Construction of Chiral Tri- and Tetra-Arylmethanes Bearing Quaternary Carbon Centers: Copper-Catalyzed Enantioselective Propargylation of Indoles with Propargylic Esters

Article abstract of DOI:10.1002/anie.201604182

Copper-catalyzed enantioselective propargylation of indoles with propargylic esters and sequential Huisgen cycloaddition with azides lead to the construction of chiral triarylmethanes, bearing a quaternary carbon center, with high to excellent enantioselectivities. The result described herein can be used in the enantioselective preparation of a tetraarylmethane.

Full text of DOI:10.1002/anie.201604182

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604182
German Edition: DOI: 10.1002/ange.201604182
Enantioselectivity
Construction of Chiral Tri- and Tetra-Arylmethanes Bearing
Quaternary Carbon Centers: Copper-Catalyzed Enantioselective
Propargylation of Indoles with Propargylic Esters
Kouhei Tsuchida, Yasushi Senda, Kazunari Nakajima, and Yoshiaki Nishibayashi*
Abstract: Copper-catalyzed enantioselective propargylation of
indoles with propargylic esters and sequential Huisgen cyclo-
addition with azides lead to the construction of chiral triaryl-
methanes, bearing a quaternary carbon center, with high to
excellent enantioselectivities. The result described herein can be
used in the enantioselective preparation of a tetraarylmethane.
Based on this background, we envisaged the catalytic
propargylation of aromatic compounds with tertiary prop-
argylic alcohol derivatives bearing an aromatic moiety at the
propargylic position, and subsequent Huisgen cycloaddition
to realize the enantioselective preparation of triarylmethanes
bearing a quaternary carbon center. In fact, the copper-
catalyzed enantioselective propargylation of indoles with
propargylic esters bearing aromatic and trifluoromethyl
moieties at the propargylic position and sequential Huisgen
cycloaddition with azides proceeded to give the correspond-
ing triarylmethanes bearing a quaternary carbon center in
high yields with excellent enantioselectivities (up to 97% ee).
Furthermore, the present reaction system can be applicable to
the enantioselective preparation of a tetraarylmethane (78%
ee) when a tertiary propargylic ester, bearing two different
aromatic moieties at the propargylic position, is used as
a substrate. This reaction is the first successful example of the
enantioselective preparation of a tetraarylmethane. Herein,
we describe preliminary results.
At first, we investigated the copper-catalyzed propargy-
lation of indoles with tertiary propargylic esters because this
transformation is considered to be a key step towards the
construction of chiral triarylmethanes bearing a quaternary
carbon center. Treatment of 1,1,1-trifluoro-2-phenylbut-3-yn-
2-yl perfluorobenzoate (1a) with 2 equivalents of indole (2a)
and 1.2 equivalents of N,N-diisopropylethylamine in the
presence of 5 mol% of CuOTf·1/2C6H6 and 10 mol% of
(4S,5R)-diPh-Pybox (L1) in methanol at room temperature
for 1 hour gave 3-(1,1,1-trifluoro-2-phenylbut-3-yn-2-yl)-1H-
indole (3a) in 41% yield with 47% ee (S; Table 1, entry 1).
Unfortunately, other propargylic esters such as acetate and
tert-butyl carbonate were not applicable. The reactivity and
enantioselectivity dramatically depend on the nature of the
base employed. In fact, cyclic amines worked as more
effective bases to promote the catalytic reactions smoothly
(Table 1, entries 2–8). Especially, the use of 4-methylmorpho-
line (B1) as a base achieved the best reactivity and
enantioselectivity (Table 1, entry 2).
D
evelopment of the asymmetric synthesis of all-carbon
quaternary stereocenters in a catalytic manner is one of the
most important subjects in modern organic chemistry because
the all-carbon quaternary stereocenter is involved as a uni-
versal structure in many natural products and pharmaceut-
icals.[1] Particularly, the construction of tri- and tetra-aryl-
methanes bearing a quaternary carbon center remains a sig-
nificant challenge in materials science and medicinal chemis-
try.[2,3]
Transition metal-catalyzed allylic substitution reactions
are well known as one of the most reliable strategies for the
enantioselective construction of all-carbon quaternary ste-
reocenters at the allylic position of allyllic substituted
products with high enantioselectivity.[1a,b,4] In sharp contrast
to the allylic substitution reactions, the enantioselective
construction of all-carbon quaternary stereocenters at the
propargylic position of propargylic substituted products has
not yet been achieved, although various propargylic substi-
tution reactions have been reported by using a variety of
transition metals as catalysts.[5] Especially, ruthenium- and
copper-catalyzed substitution reactions of propargylic alcohol
derivatives bearing a terminal alkyne moiety with various
nucleophiles gave the corresponding propargylic substituted
products with a high enantioselectivity, where transition
metal–allenylidene complexes were key reactive intermedi-
ates.[5–9]
One of synthetic advantages of propargylic substitution
reactions is that propargylic substituted products possess
a terminal alkyne moiety, which can be easily converted into
various groups in a single step. Typically, Huisgen cyclo-
addition between terminal alkynes and azides gives the
corresponding 1,2,3-triazoles in high yields with an excellent
selectivity and is widely used as a synthetic tool for the
construction of target molecules in many research areas.[10,11]
The use of other pybox ligands such as (S)-Ph-Pybox (L2),
(S)-Me-Pybox (L3), and (R)-Cl-MeO-BIPHEP (L4), which
were previously reported to work as effective optically active
ligands toward copper-catalyzed enantioselective propargylic
amination and etherification,[8] did not give satisfactory
results (Table 1, entries 9–11). When the reaction using L1
was carried out at a lower reaction temperature, such as 08C,
3a was obtained in 81% yield with 91% ee (Table 1,
entry 12). Use of a larger amount of B1 (2 equiv) was
effective in leading to the reaction completion in a shorter
reaction time (Table 1, entry 13). The highest enantioselec-
[*] K. Tsuchida, Y. Senda, Dr. K. Nakajima, Prof. Dr. Y. Nishibayashi
Department of Systems Innovation, School of Engineering
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: ynishiba@sys.t.u-tokyo.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604182.
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Table 1: Copper-catalyzed enantioseletive propargylation of indole with
1,1,1-trifluoro-2-phenylbut-3-yn-2-yl perfluorobenzoate (1a).[a]
Table 2: Enantioseletive propargylation of 1-methylIndole (2b) with
propargylic perfluorobenzoates (1).[a]
Entry
R1 (1)
t [h]
Yield [%][b]
ee [%][c]
Entry
2
Ligand
Base
t [h]
Yield [%][b]
ee [%][c]
1[d]
2
4-FC6H4 (1b)
64
24
110
72
72
72
72
30
192
64
76 (3c)
71 (3d)
82 (3e)
82 (3 f)
59 (3g)
86 (3h)
75 (3i)
0
95
93
94
95
94
96
97
–
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
iPr2NEt
B1
B2
B3
B4
B5
B6
DABCO
B1
B1
1
6
39
14
6
11
18
0.5
7
6
5
92
48
24
41
81
71
80
72
79
20
42
38
13
trace
81
79
85
47 (S)
86 (S)
87 (S)
84 (S)
85 (S)
85 (S)
72 (S)
80 (S)
34 (S)
28 (S)
–
4-ClC6H4 (1c)
4-BrC6H4 (1d)
4-MeOC6H4 (1e)
4-PhC6H4 (1 f)
4-MeC6H4 (1g)
3-MeC6H4 (1h)
2-MeC6H4 (1i)
2-naphthyl (1j)
2-thienyl (1k)
3[d]
4[d]
5
6[d]
7[d]
8[e]
9[d]
10[d]
85 (3j)
84 (3k)
95
97
10
11
12[d]
13[d,e]
14[d,e]
[a] Reaction of 1 (0.20 mmol) with 2b (0.40 mmol) in the presence of
CuOTf·1/2C6H6 (0.010 mmol), L1 (0.020 mmol), and B1 (0.40 mmol) in
methanol (2 mL) at 08C. [b] Yield of isolated product. [c] Determined by
HPLC. [d] At À108C. [e] At room temperature.
B1
B1
B1
B1
91 (S)
91 (S)
95 (S)
methyl-2-oxoindolin-3-yl perfluorobenzoate (1m) with
2 equivalents of 2a at À108C gave the corresponding
propargylated indole 3m in 93% yield with 88% ee (R)
[Eq. 2].[12] This result indicates that a propargylic ester
bearing a cyclic moiety at the propargylic position is
applicable as a substrate.
[a] Reaction of 1a (0.20 mmol) with 2a (0.40 mmol) in the presence of
CuOTf·1/2C6H6 (0.010 mmol), ligand (0.020 mmol), and base
(0.24 mmol) in methanol (2 mL) at room temperature. [b] Yield of
isolated product. [c] Determined by HPLC. [d] At 08C. [e] 2 equiv of B1.
DABCO=1,4-diazabicyclo[2.2.2]octane, Tf=trifluoromethanesulfonyl.
tivity (95% ee) was observed in the reaction of 1a with 1-
methylindole (2b) under the same reaction conditions
(Table 1, entry 14).
Reactions of other propargylic perfluorobenzoates with
2b were carried out by using L1 as an optically active ligand at
0 or À108C in methanol. Typical results are shown in Table 2.
Introduction of a substituent such as fluoro, chloro, bromo,
methoxy, phenyl, and methyl group at the para-position of the
benzene ring of the propargylic perfluorobenzoates (1b–g)
gave
a similarly high enantioselectivities (93–96% ee)
(Table 2, entries 1–6).[12,13] Although the presence of
a methyl group at the meta-position of the benzene ring of
the propargylic perfluorobenzoate 1h gave the highest
enantioselectivity (97% ee; Table 2, entry 7), no reaction
occurred at all with that bearing the ortho-methyl-substituted
benzene ring (Table 2, entry 8). A similarly high enantiose-
lectivity was observed in the use of either 2-naphthyl or 2-
thienyl group at the propargylic position of the propargylic
perfluorobenzoate (Table 2, entries 9 and 10).
In contrast to the reaction of 2-phenylbut-3-yn-2-yl
perfluorobenzoate (1l) with 2 equivalents of 2a under similar
reaction conditions, where 3l was obtained in a low yield
together with the formation of the corresponding methyl
ether (2-phenylbut-3-yn-2-yl methyl ether) and 2-phenylbut-
1-en-3-yne as shown in Eq 1, the reaction of 3-ethynyl-1-
Propargylation of other indoles (2c–i) also proceeded
smoothly to give the corresponding propargylated indoles
(3n–t) in good to high yields with an excellent enantioselec-
tivity (89–96% ee; Table 3, entries 1–7). Reactions of 1a with
2,4-dimethylpyrroles (2j and 2k) gave the corresponding
propargylated pyrroles (3u and 3v) in high yields with
a slightly lower enantioselectivity (Table 3, entries 8 and 9).
To obtain more information on the reactive species of the
real copper catalyst, we prepared the copper-pybox complex
[Cu2(L1)2(m-Cl)][CuCl2][13,14] (4) from the reaction of CuCl
with 0.7 equivalents of L1 in acetone at room temperature for
24 hours (Scheme 1a). The molecular structure of 4 was
unambiguously characterized by X-ray crystallography, and
an ORTEP drawing of the cationic part of 4 is shown in
2
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Table 3: Enantioseletive propargylation of indoles and pyrroles (2) with
propargylic perfluorobenzoates (1a).[a]
A proposal of the dicopper complex, such as 4, as
a reactive species in the present propargylation is also
supported by a nonlinear relationship[15] between the ee value
of optically active ligand L1 and the ee value of 3a, which is
produced by treatment of 1a with 2a in methanol at 08C for
48 hours in the presence of 5 mol% of CuOTf·1/2C6H6 and
10 mol% of L1 as shown in Scheme 1c. This result provides
direct evidence that a dinuclear copper complex works as
a key reactive species in the propargylation.[8k]
Based on the results of enantioselective propargylation of
indoles shown in Tables 2 and 3, we subjected propargylation
products to a subsequent Huisgen cycloaddition to obtain
chiral triarylmethanes bearing a trifluoromethyl moiety.
Typical results are shown in Table 4. Treatment of 1a with
Entry R1
R2 (2)
t [h] Yield [%][b] ee [%][c]
1
2
3
H
H
H
6-Me (2c)
7-Me (2d)
7-OMe (2e)
7-OMe (2 f)
– (2g)
17
20
22
120
20
20
72
20
48
90 (3n)
86 (3o)
82 (3p)
61 (3q)
86 (3r)
57 (3s)
86 (3t)
83 (3u)
88 (3v)
90
93
89
96
89
92
96
80
80
4[d] Me
5
Et
6[d] allyl
– (2h)
7[d] lilolidine (2i)
8
2,4-dimethylpyrrole (2j)
9[d] 3-ethyl-2,4-dimethylpyrrole (2k)
Table 4: One-pot enantioselective synthesis of triayrlmethane (5).[a]
[a] Reaction of 1a (0.20 mmol) with 2 (0.40 mmol) in the presence of
CuOTf·1/2C6H6 (0.010 mmol), L1 (0.020 mmol), and B1 (0.40 mmol) in
methanol (2 mL) at 08C. [b] Yield of isolated product. [c] Determined by
HPLC. [d] At À108C.
Entry Ar (1)
Ph
R
t1, t2 [h] Yield [%][b] ee [%][c]
1
(1a) Bn
24, 40
72, 24
89 (5a)
86 (5b)
88 (5c)
77 (5d)
85 (5e)
96
97
95
96
95
2[d] 2-thienyl (1k) Bn
3
4
5
Ph
Ph
Ph
(1a) CH2(4-C6H4Me) 24, 20
(1a) CH2(1-pyrenyl)
(1a) CH2CO2Me
24, 24
24, 24
6
Ph
(1a)
24, 24
84 (5 f)
20:1[e]
[a] After reaction of 1 (0.20 mmol) with 2b (0.40 mmol) in the presence
of CuOTf·1/2C6H6 (0.010 mmol), L1 (0.020 mmol), and B1 (0.40 mmol)
in methanol (2 mL) at 08C, treatment with azides (0.30 mmol) and
iPr2NEt (0.40 mmol) was carried out in one pot. [b] Yield of isolated
product. [c] Determined by HPLC. [d] At À108C for propargylation
reaction. [e] Diastereomeric ratio. THF=tetrahydrofuran.
2 equivalents of 2b and 2 equivalents of B1 in the presence of
5 mol% of CuOTf·1/2C6H6 and 10 mol% of L1 in methanol
at 08C for 24 hours, followed by treatment with 1.1 equiv-
alents of benzyl azide and 2 equivalents of N,N-diisopropy-
lethylamine in THF at 408C for 40 hours gave 3-(1-(1-benzyl-
1H-1,2,3-triazol-4-yl)-2,2,2-trifluoro-1-phenylethyl)-1-
methyl-1H-indole (5a) in 89% yield with 96% ee (Table 4,
entry 1). Separately, we carried out the reaction of 3b (95%
ee) with 1.1 equivalents of benzyl azide and 2 equivalents of
N,N-diisopropylethylamine in the presence of 5 mol% of
CuOTf·1/2C6H6 and 10 mol% of L1 in THF at 408C for
20 hours to give 5a in 99% yield with 95% ee. This result
indicates that the Huisgen cycloaddition between 3b and
benzyl azide took place without loss of the optical purity. A
similarly high enantioselectivity was observed in the use of
a 2-thienyl group at the propargylic position of the prop-
argylic perfluorobenzoate (Table 4, entry 2). The use of other
substituents, such as p-tolyl, 1-pyrenyl, and methoxycarbonyl
groups, on the azide under the same reaction conditions gave
the corresponding triarylmethanes in high yields with an
Scheme 1. Preparation of a dinuclear copper complex bearing a pybox
ligand, and its catalytic activity.
Scheme 1a. Then, we carried out the catalytic reaction by
using 4 as a catalyst as shown in Scheme 1b. Although the
enantioselectivity of the product 3b is almost the same with
that obtained by using the copper complex formed in situ
from CuCl and L1, the yield of 3b is lower. At present, we
have not yet discovered the reason, but the anion [CuCl2]À in
4 may inhibit the catalytic reaction. This result indicates that
the dinuclear copper complex bearing 2 equivalents of L1
may work as a reactive species.
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excellent enantioselectivity (Table 4, entries 3–5). Here, the
reaction with optically active 2-azidoethyl 2,3,4,6-tetra-O-
acetyl-b-d-glucopyranoside also proceeded smoothly with an
excellent diastereoselectivity (Table 4, entry 6). When 1m
was used as propargylic ester bearing a cyclic moiety at the
propargylic position, the corresponding triarylmethane was
obtained in 95% yield with 87% ee (R) [Eq. 3]. The result of
the sequential reactions provides a synthetically useful
approach to construct chiral triarylmethanes bearing a qua-
ternary carbon center.
herein as opening a new synthetic route towards chiral tri- and
tetra-arylmethanes. Further application of this methodology
is now in progress.
Acknowledgments
The present project is supported by CREST from JST. We
thank the Grants-in-Aid for Scientific Research (Nos.
26288044, 26105708, 15K13687, 15H05798) from JSPS and
MEXT for financial support. We thank Prof. Dr. Kyoko
Nozaki and Yusuke Mitsushige at The University of Tokyo for
19F NMR spectroscopy measurements.
Keywords: alkynes · copper · cycloadditions · enantioselectivity ·
synthetic methods
Finally, we applied the present reaction system to the
enantioselective preparation of a tetraarylmethane by using
a tertiary propargylic esters, bearing two different aromatic
moieties at the propargylic position, as substrates. We
investigated the copper-catalyzed propargylation of indoles
with 1-phenyl-1-(pyridin-2-yl)prop-2-ynyl perfluorobenzoate
(1n) with 2 equivalents of 2b and 2 equivalents of B1 in the
presence of 5 mol% of CuOTf·1/2C6H6 and 10 mol% of L1 in
methanol at À108C for 48 hours followed by treatment with
2 equivalents of benzyl azide and 2 equivalents of N,N-
diisopropylethylamine in THF at 408C for 40 hours to give
3-((1-benzyl-1H-1,2,3-triazol-4-yl)(phenyl)(pyridin-2-
yl)methyl)-1-methyl-1H-indole (6a) in 28% yield with 78%
ee (Scheme 2). Unfortunately, the sequential Huisgen cyclo-
addition did not proceed smoothly, probably because of the
steric hindrance at the propargyl position of the indole, even
though the propargylation took place with a high enantiose-
lectivity.
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In summary, we have succeeded in novel enantioselective
copper-catalyzed proparygylation of indoles with propargylic
esters. This reaction is the first successful example of
enantioselective construction of an all-carbon quaternary
stereocenter based on a propargyl substitution strategy. The
major advantage of this strategy is that a further derivatiza-
tion of the terminal alkyne moiety, into an aromatic ring,
which is quite useful for the construction of chiral all-carbon
substituted tri- and tetra-arylmethanes. The one-pot proce-
dure demonstrated in this manuscript provides the first
successful example of the enantioselective preparation of
a tetraarylmethane. We consider the methodology described
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[12] See the Supporting Information for the determination of the
absolute configuration of the propargylated indoles.
[13] CCDC 1477214 (3z),
1477215 (3m’), and
1477216
(4·C4H10O·0.5C3H6O) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
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Received: April 29, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Enantioselectivity
All-star all-carbon: The title reaction leads
to the enantioselective construction of an
all-carbon quaternary stereocenter. The
subsequent derivatization of terminal
alkyne moiety, into aromatic rings, is
useful for the construction of chiral all-
carbon substituted tri- and tetra-arylme-
thanes. The one-pot procedure demon-
strated herein provides a successful
example of the enantioselective prepara-
tion of a tetraarylmethane.
K. Tsuchida, Y. Senda, K. Nakajima,
Y. Nishibayashi*
&&&& — &&&&
Construction of Chiral Tri- and Tetra-
Arylmethanes Bearing Quaternary Carbon
Centers: Copper-Catalyzed
Enantioselective Propargylation of
Indoles with Propargylic Esters
Enantioselektivitꢀt
Von Kohlenstoff umgeben: Die Titelreak-
tion fꢀhrt enantioselektiv ein vollstꢁndig
kohlenstoffsubstituiertes quartꢁres Ste-
reozentrum ein. anschließende
K. Tsuchida, Y. Senda, K. Nakajima,
Y. Nishibayashi*
&&&& — &&&&
Umwandlung des endstꢁndigen Alkins in
aromatische Ringe ergibt chirale Tri- und
Tetraarylmethane in einer Eintopfproze-
dur.
Construction of Chiral Tri- and Tetra-
Arylmethanes Bearing Quaternary Carbon
Centers: Copper-Catalyzed
Enantioselective Propargylation of
Indoles with Propargylic Esters
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Enantioselectivity
All-star all-carbon: The title reaction leads
to the enantioselective construction of an
all-carbon quaternary stereocenter. The
subsequent derivatization of terminal
alkyne moiety, into aromatic rings, is
useful for the construction of chiral all-
carbon substituted tri- and tetra-arylme-
thanes. The one-pot procedure demon-
strated herein provides a successful
example of the enantioselective prepara-
tion of a tetraarylmethane.
K. Tsuchida, Y. Senda, K. Nakajima,
Y. Nishibayashi*
&&&& — &&&&
Construction of Chiral Tri- and Tetra-
Arylmethanes Bearing Quaternary Carbon
Centers: Copper-Catalyzed
Enantioselective Propargylation of
Indoles with Propargylic Esters
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!