Copper-Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza-[n.2.1] Skeletons

Article abstract of DOI:10.1002/anie.201904698

Catalytic cycloisomerization-initiated cascade cyclizations of terminal alkynes have received tremendous interest, and been widely used in the facile synthesis of a diverse array of valuable complex heterocycles. However, these tandem reactions have been mostly limited to noble-metal catalysis, and are initiated by an exo-cyclization pathway. Reported herein is an unprecedented copper-catalyzed endo-cyclization-initiated tandem reaction of indolyl homopropargyl amides, where copper catalyzes both the hydroamination and Friedel–Crafts alkylation process. This method allows the practical and atom-economical synthesis of valuable bridged aza-[n.2.1] skeletons (n=3–6) with wide substrate scope, and excellent diastereoselectivity and enantioselectivity by a chirality-transfer strategy. Moreover, the mechanistic rationale for this novel cascade cyclization is also strongly supported by control experiments, and is distinctively different from the related gold catalysis.

Full text of DOI:10.1002/anie.201904698

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Copper-Catalyzed Cascade Cyclization of Indolyl Homopropargyl
Amides: Stereospecific Construction of Bridged Aza-[n.2.1]
Skeletons
Authors: Longwu Ye, Tong-De Tan, Xin-Qi Zhu, Hao-Zhen Bu,
Guocheng Deng, Yang-Bo Chen, and Rai-Shung Liu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904698
Angew. Chem. 10.1002/ange.201904698
Link to VoR: http://dx.doi.org/10.1002/anie.201904698
http://dx.doi.org/10.1002/ange.201904698

10.1002/anie.201904698
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Cyclizations
Copper-Catalyzed Cascade Cyclization of Indolyl Homopropargyl
Amides: Stereospecific Construction of Bridged Aza-[n.2.1] Skeletons
Tong-De Tan, Xin-Qi Zhu, Hao-Zhen Bu, Guocheng Deng, Yang-Bo Chen, Rai-Shung Liu, Long-Wu Ye*
Abstract: Catalytic cycloisomerization-initiated cascade cyclizations
of terminal alkynes have received tremendous interest, and been
widely used in the facile synthesis of a diverse array of valuable
complex heterocycles. However, these tandem reactions have been
mostly limited to noble-metal catalysis, and initiated via an exo-
cyclization pathway. Reported herein is an unprecedented copper-
catalyzed endo-cyclization-initiated tandem reaction of indolyl
homopropargyl amides, where copper catalyzes both the
hydroamination and Friedel−Crafts alkylation process. This method
allows the practical and atom-economical synthesis of valuable
bridged aza-[n.2.1] skeletons (n = 3–6) with wide substrate scope,
and excellent diastereoselectivity and enantioselectivity by a chirality-
transfer strategy. Moreover, the mechanistic rationale for this novel
cascade cyclization is also strongly supported by control experiments,
which is distinctively different from the related gold catalysis.
compared to their homologous counterparts, and only very
limited methods have been developed thus far.[2,3] In particular,
there is
a lack of efficient synthetic methods for their
enantioselective synthesis.[2b,3e,3f]
Due to the unique π-acidic property of Au(I) catalyst, gold-
catalyzed cyclization reaction of terminal alkynes with internal
nucleophiles, typically via an exo cyclization, has received
tremendous interest since the last decade (Scheme 1a), and
been widely used in the facile synthesis of an incredible variety of
the valuable cyclic compounds.[4,5] Meanwhile, copper-catalyzed
such a cyclization has been far less vigorously investigated,[6] and
the internal nucleophiles here are limited to the more nucleophilic
electron-rich amines, thus severely limiting their further synthetic
applications as the N-protecting groups of the formed products
are difficult to be removed.
a) Au- vs Cu-catalyzed cyclization of terminal alkynes with internal nucleophiles
The tropane (8-azabicyclo[3.2.1]octane) skeleton defines the core
structure of more than 600 alkaloids with multiple bioactivities.[1]
Among these, the indole-based tropanes are particularly
important structural motifs that have been found in a wide range
of biologically significant molecules (Figure 1).[2] However, these
bridged scaffolds are regarded as difficult structures to access as
the bridge segments make the molecules structurally less flexible
NuH
exo
NuH
exo
endo (rare pathway)
endo (rare pathway)
R
R
n
n
[Au]
[Cu]
well established
rarely reported
NuH: OH, NR'H, (hetero)Ar...
Typical pathway: exo-cyclization
b) Au-catalyzed tandem exo-hydroalkoxylation/hydroalkoxylation
R
HO
HO
O
R
O
R
[Au]
n
HO
n
O
n
(n = 1, 2)
c) Au- or Pt-catalyzed tandem exo-hydroalkoxylation/Prins-type cyclization
OR
OR
Prins-type
cyclization
OH
X
[Au] or [Pt]
ROH
R
O
X
R
O
X
R
d) Au-catalyzed tandem exo-hydroalkoxylation/semi-pinacol rearrangement
O
H
[Au]
H
R
H
n
HO
n
OH
[Au]
O
R
R
O
n
OH
(n = 0, 1)
H
Figure 1. Indole-based tropanes in bioactive molecules.
e) Cu-catalyzed tandem endo-hydroamination/Friedel-Crafts alkylation
Anti-Markovnikov
addition
Markovnikov
addition
R1
NHPG
N
Cu
PG
R1
n
[]
T.-D. Tan, X.-Q. Zhu, H.-Z. Bu, G. Deng, Y.-B. Chen, Prof. Dr. L.-W.
Ye
n
R
R
N
R2
NR2
(n = 0, 1, 2, 3)
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory for Chemical Biology of Fujian Province, and College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China
anti-Markovnikov addition outcompetes the typical Markovnikov addition
copper catalysis
complete chirality transfer
cascade cyclization
valuable chiral bridged aza-[n.2.1] skeletons
broad substrate scope
E-mail: longwuye@xmu.edu.cn
Prof. Dr. R.-S. Liu
Scheme 1. Transition-metal-catalyzed cycloisomerization-initiated
tandem reactions for the synthesis of bridged scaffolds.
Department of Chemistry, National Tsing-Hua University, Hsinchu,
Taiwan
Prof. Dr. L.-W. Ye
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
The search for new avenues to molecular complexity from
simple starting materials has been one of the major objectives of
organic chemists in the past decades. In this context, tandem
reactions have emerged as powerful tools to accomplish this goal
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
as it offers the opportunity of building up architecturally complex
molecules in rapid, efficient, and economical ways.[7] Following
this concept, transition-metal-catalyzed alkyne hydroalkoxylation
and hydroamination initiated cascade cyclizations have been well
documented to be a powerful method to synthesize a variety of
structurally complex heterocycles,[4] especially the valuable
bridged heterocycles.[8-11] For example, Michelet and Genẽt in
(Table 1, entry 9).[19] Interestingly, Brønsted acids promoted
selective formation of 2aa (Table 1, entries 12–13). Further
screening of solvents such as toluene and chlorobenzene led to a
slightly decreased yield (Table 1, entries 14–15). Finally, it should
be mentioned that the reaction of unprotected and methyl-
protected indolyl homopropargyl amides in the presence of
CuOTf only led to the formation of the corresponding carbazoles
as main products.[17] Thus, both the metal catalyst and protecting
group of the substrate are the key to achieve the desired cascade
cyclization.
2005
reported
a
gold-catalyzed
tandem
exo-
hydroalkoxylation/hydroalkoxylation of bis-homopropargylic diols,
allowing the facile formation of functionalized strained bicyclic
ketals (Scheme 1b).[8a] A related platinum-catalyzed tandem
cycloisomerization of alkyne-diols was subsequently disclosed by
Ley et al. for the synthesis of [3.2.1]bicyclic acetals, and notable
is that endo-hydroalkoxylation was observed in case of internal
akynes.[8b] In 2006, Barluenga and co-workers reported an
outstanding protocol for the gold- or platinum-catalyzed tandem
exo-hydroalkoxylation/Prins-type cyclization, leading to a variety
of 9-oxabicyclo[3.3.1]nonanes (Scheme 1c).[9a,9b] On the basis of
this work, the relevant tandem exo-hydroalkoxylation
/hydroarylation was further developed by the same group.[9c,9d]
Such a hydroalkoxylation/Prins-type cyclization has also been
aptly exploited by Liu and Wang.[10] In 2015, Yang and co-workers
demonstrated an elegant approach for the efficient synthesis of
Table 1. Optimization of reaction conditions.[a]
oxabicyclo[3.2.1]octanes
via
gold-catalyzed
exo-
hydroalkoxylation/semi-pinacol rearrangement (Scheme 1d).[11]
Despite these remarkable achievements, these intramolecular
tandem reactions have so far been limited to the noble-metal
catalysts (Au and Pt), and initiated via an exo-cyclization pathway
in terms of terminal alkynes.
By utilizing the steric strain in ring formation to achieve anti-
Markovnikov regioselectivity, our group has developed several
gold-catalyzed 5-endo-dig hydroamination-initiated tandem
reactions, affording valuable five-membered N-heterocycles.[12]
Inspired by these results, we envisioned that the synthesis of
indole-based tropanes might be achieved via such an anti-
Markovnikov hydroamination-initiated cascade cyclization of
indolyl homopropargyl amides (Scheme 1e).[13] However,
achieving this cascade reaction is highly challenging: (1) how to
prevent the competing exo cyclization of the terminal alkyne
partner by the highly nucleophilic indole moiety via a typical
Markovnikov addition;[5] and (2) how to achieve the desired
cascade cyclization but not stopping at the dihydropyrrole
intermediate.[14] Herein, we describe the realization of
unprecedented copper-catalyzed cascade cyclization of indolyl
homopropargyl amides,[15] allowing the practical and atom-
economical synthesis of a diverse array of valuable bridged aza-
[n.2.1] skeletons (n = 3–6) with excellent diastereoselectivity and
enantioselectivity by a chirality-transfer strategy. Furthermore, a
mechanistic rationale for this serial cascade cyclization is strongly
supported by a variety of control experiments, and importantly, its
mechanism is distinctively different from the related gold catalysis.
At the outset, indole-tethered chiral homopropargyl amide 1a
was chosen as the model substrate.[16] As outlined in Table 1,[17]
typical gold catalysts such as Ph3PAuNTf2 and IPrAuNTf2 could
indeed catalyze the cascade cyclization reaction to produce the
desired aza-[3.2.1] skeleton 2a but in low yields (<25%). In these
cases, 2aa or 2ab was formed as the main product presumably
through a direct gold-catalyzed Markovnikov cycloisomerization-
initiated tandem reaction (Table 1, entries 1–4).[17] We then
investigated platinum and silver catalysts (Table 1, entries 5–7)
and were delighted to find that 58% yield of 2a was achieved in
the presence of AgOTf (Table 1, entry 7).[17,18] Gratifyingly,
subsequent studies revealed that copper catalysts could catalyze
the cascade cyclization smoothly (Table 1, entries 8–11), and 2a
was fromed in 85% yield by employing CuOTf as the catalyst
[a] Reaction conditions: 1a (0.05 mmol), catalyst (10 mol %) in solvent
1
(0.5 mL) at rt−80 °C in vials. [b] Measured by H NMR using diethyl
phthalate as internal standard. [c] 5 mol % of catalyst was used. [d]
20 mol % of catalyst was used.
According to Ellman’s chemistry (Figure 2),[12] chiral indolyl
homopropargyl amides 1 were easily prepared with excellent
enantiomeric excesses (98−99% ee) by starting from readily
available indolyl aldehydes and (R)-(+)-tert-butylsulfinamide. With
the optimal reaction conditions (Table 1, entry 9) and chiral indolyl
homopropargyl amides 1 in hand, the scope of this cascade
cyclization was explored (Table 2). Initial investigation of N-
protecting groups of amide moiety demonstrated that the reaction
proceeded smoothly with different sulfonyl groups to furnish the
desired aza-[3.2.1] skeletons 2a–d in 68−84% yields (Table 2,
entries 1–4), and the Ts-protected homopropargyl amide 1a gave
the best result (Table 2, entry 1). Gratifyingly, the use of substrate
containing Bs protecting group of indole moiety gave
a
significantly improved yield (Table 2, entry 5). In addition, amides
containing different substituents on the indole ring also underwent
smooth cascade cyclization, producing the corresponding 2f–n in
good to excellent yields (Table 2, entries 6–14), Finally, it was
found that the reaction also occurred well with (S)-(+)-tert-
butylsulfinamide-derived 1e′, and thus the other enatiomer 2e′
was specifically produced (Table 2, entry 15). Importantly, the
2
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
chirality of 1 can be completely transferred to the chiral indole-
fused tropanes and excellent diastereoselectivity (d.r. > 50:1) can
be achieved in all cases. The molecular structure of 2h was
further confirmed by X-ray diffraction (Figure 3).[20]
Figure 2. Synthesis of chiral homopropargyl amides using Ellman’s
Figure 3. Structure of compound 2h in its crystal.
chemistry.
Table 2. Construction of bridged aza-[3.2.1] skeletons 2.[a]
Besides the formation of bridged aza-[3.2.1] skeletons, this
copper-catalyzed cascade cyclization was also viable for the
construction of other valuable bridged aza-[n.2.1] skeletons. As
shown in Table 3, the reaction proceeded efficiently with a variety
of chiral indolyl homopropargyl amides 3, also prepared with
excellent ees (98−99% ee) by Ellman’s tert-butylsulfinimine
chemistry, affording the corresponding functionalized bridged
aza-[n.2.1] skeletons 4 in mostly excellent yields with complete
chirality transfer. It was found that amides containing various
substituents on the indole ring were suitable substrates for this
reaction to furnish the desired aza-[4.2.1] skeletons 4a–f in 81–
93% yields (Table 3, entries 1–6). Of note, (S)-(+)-tert-
butylsulfinamide-derived 3a′ also underwent smooth cyclization to
produce the desired 4a′ in 89% yield and the reaction was
stereospecific (Table 3, entry 7). Moreover, this cascade
cyclization could also be extended to the preparation of the aza-
[n.2.1] skeletons 4g–i (n = 5,6) in high yields (Table 3, entries 8–
10). Thus, this protocol provides an efficient and practical route
for the construction of the indole-fused medium-sized ring
compounds with excellent diastereoselectivity (d.r. > 50:1) and
enantioselectivity.
Entry
Substrate
Product
Yield (%)
NH
PG
PGN
N
Ts
N
Ts
1
2
3
4
1a, PG = Ts, 99% ee
1b, PG = Ms, 99% ee
1c, PG = Bs, 99% ee
1d, PG = MBS, 99% ee
2a, PG = Ts, 99% ee
2b, PG = Ms, 99% ee
2c, PG = Bs, 99% ee
2d, PG = MBS, 99% ee
84
68
73
77
NH
Ts
TsN
N
Bs
N
Bs
Interestingly, this cascade cyclization was also extended to 3-
substituted indole-tethered homopropargyl amides 5, and the
desired aza-[3.2.1] skeletons 6a–h were formed in generally good
yields, as summarized in Table 4. Notably, the reaction could be
extended to sterically hindered indolyl amide 5h, and the desired
6h was formed in 76% yield (Table 4, entry 8). In addition, (S)-(+)-
tert-butylsulfinamide-derived 5a could also undergo smooth
cyclization to deliver 6a and the reaction was stereospecific
(Table 4, entry 9). Furthermore, this protocol was also used in the
synthesis of aza-[4.2.1] skeleton 6i in 78% yield (Table 4, entry
10). Importantly, complete chirality transfer and excellent
diastereoselectivity (d.r. > 50:1) were achieved in all cases. The
molecular structure of 6e was further confirmed by X-ray
diffraction (Figure 4).[20]
5
1e, 99% ee
2e, 99% ee
96
R
NH
Ts
R
TsN
N
Bs
N
Bs
6[b]
7[b]
8[b]
9[b]
10
1f, R = F, 99% ee
1g, R = Cl, 99% ee
1h, R = Br, 99% ee
1i, R = CN, 99% ee
1j, R = OMe, 99% ee
2f, R = F, 99% ee
2g, R = Cl, 99% ee
2h, R = Br, 99% ee
2i, R = CN, 99% ee
2j, R = OMe, 99% ee
81
86
89
75
78
NH
Ts
TsN
N
R
N
R
Bs
Bs
11[b]
12[b]
13[b]
14
75
70
78
87
1k, R = Cl, 99% ee
1l, R = Br, 99% ee
1m, R = CO2Me, 98% ee
1n, R = Me, 99% ee
2k, R = Cl, 99% ee
2l, R = Br, 99% ee
2m, R = CO2Me, 98% ee
2n, R = Me, 99% ee
NH
Ts
TsN
N
Bs
N
Bs
15
1e', 98% ee
2e', 98% ee
94
[a] Reaction conditions: 1 (0.2 mmol), CuOTf (0.02 mmol), DCE (2
mL), 80 oC, 5 h, in vials; yields are those for the isolated products; ees
are determined by HPLC analysis. [b] Reaction time: 10 h.
Figure 4. Structure of compound 6e in its crystal.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
Table 3. Construction of bridged aza-[n.2.1] skeletons 4.[a]
Entry
Substrate
Product
Yield (%)
NHPG
Entry
Substrate
Product
Yield (%)
PGN
Ts
N
Bs
NH
N
Bs
N
Ts
1
2
5a, PG = Ts, 99% ee
5b, PG = Ms, 99% ee
6a, PG = Ts, 99% ee
6b, PG = Ms, 99% ee
83
67
N
Bs
N
Bs
NHTs
1
3a, 99% ee
4a, 99% ee
93
TsN
Ts
N
Bs
NH
R
N
Bs
N
R
R
Ts
R
3
4
5
6
5c, R = Cl, 98% ee
5d, R = Br, 98% ee
5e, R = Me, 98% ee
5f, R = OMe, 98% ee
6c, R = Cl, 98% ee
6d, R = Br, 98% ee
6e, R = Me, 98% ee
6f, R = OMe, 98% ee
83
75
85
80
N
Bs
N
Bs
2[b]
3[b]
4
3b, R = Cl, 98% ee
3c, R = Br, 98% ee
3d, R = Me, 98% ee
4b, R = Cl, 98% ee
4c, R = Br, 98% ee
4d, R = Me, 98% ee
90
85
91
NHTs
Me
TsN
Me
Ts
N
Bs
NH
N
Bs
N
Ts
7
5g, 99% ee
6g, 98% ee
81
76
82
78
N
Bs
R
N
R
NHTs
NHTs
NHTs
Me
Bs
Me
5[b]
6
3e, R = CO2Me, 99% ee
3f, R = Me, 98% ee
4e, R = CO2Me, 99% ee 81
4f, R = Me, 98% ee
TsN
87
N
Bs
N
Bs
5h, 98% ee
Ts
NH
N
8
6h, 98% ee
Ts
N
N
Bs
TsN
Bs
N
Bs
7
3a', 99% ee
4a', 99% ee
89
N
Bs
5a', 97% ee
Ts
9
6a', 97% ee
NH
N
Ts
2
TsN
2
N
N
Bs
[5.2.1]
Bs
N
Bs
N
Bs
5i, 98% ee
8
9
3g, 98% ee
4g, 98% ee
91
81
10
6i, 98% ee
Ts
Ts
N
NH
Ts
MsN
[a] Reaction conditions: 5 (0.2 mmol), CuOTf (0.02 mmol), DCE (2
mL), 80 oC, 5 h, in vials; yields are those for the isolated products; ees
are determined by HPLC analysis.
NMs
N
N
Bs
[5.2.1]
Bs
3h, 95% ee
4h, 95% ee
In addition, other heterocycle-tethered homopropargyl amides
7a-c, and even alkoxy arene-substituted amide 7d were suitable
substrates for such a copper-catalyzed cascade cyclization,
delivering the desired aza-[3.2.1] skeletons 8a–d in 56–86%
yields [Eq. (1-3)]. It is notable that these heterocycle-based and
aryl-based tropanes[3] can be found in various bioactive
molecules, and their enantioselective synthesis often exhibits low
efficiency.[2c] Interestingly, the cascade cyclization of indolyl
alkyne 7e under this copper catalysis could also produce the
corresponding aza-[3.2.1] skeleton 8e in 91% yield [Eq. (4)] via a
presumable 5-exo-dig cyclization/Friedel−Crafts alkylation.[17]
Moreover, this copper catalysis was also extended to the methyl-
and ethyl-substituted internal alkynes 7f and 7g, and the desired
N
NH
Ts
MsN
2
NMs
N
Bs
N
Bs
[6.2.1]
10
3i, 99% ee
4i, 99% ee
82
[a] Reaction conditions: 3 (0.2 mmol), CuOTf (0.02 mmol), DCE (2
mL), 80 oC, 5 h, in vials; yields are those for the isolated products; ees
are determined by HPLC analysis. [b] Reaction time: 10 h.
Table 4. Construction of bridged aza-[n.2.1] skeletons 6.[a]
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
O
O
1) Li/Naphthalene
THF, -78 o
products 8e and 8g could be obtained in 88% and 58% yields,
respectively [Eq. (5)].[21] Again, complete chirality transfer and
excellent diastereoselectivity (d.r. > 50:1) were achieved in all
these cases.
F3C
S
Br
BocN
HN
lit. 2c
C
2h
(99% ee)
2) Boc2O, Et3N
DCM, RT
N
N
HCl
H
2ha, 99% ee, 62%, 2 steps
5-HT6 antagonist
1) NaOH (20 equiv)
MeOH, reflux
N
N
CuOTf (10 mol %)
Ts
Ts
3a
(99% ee, 2.5 mmol)
DCE (0.1 M)
80 oC, 30 h
2) CH3I (1.5 equiv)
NaH (1.1 equiv)
DMF, 0 oC - RT
N
Bs
N
4aa, 98% ee
72%, 2 steps
4a, 1.04 g, 89%, 99% ee
NHTs
N
Ts
Cl
(iv)
(i)
N
N
4ae, 88%, 98% ee
4ab, 98%, 97% ee
4aa
(iii)
(ii)
O
N
NHTs
Ts
N
N
4ad, 81%, 98% ee
4ac, 88%, 98% ee (dr: 3.3:1)
Conditions: (i) Et3SiH (3 equiv), TsOH (2 equiv), DCE, 60 oC, 3 h. (ii) 2-methylfuran (3 equiv),
Bi(OTf)3 (10 mol %), THF, 60 oC, 10 h. (iii) TiCl4 (5 equiv), DMF, 80 oC, 10 h. (iv) TiCl4 (8
equiv), DMF, 80 oC, 30 h.
Cl
1) Na/Naphthalene
THF, -78 o
MeN
MeN
OTs
NaH, DMF, 80 o
C
Cl
6g
(98% ee)
N
2) formalin, NaBH3CN
AcOH, MeOH, RT
C
N
H
6gb
, 55%
6ga, 49%, 2 steps
inhibitor of histamine and
imidazoline receptor
Scheme 2. Gram scale reaction and synthetic applications.
selective methyl protection, and subsequent alkylation to
produce 6gb, a known inhibitor of histamine and imidazoline
receptor.[2a] Importantly, enantioselectivity was well maintained in
all cases, and excellent diastereoselectivity (d.r. > 50:1) was
achieved except for the case of the formation of 4ac.
To probe the reaction mechanism, we first performed
deuterium labelling studies [Eq. (6)]. It was found that no
deuterium was incorporated into the product 2e in the presence of
CuOTf as catalyst and H2O (5 equiv) as additive when starting
from the deuterium-labelled substrate 1e (88% D). However,
almost no deuterium loss was observed if employing
BrettPhosAuNTf2 as catalyst. Similarly, 63% deuterium
incorporation at C10 position was observed by using CuOTf as
catalyst and D2O (5 equiv) as additive. These results indicate that
the copper acetylide complex is presumably involved in such a
copper catalysis while the reaction is initiated through the direct π
activation of the alkyne in case of gold catalysis.[12] In addition, we
indeed detected the formation of the indolyl dihydropyrrole 2ea by
monitoring the cascade cyclization of 1e using NMR spectroscopy
under standard reaction conditions, but attempts to isolate 2ea in
the Cu-catalyzed reaction system failed. To our delight, the
Further transformations of the as-synthesized bridged aza-
[n.2.1] skeletons were also explored (Scheme 2). For example,
the formal synthesis of a reported 5-HT6 antagonist[2c] was
achieved in 62% yield (2 steps) starting from the corresponding
bridged heterocycle 2h by a facile deprotection of both sulfonyl
groups and selective Boc protection of nitrogen on the
bridgehead. In addition, the N–Bs group in 4a, which could be
prepared on a gram scale in 89% yield, was easily converted into
the corresponding N–Me group, affording the desired 4aa in 72%
yield (2 steps). 4aa could undergo facile ring-opening by Et3SiH
and 2-methylfuran to deliver the valuable indole-fused
cyclooctane 4ab and 4ac, respectively.[22] Moreover, 4aa could
also be selectively transformed into aza-[4.2.1] skeleton 4ad and
chlorinated aza-[4.2.1] skeleton 4ae in 81% and 88% yield,
respectively.[23,24] The molecular structure of 4ad was further
confirmed by X-ray diffraction (Figure 5).[20] Finally, it was found
that 6g could undergo deprotection of both sulfonyl groups,
o
cyclization of 1e catalyzed by Ag2CO3 (20 mol %) at 80 C could
only led to the formation of 2ea in 68% yield, and almost no
bridged heterocycle 2e was obtained.[17] As shown in Eq. (7), we
further found that 2ea could be readily converted into the desired
2e in the presence of copper or proton acid catalyst while low
efficiency was observed without catalyst. These results strongly
support the notion that 2ea is the key intermediate for this
cascade cyclization and copper catalyzes both an initial
hydroamination step and
a subsequent Friedel-Crafts-type
alkylation step. Considering that the Csp3-Cu bond is very difficult
to be protonated, proton generated from the reaction of copper
catalyst with trace water in the reaction system, that is the hidden
Brønsted acid,[25] is probably the real species promoting this
Friedel-Crafts alkylation process.
Figure 5. Structure of compound 4ad in its crystal.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
In summary, we have developed an unprecedented copper-
catalyzed anti-Markovnikov cycloisomerization-initiated tandem
reaction of readily available indolyl homopropargyl amides, where
the cheap and environmentally friendly copper catalyzes both the
hydroamination and Friedel−Crafts alkylation process. The
protocol allows the practical and atom-economical synthesis of
valuable bridged aza-[n.2.1] skeletons (n = 3–6) with wide
substrate scope, and excellent diastereoselectivity (d.r. > 50/1)
and enantioselectivity (95-99% ee) by a chirality-transfer strategy.
In addition, the synthetic usefulness of the bridged heterocycles is
demonstrated through the synthesis of an inhibitor of histamine
and imidazoline receptor and a key intermediate of a reported 5-
HT6 antagonist. Moreover, mechanistic studies revealed that the
copper acetylide complex is presumably involved in this copper-
catalyzed cascade cyclization, which is distinctively different from
the related gold catalysis. The development of novel non-noble
metal-catalyzed cascade cyclization reactions of alkynes for
heterocycle synthesis and mechanistic investigations are the
subjects of ongoing research in our laboratory.
Based on the above experimental observations and our
previous results,[12] a rationale for the formation of the bridged
heterocycle 2e is provided in Scheme 3. The reaction starts with
formation of the copper acetylide complex A, which distinguishes
this process from the related gold-catalyzed cyclization
reactions,[12,9a,9b] where the Lewis acid-type activation of the
starting alkyne is presumably involved. Intermediate A then
undergoes 5-endo-dig cyclization to afford the vinyl copper
intermediate C,[6a,26] probably involving the formation of σ,π-
bis(copper) acetylides B by the assistance of another CuOTf
serving as π acid.[27] Subsequent protodemetallation leads to
indolyl dihydropyrrole 2ea, which could be finally converted into
the corresponding product 2e through a Lewis acid or proton[8b]
catalyzed Friedel-Crafts alkylation. In the cases where 3-
Acknowledgements
We are grateful for the financial support from the National Natural
Science Foundation of China (21622204 and 21772161), the
President
Research
Funds
from
Xiamen
University
(20720180036), Science & Technology Cooperation Program of
Xiamen (3502Z20183015), PCSIRT and NFFTBS (J1310024).
We also thank Mr Zanbin Wei from Xiamen University for
assistance with X-ray crystallographic analysis.
substituted indole-tethered homopropargyl amides
5
are
employed, the described sequence presumably involves the
cyclization onto C3 position of indole moiety followed by
subsequent 1,2-migration.[5i] Finally, it is noted that the
stereospecificity of the reaction might be attributed to the fact that
the Friedel-Crafts type reaction operating is geometrically forced
to proceed with a chirality transfer, and the nature of the bicyclic
motifs obtained also accounts for the chiral induction.
Conflict of interest
The authors declare no conflict of interest.
Keywords: heterocycles · cyclizations · stereoselectivity · copper
catalysis · tandem reaction
[1] For selected reviews, see: a) G. P. Pollini, S. Benetti, C. D. Risi, V.
Zanirato, Chem. Rev. 2006, 106, 2434; b) A. J. Humphrey, D. O’Hagan,
Nat. Prod. Rep. 2001, 18, 494.
[2] For selected examples, see: a) S. Chakravarty, A. A. Protter, R. P. Jain, M.
J. Green, PCT Int. Appl. WO 2014031170A1, 2014; b) R. Narayan, J. O.
Bauer, C. Strohmann, A. P. Antonchick, H. Waldmann, Angew. Chem. Int.
Ed. 2013, 52, 12892; c) M. L. Isherwood, P. R. Guzzo, A. J. Henderson, M.
M. Hsia, J. Kaur, K. Nacro, V. R. Narreddula, S. Panduga, R. Pathak, B.
Shimpukade, V. Tan, K. Xiang, Z. Qiang, A. Ghosh, Tetrahedron:
Asymmetry 2012, 23, 1522; d) A. A. Protter, S. Chakravarty, PCT Int. Appl.
WO 2012112961A1, 2012; e) S. Chakravarty, B. P. Hart, R. P. Jain, PCT
Int. Appl. WO 2011103430A1, 2011; f) S. Chakravarty, B. P. Hart, R. P.
Jain, PCT Int. Appl. WO 20111044134A1, 2011.
[3] For recent examples, see: a) S. Harada, R. Kato, T. Nemoto, Adv. Synth.
Catal. 2016, 358, 3123; b) Q. Li, X. Jiang, C. Fu, S. Ma, Org. Lett. 2011,
13, 466; c) S. Xing, W. Pan, C. Liu, J. Ren, Z. Wang, Angew. Chem. Int.
Ed. 2010, 49, 3215; d) R. Grigg, A. Somasunderam, V. Sridharan, A.
Keep, Synlett 2009, 97; e) J.-H. Xu, S.-C. Zheng, J.-W. Zhang, X.-Y. Liu,
B. Tan, Angew. Chem. Int. Ed. 2016, 55, 11834; f) D. M. Schultz, J. P.
Wolfe, Org. Lett. 2011, 13, 2962.
[4] For recent selected reviews, see: a) R. Dorel, A. M. Echavarren, Chem.
Rev. 2015, 115, 9028; b) J. A. Goodwin, A. Aponick, Chem. Commun.
2015, 51, 8730; c) J. A. Palmes, A. Aponick, Synthesis 2012, 44, 3699; d)
F. Rodríguez, F. J. Fañanás, Synlett 2013, 24, 1757; e) W. Zhao, Chem.
Rev. 2010, 110, 1706; f) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev.
2008, 108, 3351; g) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180.
[5] For representative examples on the Au-catalyzed intramolecular
hydroarylation of alkynes, see: a) L. Zhang, Y. Wang, Z.-J. Yao, S. Wang,
Z.-X. Yu, J. Am. Chem. Soc. 2015, 137, 13290; b) D. Pflästerer, S.
Schumacher, M. Rudolph, A. S. K. Hashmi, Chem. Eur. J. 2015, 21,
11585; c) D. Pflästerer, E. Rettenmeier, S. Schneider, E. de Las Heras
Ruiz, M. Rudolph, A. S. K. Hashmi, Chem. Eur. J. 2014, 20, 6752; d) Z.
Scheme 3. Proposed mechanistic pathway.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
Dong, C.-H. Liu, Y. Wang, M. Lin, Z.-X. Yu, Angew. Chem. Int. Ed. 2013,
52, 14157; e) L. Huang, H.-B. Yang, D.-H. Zhang, Z. Zhang, X.-Y. Tang,
Q. Xu, M. Shi, Angew. Chem. Int. Ed. 2013, 52, 6767; f) L. Liu, L. Zhang,
Angew. Chem. Int. Ed. 2012, 51, 7301; g) C. Gronnier, Y. Odabachian, F.
Gagosz, Chem. Commun. 2011, 47, 218; h) D. B. England, A. Padwa,
Org. Lett. 2008, 10, 3631; i) C. Ferrer, C. H. M. Amijs, A. M. Echavarren,
Chem. Eur. J. 2007, 13, 1358; j) C. Ferrer, A. M. Echavarren, Angew.
Chem. Int. Ed. 2006, 45, 1105; for an Au-catalyzed intramolecular
hydroamination of alkynes, see: k) X.-Y. Liu, C.-M. Che, Angew. Chem.
Int. Ed. 2008, 47, 3805; for an Ag-catalyzed intramolecular
hydroamination of alkynes, see: l) X.-L. Yu, L. Kuang, S. Chen, X.-L. Zhu,
Z.-L. Li, B. Tan, X.-Y. Liu, ACS Catal. 2016, 6, 6182.
Zhou, X.-Q. Zhu, J.-Z. Yan, X. Lu, L.-W. Ye, Angew. Chem. Int. Ed. 2017,
56, 605; e) C. Shu, Y.-H. Wang, B. Zhou, X.-L. Li, Y.-F. Ping, X. Lu, L.-W.
Ye, J. Am. Chem. Soc. 2015, 137, 9567; f) L. Li, B. Zhou, Y.-H. Wang, C.
Shu, Y.-F. Pan, X. Lu, L.-W. Ye, Angew. Chem. Int. Ed. 2015, 54, 8245; g)
A.-H. Zhou, Q. He, C. Shu, Y.-F. Yu, S. Liu, T. Zhao, W. Zhang, X. Lu, L.-
W. Ye, Chem. Sci. 2015, 6, 1265.
[16] For recent Au- or Ag-catalyzed tandem reactions based on
homopropargyl amides or alcohols, see: a) T. Arto, F. J. Fañanás, F.
Rodríguez, Angew. Chem. Int. Ed. 2016, 55, 7218; b) S. Hosseyni, L.
ojtas, M. Li, X. Shi, J. Am. Chem. Soc. 2016, 138, 3994; c) S. Fustero, P.
Bello, J. Mirό, M. Sánchez-Rosellό, M. A. Maestro, J. González, C. del
Pozo, Chem. Commun. 2013, 49, 1336; d) S. Tong, C. Piemontesi, Q.
Wang, M.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2017, 56, 7958.
[17] For details, please see the Supporting Information (SI).
[18] For recent examples on the Ag-mediated cycloisomerization of
homopropargyl amides, see: a) H. M. Wisniewska, E. R. Jarvo, Chem. Sci.
2011, 2, 807; b) R. Martin, A. Jäger, M. Böhl, S. Richter, R. Fedorov, D. J.
Manstein, H. O. Gutzeit, H.-J. Knölker, Angew. Chem. Int. Ed. 2009, 48,
8042; for the relevant Ag-catalyzed synthesis of carbazoles, see: c) P.
Tharra, B. Baire, Org. Lett. 2018, 20, 1118; d) M. J. James, R. E. Clubley,
K. Y. Palate, T. J. Procter, A. C. Wyton, P. O’Brien, R. J. K. Taylor, W. P.
Unsworth, Org. Lett. 2015, 17, 4372.
[19] For preliminary studies of the Cu-catalyzed exo-hydroalkoxylation
reactions, see: N. T. Patil, V. S. Raut, R. D. Kavthe, V. V. N. Reddy, P. V.
K. Raju, Tetrahedron Lett. 2009, 50, 6576; for studies of the Cu-catalyzed
exo-hydroamination reactions, see refs 6c-6d.
[20] CCDC 1587212 (2h), 1872352 (6e) and 1872354 (4ad) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre.
[21] For the relevant Pt-catalyzed 5-endo-dig cyclization initiated tandem
reaction, see: S. Bhuvaneswari, M. Jeganmohan, C.-H. Cheng, Chem.
Eur. J. 2007, 13, 8285.
[6] For recent representative examples, see: a) Y. Kong, Y. Liu, B. Wang, S.
Li, L. Liu, W. Chang, J. Li, Adv. Synth. Catal. 2018, 360, 1240; b) H. K.
Wang, C. Wang, K. M. Huang, L. Y. Liu, W. X. Chang, J. Li, Org. Lett.
2016, 18, 2367; c) J. Han, B. Xu, G. B. Hammond, Org. Lett. 2011, 13,
3450; d) J. Han, B. Xu, G. B. Hammond, J. Am. Chem. Soc. 2010, 132,
916.
[7] For recent selected reviews, see: a) Z. Zheng, Z. Wang, Y. Wang, L.
Zhang, Chem. Soc. Rev. 2016, 45, 4448; b) C. M. R. Volla, I. Atodiresei,
M. Rueping, Chem. Rev. 2014, 114, 2390; c) X. Zeng, Chem. Rev. 2013,
113, 6864; d) H. Pellissier, Chem. Rev. 2013, 113, 442.; e) L.-Q. Lu, J.-R.
Chen, W.-J. Xiao, Acc. Chem. Res. 2012, 45, 1278; f) C. Grondal, M.
Jeanty, D. Enders, Nat. Chem. 2010, 2, 167.
[8]
a) S. Antoniotti, E. Genin, V. Michelet, J.-P. Genẽt, J. Am. Chem. Soc.
2005, 127, 9976; b) A. Diéguez-Vázquez, C. C. Tzschucke, W. Y. Lam,
S. V. Ley, Angew. Chem. Int. Ed. 2008, 47, 209.
[9]
a) J. Barluenga, A. Diéguez, A. Fernández, F. Rodríguez, F. J. Fañanás,
Angew. Chem. Int. Ed. 2006, 45, 2091; b) J. Barluenga, A. Fernández, A.
Diéguez, F. Rodríguez, F. J. Fañanás, Chem. Eur. J. 2009, 15, 11660; c)
J. Barluenga, A. Fernández, A. Satrústegui, A. Diéguez, F. Rodríguez, F.
J. Fañanás, Chem. Eur. J. 2008, 14, 4153; d) F. J. Fañanás, A.
Fernández, D. Ҫevic, F. Rodríguez, J. Org. Chem. 2009, 74, 932; for a
Brønsted acid catalysed double intramolecular Michael addition, see: e)
A. Mendoza, P. Pardo, F. Rodríguez, F. J. Fañanás, Chem. Eur. J. 2010,
16, 9758.
[22] The cycloocta[b]indole skeleton can be found in various natural products
and bioactive molecules, see: C. Zhu, X. Zhang, X. Lian, S. Ma, Angew.
Chem. Int. Ed. 2012, 51, 7817.
[23] For a plausible mechanism for the formation of 4ad and 4ae, see below:
[10] a) S. Bhunia, K.-C. Wang, R.-S. Liu, Angew. Chem. Int. Ed. 2008, 47,
5063; b) J. K. Vandavasi, W.-P. Hu, S. S. K. Boominathan, B.-C. Guo,
C.-T. Hsiao, J.-J. Wang, Chem. Commun. 2015, 51, 12435.
[11] J. Fu, Y. Gu, H. Yuan, T. Luo, S. Liu, Y. Lan, J. Gong, Z. Yang, Nat.
Commun. 2015, 6, 8617.
[12] a) C. Shu, M.-Q. Liu, Y.-Z. Sun, L.-W. Ye, Org. Lett. 2012, 14, 4958; b) C.
Shu, M.-Q. Liu, S.-S. Wang, L. Li, L.-W. Ye, J. Org. Chem. 2013, 78, 3292;
c) Y.-F. Yu, C. Shu, B. Zhou, J.-Q. Li, J.-M. Zhou, L.-W. Ye, Chem.
Commun. 2015, 51, 2126; d) C. Shu, L. Li, C.-H. Shen, P.-P. Ruan, C.-Y.
Liu, L.-W. Ye, Chem. Eur. J. 2016, 22, 2282; e) Y.-F. Yu, C. Shu, T.-D.
Tan, L. Li, S. Rafique, L.-W. Ye, Org. Lett. 2016, 18, 5178; f) C. Shu, L. Li,
T.-D. Tan, D.-Q. Yuan, L.-W. Ye, Sci. Bull. 2017, 62, 352.
[13] For an Au-catalyzed intermolecular reaction of dihydropyrroles with
indoles, see: R. Ali, G. Singh, S. Singh, R. S. Ampapathi, W. Haq, Org.
Lett. 2016, 18, 2848.
[14] Similar indolyl dihydropyrroles did not undergo further cyclization under
Au catalysis, see: N. Gouault, M. Le Roch, C. Cornée, M. David, P. Uriac,
J. Org. Chem. 2009, 74, 5614.
[15] For catalytic cascade cyclization reactions based on ynamides by our
group, see: a) L. Li, X.-Q. Zhu, Y.-Q. Zhang, H.-Z. Bu, P. Yuan, J. Chen, J.
Su, X. Deng, L.-W. Ye, Chem. Sci. 2019, 10, 3123; b) W.-B. Shen, Q. Sun,
L. Li, X. Liu, B. Zhou, J.-Z. Yan, X. Lu, L.-W. Ye, Nat. Commun. 2017, 8,
1748; c) B. Zhou, L. Li, X.-Q. Zhu, J.-Z. Yan, Y.-L. Guo, L.-W. Ye, Angew.
Chem. Int. Ed. 2017, 56, 4015; d) W.-B. Shen, X.-Y. Xiao, Q. Sun, B.
[24] a) G. Srinivas, M. Periasamy, Tetrahedron Lett. 2002, 43, 2785; b) S.-i.
Inaba, I. Ojima, Tetrahedron Lett. 1977, 23, 2009.
[25] For selected examples on hidden Brønsted acid catalysis, see: a) J. Chen,
S. K. Goforth, B. A. McKeown, T. B. Gunnoe, Dalton Trans. 2017, 46,
2884; b) R. K. Schmidt, K. Müther, C. Mück-Lichtenfeld, S. Grimme, M.
Oestreich, J. Am. Chem. Soc. 2012, 134, 4421; c) T. T. Dang, F. Boeck, L.
Hintermann, J. Org. Chem. 2011, 76, 9353.
[26] The reaction pathway for the formation of intermediate B by alkyne
insertion into a Cu-alkoxide bond can not be excluded, see: M. J. Pouy, S.
A. Delp, J. Uddin, V. M. Ramdeen, N. A. Cochrane, G. C. Fortman, T. B.
Gunnoe, T. R. Cundari, M. Sabat, W. H. Myers, ACS Catal. 2012, 2, 2182.
[27] B. T. Worrell, J. A. Malik, V. V. Fokin, Science, 2013, 340, 457.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.201904698
Angewandte Chemie International Edition
Cyclizations
Tong-De Tan, Xin-Qi Zhu, Hao-Zhen
Bu, Guocheng Deng, Yang-Bo Chen,
Rai-Shung Liu, and Long-Wu Ye*
Page – Page
Copper-catalyzed
Cascade
Cyclization of Indolyl Homopropargyl
Amides: Stereospecific Construction
of Bridged Aza-[n.2.1] Skeletons
An unprecedented copper-catalyzed endo-cyclization-initiated tandem reaction of
indolyl homopropargyl amides is achieved, where copper catalyzes both the
hydroamination and Friedel−Crafts alkylation process. This method allows the
practical and atom-economical synthesis of valuable bridged aza-[n.2.1] skeletons
(n = 3–6) with wide substrate scope, and excellent diastereoselectivity and
enantioselectivity by a chirality-transfer strategy.
8
This article is protected by copyright. All rights reserved.