’, and 6. The nucleophilic
addition of indole 2 to the intermediate 6 would be
accelerated under more concentrated conditions of catalysts.
Interestingly, when N-phenyl-N-(prop-2-yn-1-yl)aniline
(1j) was employed in the intramolecular hydroarylation-
Zn(OAc)2 (20 mol%) in dichloroethane at 1208C for 24 h
under nitrogen atmosphere. N-(prop-2-ynyl)anilines (R2 =
R3 = H) having various substituents at R1, such as benzyl
(1a) and methyl (1b), underwent the intramolecular hydro-
arylation-redox CDC with 2a to give corresponding N-
substituted-1,2,3,4-tetrahydroquinolines 3aa and 3ba in
80% and 63% yields, respectively (entries 1 and 2). The
À
reaction took place with a C C triple bond in the presence of
À
a C C double bond: N-allyl-1,2,3,4-tetrahydroquinoline 3ca
was predominantly obtained from 1c in 63% yield (entry 3).
Then, the effect of substituents at the para position (R2 group)
of an aniline moiety was examined. N-Benzyl-N-(prop-2-
ynyl)anilines with various functional groups at R2, such as
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phenyl-1,2,3,4-tetrahydroquinoline 3ja was treated with
3 equivalents of indole 2a in the presence of Zn(OAc)2
(20 mol%) at 1208C in dichloroethane for 24 h, diindole-
substituted ring-opening product 8a was obtained in 96%
yield [Eq. (1)]. Furthermore, when 3ja was treated with 5-
methoxy-1H-indole 2b instead of 2a, five products were
obtained along with the recovery of 3ja (5% yield), as shown
in [Eq. (2)]. 2-(3-(1H-indol-3-yl)-3-(5-methoxy-1H-indol-3-
yl)propyl)-N-phenylaniline 9 was obtained from 3ja through
a ring-opening reaction similar to Equation (1). N-phenyl-
1,2,3,4-tetrahydroquinoline 3jb was probably produced from
9 in which indole 2a acted as the leaving group. Diindole-
substituted ring-opening products 8a and 8b were generated
from corresponding N-phenyl-1,2,3,4-tetrahydroquinolines
3ja and 3jb, and indoles 2a and 2b, respectively.
Scheme 3. Deuterium labeling study.
redox CDC with indole (2a) in dichloroethane, the expected
N-phenyl-1,2,3,4-tetrahydroquinoline 3ja was obtained in
only 24% yield along with the generation of diindole-
substituted ring-opening product 8a as the major product in
75% yield (Table 3, entry 1). The use of 4 equivalents of 2a
Table 3: Intramolecular hydroarylation-redox CDC and diindole-substi-
tuted ring-opening reactions of N-phenyl-N-(prop-2-yn-1-yl)aniline (1j).[a]
Entry
Indole
Yield of 3 [%]
Yield of 8 [%]
1[a]
2[b]
3[b]
4[c]
5[d]
2a (R=H)
2a
2b (R=OMe)
2c (R=Br)
2a
24 (3ja)
N.D. (3ja)
N.D. (3jb)
9 (3jc)
75 (8a)
98 (8a)
89 (8b)
72 (8c)
N.D. (8a)
Based on these observations, the generation mechanism
of diindole-substituted ring-opening product 8a is shown in
Scheme 4. The nitrogen atom of 1,2,3,4-tetrahydroquinoline
3ja would coordinate with Zn(OAc)2 to induce the ring-
opening reaction, and the resulting iminium cation would
undergo nucleophilic attack by indole 2a to afford corre-
sponding diindole-substituted ring-opening product 8a. The
reaction is probably reversible and diindole-substituted ring-
opening product 8a can be cyclized under the zinc-catalyzed
conditions to give cyclized product 3ja with the release of an
indole molecule as the leaving group.
65 (3ja)
[a] Reaction conditions: 1j (0.25 mmol), 2a (0.75 mmol, 3 equiv), and
Zn(OAc)2 (20 mol%) in dichloroethane (0.25 mL) at 1208C for 24 h
under nitrogen. [b] Four equivalents of 2a (1.0 mmol) was used. [c] Four
equivalents of 2a (1.0 mmol) was employed in toluene at 1508C.
[d] Reaction conditions: 1j (0.25 mmol), 2a (0.5 mmol, 2 equiv), and
Cu(OAc)2 (20 mol%) in dichloroethane (0.5 mL) at 1008C for 12 h under
nitrogen.
afforded 8a predominantly (entry 2). Whereas 4-methoxyin-
dole (2b) gave disubstituted ring-opening product 8b pre-
dominantly (89% yield) under the same conditions, 4-
bromoindole (2c) required a higher reaction temperature
for the reaction to proceed. Indeed, the corresponding
disubstituted ring-opening product 8c was obtained in 72%
yield at 1508C in toluene using a sealed tube, along with
a small amount of cyclized product 3jc (9% yield, entry 4).
The intramolecular hydroarylation-redox CDC proceeded
predominantly when the reaction was carried out in the
presence of Cu(OAc)2 (20 mol%) at 1008C in dichloroethane
for 12 h, revealing that both the intramolecular hydroaryla-
tion-redox CDC and the diindole-substituted ring-opening
reaction can be controlled by the selection of the catalyst.
To clarify the generation mechanism of the diindole-
substituted products, two reactions were examined. When N-
Scheme 4. Plausible mechanism for the generation of 8a.
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In conclusion, we succeeded in the synthesis of 2-
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2
3
À
lines with indoles. Three C H bonds (two sp and one sp )
were activated in one shot and these hydrogen atoms were
trapped by a propargylic triple bond in the molecule. As
a functionalization protocol for tetrahydroquinolines has not
been established yet, we believe that the intramolecular
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the functionalization at C-2 position of tetrahydroquinolines.
Work aimed at further extension of the redox CDC is in
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À
Keywords: C H activation · cross-dehydrogenative coupling ·
intramolecular hydroarylation · tetrahydroquinoline ·
zinc catalysts
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Received: March 9, 2016
Published online: April 21, 2016
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