Copper-Catalyzed Azide–Ynamide Cyclization to Generate α-Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N-Heterocycles

Article abstract of DOI:10.1002/anie.202007206

Here an efficient copper-catalyzed cascade cyclization of azide-ynamides via α-imino copper carbene intermediates is reported, representing the first generation of α-imino copper carbenes from alkynes. This protocol enables the practical and divergent synthesis of an array of polycyclic N-heterocycles in generally good to excellent yields with broad substrate scope and excellent diastereoselectivities. Moreover, an asymmetric azide–ynamide cyclization has been achieved with high enantioselectivities (up to 98:2 e.r.) by employing BOX-Cu complexes as chiral catalysts. Thus, this protocol constitutes the first example of an asymmetric azide–alkyne cyclization. The proposed mechanistic rationale for this cascade cyclization is further supported by theoretical calculations.

Full text of DOI:10.1002/anie.202007206

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Copper-Catalyzed Azide-Ynamide Cyclization for Generation
of α-Imino Copper Carbenes: Divergent and Enantioselective
Access to Polycyclic N-Heterocycles
Authors: Longwu Ye, Xin Liu, Ze-Shu Wang, Tong-Yi Zhai, Chen Luo,
Yi-Ping Zhang, Yang-Bo Chen, Chao Deng, and Rai-Shung
Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007206
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10.1002/anie.202007206
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Asymmetric Catalysis
Copper-Catalyzed Azide-Ynamide Cyclization for Generation of α-Imino
Copper Carbenes: Divergent and Enantioselective Access to Polycyclic
N-Heterocycles
Xin Liu, Ze-Shu Wang, Tong-Yi Zhai, Chen Luo, Yi-Ping Zhang, Yang-Bo Chen, Chao Deng,* Rai-Shung
Liu, and Long-Wu Ye*
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
acetylenic Schmidt reaction of homopropargyl azides,[7] which
Abstract: Here an efficient copper-catalyzed cascade cyclization of
azide-ynamides via α-imino copper carbene intermediates is reported,
which represents the first generation of α-imino copper carbenes from
alkynes. This protocol enables the practical and divergent synthesis
of an array of polycyclic N-heterocycles in generally good to excellent
yields with broad substrate scope and excellent diastereoselectivities.
Moreover, such an asymmetric azide-ynamide cyclization has been
achieved with high enantioselectivities (up to 98:2 e.r.) by employing
BOX-Cu complexes as chiral catalysts. Thus, this protocol constitutes
the first example of asymmetric azide-alkyne cyclization. The
proposed mechanistic rationale for this cascade cyclization is further
supported by theoretical calculations.
represents the first example of azide-alkyne cascade cyclization
via α-imino metal carbenes. Following this concept, gold-
catalyzed cascade cyclizations of azide-alkynes have been
extensively exploited over the past decade by Zhang,[8] Gagosz,[9]
Ohno,[10] and others.[11,12] Despite these significant achievements,
these cyclizations have so far been limited to the noble-metal
catalysts. Furthermore, no catalytic asymmetric azide-alkyne
cyclizations have been reported to the best of our knowledge.
Notably, the generation of α-imino rhodium carbenes from 1,2,3-
triazoles, which are formed by copper-catalyzed cycloaddition of
alkynes with azides, has also been vigorously explored, but only
aldimine carbenes can be accessed by this strategy.[12c]
Introduction
The generation of α-imino metal carbenes from readily
available alkynes via nitrene transfer pathways represents a
significant advance in metal carbene chemistry,[1-6] providing rapid
access into structurally complex nitrogen-containing molecules,
especially the diverse nitrogen heterocycles. As a result, various
efficient synthetic methods have been established mainly based
on the use of azides,[2] isoxazoles,[3] pyridine aza-ylides[4] and
sulfur aza-ylides[5] as nitrene transfer reagents. Among these,
catalytic azide-alkyne cyclization via α-imino metal carbenes is
particularly attractive,[2] because this approach allows the efficient
and rapid assembly of valuable N-heterocycles in a more flexible
and atom-economic way (Scheme 1a).[7-12] In 2005, Toste and co-
workers disclosed an elegant protocol for the gold-catalyzed
[]
X. Liu, Z.-S. Wang, T.-Y. Zhai, C. Luo, Y.-P. Zhang, Y.-B. Chen, Prof.
Dr. L.-W. Ye
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory of Chemical Biology of Fujian Province, and College of
Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China
Scheme 1. Generation of α-imino metal carbenes from azide-alkyne cyclization.
E-mail: longwuye@xmu.edu.cn
Prof. Dr. C. Deng
Jiangsu Key Laboratory of Pesticide Science and Department of
Chemistry, College of Sciences, Nanjing Agricultural University,
Nanjing 210095, China
As a continuation of our work on developing ynamide
chemistry for heterocycle synthesis,[13,14,3k,l,11d,12] we herein report
an efficient copper-catalyzed cascade cyclization of azide-
ynamides via α-imino copper carbene intermediates (Scheme 1b),
which represents the first generation of α-imino copper carbenes
from alkynes.[15] This protocol enables the practical and divergent
synthesis of an array of polycyclic N-heterocycles in generally
good to excellent yields with broad substrate scope. Moreover,
such an asymmetric azide-ynamide cyclization has been
achieved with high enantioselectivities (up to 98:2 e.r.) by the use
of bisoxazoline–copper (BOX–Cu) complexes as chiral catalysts,
thus constituting the first example of asymmetric azide-alkyne
E-mail: chaodeng@njau.edu.cn
Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University,
Hsinchu, Taiwan 30013, Republic of China
Prof. Dr. L.-W. Ye
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
1
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10.1002/anie.202007206
Angewandte Chemie International Edition
cyclization. In this article, we wish to report the results of our
detailed investigations of this copper-catalyzed azide-ynamide
cyclization, including substrate scope, synthetic applications, and
mechanistic studies.
at 60 oC (entry 11) or in other solvents such as toluene and PhCl
(entries 12 and 13). The reaction failed to give even a trace of 2a
in the absence of the catalyst, and isoquinoline 2a
obtained in 62% yield (entry 14). Finally, it should be mentioned
that no triazole formation via azide−ynamide cycloaddition was
observed in all cases.[17] Especially, no triazole formation was
detected even when ynamide 1a was subjected to Huang's
reaction conditions.[16,17] Instead, 2a was formed in 49% yield.
With the optimal reaction conditions in hand (Table 1, entry
5), the scope of this copper-catalyzed cascade cyclization was
then explored, as summarized in Table 2. Initially, different N-
protecting groups of the ynamides were investigated and the
reaction could proceed smoothly with Ts-, Bs-, Ns-, SO2Ph- and
Ms-protected (azido)ynamides 1, affording the desired tetracyclic
heterocycles 2a–2e in 63–83% yields. In addition, various aryl-
substituted benzyl-tethered (azido)ynamides bearing both
electron-withdrawing and electron-donating groups were well
tolerated in this reaction, leading to the corresponding
cyclopropanation products 2f–2m in generally good yields. The
reaction was also extended to the thienyl- and furanyl-substituted
(azido)ynamides to furnish 2n and 2o in 76% and 67% yields,
respectively. Different substituents such as F, Cl, Br, Me, and
OMe on the phenyl ring were also examined and the expected
products 2p–2v could be formed in 63–88% yields. Interestingly,
the reaction was also viable for the construction of piperidine-
fused tetracyclic heterocycle 2w in 71% yield. Moreover, methyl-,
ethyl- and even dimethyl-substituted N- allyl (azido)ynamides
Results and Discussion
The N-styryl benzyl-tethered (azido)ynamide 1a was chosen
as the model substrate to optimize the reaction conditions, and
selected results are listed in Table 1.[16] Based on our previous
work on the Cu(I)-catalyzed cascade cyclization of ynamides,[14a,c]
the Cu(I) catalysts were first investigated. To our delight, the
desired tetracyclic heterocycle product 2a could be obtained in
18% yield by employing 10 mol % of CuOTf as catalyst in DCE at
80 oC, albeit together with a significant amount of undesired
isoquinoline product 2a (entry 1). We then examined other Cu(I)
catalysts
(entries 2–5) and were delighted to find that
Cu(CH3CN)4BF4 gave the best result, affording the desired
product 2a in 86% yield (entry 5). Of note, the use of Cu(OTf)2 as
catalyst led to a significantly decreased yield (entry 6). Other
Lewis acids such as Zn(OTf)2 and Sc(OTf)3 and Brønsted acids
such as CF3CO2H and MsOH were investigated as well, but the
isoquinoline 2a was formed as main product(entries 7–10). In
addition, the reaction proved to be less efficient when performed
Table 1. Optimization of reaction conditions for the cascade cyclization of N-
styryl (azido)ynamide 1a.[a]
Table 2. Reaction scope of the cascade cyclization of N-allyl (azido)ynamides
1.[a]
Entry Catalyst
Reaction conditions Yield [%][b]
1
Cu(OTf)
CuI
DCE, 80 oC, 4 h
DCE, 80 oC, 4 h
DCE, 80 oC, 4 h
18 (54)
21 (50)
74 (8)
2
3
CuCl
4
Cu(CH3CN)4PF6 DCE, 80 oC, 4 h
82 (5)
5
Cu(CH3CN)4BF4 DCE, 80 oC, 4 h
86 (<5)
32 (30)
<1 (67)
<1 (71)
<1 (55)
10 (78)
75 (7)
6
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
CF3CO2H
MsOH
DCE, 80 oC, 16 h
DCE, 80 oC, 3 h
DCE, 80 oC, 3 h
DCE, 80 oC, 2 h
DCE, 80 oC, 2 h
7
8
9
10
11
12
13
14
Cu(CH3CN)4BF4 DCE, 60 oC, 27 h
Cu(CH3CN)4BF4 toluene, 80 oC, 6 h
Cu(CH3CN)4BF4 PhCl, 80 oC, 5 h
25 (35)
41 (24)
<1 (62)
none
DCE, 80 oC, 5 h
[a] Reaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol),
o
o
[a] Reaction conditions: 1 (0.2 mmol), Cu(CH3CN)4BF4 (0.02
mmol), DCE (4 mL), 80 oC, 4 h, in vials; isolated yields are
reported. PG = protecting group, Bs = 4-bromobenzenesulfonyl,
Ns = 4-nitrobenzenesulfonyl.
solvent (2 mL), 60 C to 80 C, 2-27 h, in vials. [b] Measured by
1H NMR using 2,6-dimethoxytoluene as the internal standard. The
yield of 2a given within parentheses. DCE = 1,2-dichloroethane,
Tf = trifluoromethanesulfonyl.
2
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10.1002/anie.202007206
Angewandte Chemie International Edition
were also suitable substrates for this cascade cyclization,
delivering products 2x–2z in 69–86% yields. Of note, excellent
diastereoselectivities (d.r. > 20/1) were achieved in all cases. The
molecular structure of 2k was confirmed by X-ray diffraction.[18]
In addition to N-allyl benzyl-tethered (azido)ynamides, this
copper-catalyzed cascade cyclization also occurred efficiently
with N-propargyl benzyl-tethered (azido)ynamides[11d,14c,19] at
room temperature by employing 10 mol % of Cu(CH3CN)4PF6 as
catalyst and 2 equiv of DDQ as oxidant,[16] thus allowing the
synthesis of 3H-pyrrolo[2,3-c]isoquinolines 4. Notably, the
background formation of pyrrole-fused indenes via C−H insertion
into copper carbenes was not detected.[14c] As shown in Table 3,
initial investigation of N-protecting groups of the ynamides 3
demonstrated that the reaction could proceed smoothly with
different sulfonyl groups, affording the desired tricyclic
heterocycles 4a–4d in 58–80% yields. In addition, a series of
different aryl-substituted N-propargyl (azido)ynamides were also
examined, and the corresponding pyrrole-fused isoquinoline
products 4e–4n were formed in 70–94% yields. Moreover,
thienyl- and methyl-substituted N-propargyl (azido)ynamides were
readily tolerated to produce the desired products 4o and 4p in
72% and 66% yields, respectively. This cascade cyclization also
occurred efficiently for various phenyl rings bearing both electron-
withdrawing and -donating groups, and products 4q–4u were
obtained in 78–91% yields. The molecular structure of 4m was
confirmed by X-ray diffraction.[18] Thus, this cascade cyclization
provides a highly convenient and practical route for preparation of
useful 3H-pyrrolo[2,3-c]isoquinolines.[20]
Besides intramolecular trapping of the presumable α-imino
copper carbenes by the alkene and alkyne moieties, this copper-
catalyzed tandem reaction could also be applicable to
intermolecular trapping by olefins. As shown in Eq. (1), the
o
treatment of azide-ynamides 5 with 10 equiv of styrene at 60 C
by employing 10 mol % of Cu(CH3CN)4BF4 as catalyst led to the
efficient formation of spiro-cyclopropane products 6a–6b in 76–
80% yields with excellent diastereoselectivities (d.r. > 20/1).
Importantly, this result further supports that the α-imino copper
carbene intermediate is involved in this cascade cyclization. The
molecular structure of 6a was confirmed by X-ray diffraction.[18] It
is notable that no intramolecular ortho-aryl C–H insertion was
observed, and in particular, this insertion product was not
detected even in the absence of styrene.[16]
After establishing a general and reliable method for this
copper-catalyzed tandem reaction of azide-ynamides, we focused
on the development of a chiral copper complex-catalyzed
enantioselective version. That is, the catalytic asymmetric
cascade cyclization of N-allyl (azido)ynamides 1 may lead to the
synthesis of chiral cyclopropanation products 2 with three
contiguous stereocenters. Although the use of chiral phosphine
ligands failed to give the satisfactory enantioselectivity, high
enantioselectivity could be achieved by employing chiral BOX
ligands, as summarized in Table 4. In the presence of 10 mol %
of Cu(CH3CN)4PF6 and 12 mol % of BOX ligand L1 in DCE at
50oC, the cascade cyclization of (azido)ynamide 1a could afford
the desired chiral cyclopropanation product (-)-2a in 63% yield
with the e.r. of 77:23 (entry 1). Other typical BOX ligands L2−L4
Table 3. Reaction scope of the cascade cyclization of N-propargyl
(azido)ynamides 3.[a]
were
then
examined,
but
no
significant
improved
enantioselectivity was achieved (entries 2–4). To our delight,
increasing the steric hindrance of the ligands had a significant
improvement on the enantioselectivities of product (-)-2a (entries
5–9), and an e.r. of 90.5:9.5 was achieved by using L7 as chiral
ligand (entry 7).[21] Other solvents such as DCM and CHCl3 were
also investigated, but failed to improve the enantioselectivity
(entries 10 and 11). The use of NaBArF4 (12 mol %) as additive or
Cu(CH3CN)4BF4 (10 mol %) as catalyst led to slightly decreased
enantioselectivities (entries 12 and 13). Gratifyingly, the yield
could be improved to 85% by increasing the loading of copper
complex, and the e.r. was almost unchanged (entry 14).
The scope of this asymmetric cascade cyclization was next
examined under the optimal reaction conditions (Table 4, entry
14). As depicted in Table 5, this asymmetric cyclization was also
viable for the construction of chiral piperidine-fused tetracyclic
heterocycle (-)-2w in 51% yield with the e.r. of 96:4. Different alkyl
substituents at the terminal alkene moiety were then investigated.
To our delight, the methyl- and ethyl-substituted (azido)ynamides
led to a significantly improved enantioselectivities, affording the
desired chiral tetracyclic heterocycle product (-)-2x (65%, e.r. of
95.5:4.5) and (-)-2y (68%, e.r. of 96.5:3.5), respectively. The
reaction also proceeded smoothly with other substrates such as
i
nPr-, Pr-, nBu- and Cy-substituted (azido)ynamides to produce
thedesired products (-)-2aa–(-)-2ad in 57–68% yields with the e.r.
of 90:10–93:7. Of note, terminal alkene substituted
(azido)ynamide was also suitable substrate to deliver the
corresponding product (-)-2ae in 41% yield and e.r. of 90:10.
Considering that the methyl substituted substrates could be
prepared from readily available crotyl alcohol, we chose this kind
[a] Reaction conditions:
3 (0.2 mmol), DDQ (0.4 mmol),
Cu(CH3CN)4PF6 (0.02 mmol), DCE (4 mL), RT, 5 h, in vials;
isolated yields are reported. DDQ = 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone.
3
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10.1002/anie.202007206
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Table 4. Optimization of reaction conditions for the asymmetric cascade
cyclization of N-styryl (azido)ynamide 1a.[a]
employing BOX ligand L7 with opposite configuration, the
reaction also occurred smoothly to produce the desired (+)-2x in
67% yield and e.r. of 4:96 with the opposite enantioselectivity.
Once again, excellent diastereoselectivities (d.r. > 20/1) were
achieved in all cases. Attempts to expand this asymmetric
catalysis to an intermolecular reaction with styrene have been
unsuccessful as yet.
Table 5. Reaction scope of the asymmetric cascade cyclization of N-allyl
(azido)ynamides 1.[a]
Entry
1
L
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
CHCl3
DCE
DCE
DCE
Yield [%][b]
E.r.[c]
L1
L2
L3
L4
L5
L6
L7
L8
L9
L7
L7
L7
L7
L7
63
67
62
25
44
57
56
32
55
60
65
59
65
85
77:23
77.5:22.5
79:21
73:27
86:14
89:11
90.5:9.5
84:16
88:12
87:13
62:38
88.5:11.5
85:15
91:9
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
14[f]
[a] Reaction conditions: 1a (0.05 mmol), Cu(CH3CN)4PF6 (0.005
mmol), L (0.006 mmol), DCE (1 mL), 50 oC, 72 h, in Schlenk
1
tubes. [b] Measured by H NMR using 2,6-dimethoxytoluene as
the internal standard. [c] Determined by HPLC analysis. [d]
NaBArF (12 mol %) was employed as additive. [e]
4
[a] Reaction conditions: 1 (0.1 mmol), Cu(CH3CN)4PF6 (0.015
mmol), L7 (0.018 mmol), DCE (1 mL), 50 °C, 72 h, in Schlenk
tubes; isolated yields are reported; e.r.’s are determined by HPLC
analysis. [b] Cu(CH3CN)4PF6 (20 mol %), L7 (24 mol %). [c] L7
with opposite configuration was employed as chiral ligand. MBS =
4-methoxybenzenesulfonyl.
Cu(CH3CN)4BF4 (0.005 mmol) was used as catalyst. [f]
Cu(CH3CN)4PF6 (15 mol %), L7 (18 mol %). NaBArF = sodium
4
tetrakis[3,5-bis(trifluoromethyl)phenyl] borate.
of substrates for further reaction scope studies. Then, a wide
array of (azido)ynamides bearing electron-withdrawing and -
donating substituents at different positions of the phenyl group
could be smoothly transformed into the expected chiral products
(-)-2af–(-)-2ap in moderate to good yields (58–75%) and high
enantioselectivities (e.r. of 94:6–98:2). Besides the Ts-protected
ynamide 1a, (azido)ynamides bearing various N-protected groups
such as Bs-, MBS- and SO2Ph were also tolerated, and the
desired products (-)-2aq (72%, e.r. of 95:5), (-)-2ar (49%, e.r. of
98:2), (-)-2as (50%, e.r. of 97:3) were obtained, respectively. By
Further synthetic transformations of the as-synthesized
polycyclic N-heterocycles were then explored (Scheme 2). First, a
gram-scale reaction of 1.11 g of (azido)ynamide 1a was carried
out under standard conditions, and 0.79 g of the desired product
2a was furnished in 76% yield, demonstrating the reliability of the
protocol. Then, facile deprotection of 2a by LiAlH4 in MTBE
(methyl t-butyl ether) led to the formation of the desired product
2at in 86% yield. Of note, some compounds bearing this core
4
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10.1002/anie.202007206
Angewandte Chemie International Edition
structure have been demonstrated as potent DNA alkylating
agents.[22,23] Interestingly, the treatment of 2a with NBS could led
to diastereoselective ring opening to form the brominated
isoquinoline 2au in 85% yield (d.r. > 20/1).[10c] Subsequent β-
elimination under basic conditions delivered the final tricyclic
isoquinoline 2av bearing exclusive Z configuration of the double
bond in 62% yield, and its structure was confirmed by X-ray
diffraction.[18] In addition, Suzuki coupling of chiral (-)-2ah with
arylboronic acid produced the corresponding product (-)-2aw in
89% yield with well-maintained enantioselectivity. The molecular
absolute configuration of (-)-2aw was confirmed by X-ray
diffraction analysis,[18] which also determined the absolute
configuration of the above chiral tetracyclic products (-)-2. Finally,
some derivatizations of the tricyclic heterocycle 4a were also
carried out. The treatment of 4a, also synthesized on a gram
scale in 73% yield, with KOH and phosphorus ylide could afford
the corresponding deprotection product 4aa in 88% yield and
alkenylation product 4ab in 71% yield, respectively.
product 2a and regenerate the copper catalyst. Of note, the
activation barrier for the trans-isomer is higher than the desired
cis-isomer by 6.3 kcal/mol. In the case of N-propargyl
(azido)ynamide 3a, intermediate C would be trapped by the N-
propargyl group, leading to the formation of the vinyl cation
intermediate E, which can be converted into the
thermodynamically favorable cyclopropene intermediate F.
Subsequent ring opening of cyclopropene intermediate F by trace
water
in
the
reaction
system,
followed
by
tautomerism/dehydrogenative oxidation[11d] furnishes the final
product 4a. In the cases where chiral copper complexes are
employed, the reaction undergoes asymmetric cyclopropanation
with high stereoselectivity to eventually furnish the chiral
tetracyclic N-heterocycles 2. Finally, it is notable that the reaction
pathway involving the triazole formation via azide-alkyne
cycloaddition[17] is less likely as the reaction would not afford the
desired products by this way.[16]
Scheme 3. Plausible reaction mechanism. The relative free energies are given
in kcal/mol.
Conclusions
In summary, we have developed an efficient copper-
catalyzed cascade cyclization of azide-ynamides via α-imino
copper carbene intermediates, which represents the first
generation of α-imino copper carbenes directly from alkynes. This
protocol enables the practical and divergent synthesis of an array
of polycyclic N-heterocycles in generally good to excellent yields
with broad substrate scope and excellent diastereoselectivities.
Moreover, such an asymmetric azide-ynamide cyclization has
been achieved with high enantioselectivities (up to 98:2 e.r.) by
employing BOX-Cu complexes as chiral catalysts. Thus, this
protocol constitutes the first example of asymmetric azide-alkyne
cyclization. It is worth noting that this process begins from an
acyclic precursor with no stereocenters and assembles a new
tricyclic backbone containing three new stereocenters with high
stereospecificity in one step under mild conditions. In addition, the
proposed mechanistic rationale for this cascade cyclization is also
strongly supported by theoretical calculations.
Scheme 2. Gram-scale reaction and synthetic transformations.
On the basis of the above experimental results, previous
protocols on the azide-alkyne cyclization[2,12] and density
functional theory (DFT) calculations, a plausible mechanism for
the synthesis of polycyclic N-heterocycles 2a and 4a is depicted
in Scheme 3. Initially, intramolecular nucleophilic attack of azido
group to the copper-activated ynamide moiety via the six-
membered ring transition state TS-B affords the vinyl copper
intermediate B, followed by elimination of N2, generating the α-
imino copper carbene intermediate C. This copper carbene
species is likely highly electrophilic,[24] and can be further trapped
by different nucleophilic moieties. In the case of N-allyl
(azido)ynamide 1a as substrate, intramolecular highly
diastereoselective cyclopropanation occurs to deliver the desired
Acknowledgements
5
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10.1002/anie.202007206
Angewandte Chemie International Edition
Ballesteros, Adv. Synth. Catal. 2019, 361, 758; h) J. González, J.
Santamaría, A. L. Suárez-Sobrino, A. Ballesteros, Adv. Synth. Catal. 2016,
358, 1398.
We are grateful for financial support from the NNSFC (21772161
and 21622204), the NSFFJ (2019J02001), the President
Research Funds from Xiamen University (20720180036), the
Fundamental Research Funds for the Central Universities
(20720202008), NFFTBS (J1310024), PCSIRT, the Science &
Technology Cooperation Program of Xiamen (3502Z20183015),
the Opening Project of PCOSS, Xiamen University (201909), the
Bioinformatics Center of Nanjing Agricultural University and the
Start-up Research Fund of Nanjing Agricultural University (050-
804099). We also thank Mr. Zanbin Wei from Xiamen University
for assistance with X-ray crystallographic analysis.
[7] D. J. Gorin, N. R. Davis, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 11260.
[8] a) N. Li, T.-Y. Wang, L.-Z. Gong, L. Zhang, Chem. Eur. J. 2015, 21, 3585;
b) Z.-Y. Yan, Y. Xiao, L. Zhang, Angew. Chem. Int. Ed. 2012, 51, 8624; c)
Y. Xiao, L. Zhang, Org. Lett. 2012, 14, 4662; d) B. Lu, Y. Luo, L. Liu, L. Ye,
Y. Wang, L. Zhang, Angew. Chem. Int. Ed. 2011, 50, 8358;
[9] a) G. H. Lonca, C. Tejo, H. L. Chan, S. Chiba, F. Gagosz, Chem.
Commun. 2017, 53, 736; b) C. Gronnier, G. Boissonnat, F. Gagosz, Org.
Lett. 2013, 15, 4234; c) A. Wetzel, F. Gagosz, Angew. Chem. Int. Ed.
2011, 50, 7354; for the relevant use of 2H-azirines as nitrene transfer
reagents, see: d) A. Prechter, G. Henrion, P. F. dit Bel, F. Gagosz, Angew.
Chem. Int. Ed. 2014, 53, 4959.
[10] a) Y. Kawada, S. Ohmura, M. Kobayashi, W. Nojo, M. Kondo, Y. Matsuda,
J. Matsuoka, S. Inuki, S. Oishi, C. Wang, T. Saito, M. Uchiyama, T.
Suzuki, H. Ohno, Chem. Sci. 2018, 9, 8416; b) J. Matsuoka, Y. Matsuda,
Y. Kawada, S. Oishi, H. Ohno, Angew. Chem. Int. Ed. 2017, 56, 7444; c)
Y. Tokimizu, S. Oishi, N. Fujii, H. Ohno, Org. Lett. 2014, 16, 3138.
[11] For selected examples, see: a) X. Wu, L.-L. Zheng, L.-P. Zhao, C.-F. Zhu,
Y.-G. Li, Chem. Commun. 2019, 55, 14769; b) H. Su, M. Bao, C. Pei, W.
Hu, L. Qiu, X. Xu, Org. Chem. Front. 2019, 6, 2404; c) J. Cai, B. Wu, G.
Rong, C. Zhang, L. Qiu, X. Xu, Org. Lett. 2018, 20, 2733; d) W.-B. Shen,
Q. Sun, L. Li, X. Liu, B. Zhou, J.-Z. Yan, X. Lu, L.-W. Ye, Nat. Commun.
2017, 8, 1748; e) N. Li, X.-L. Lian, Y.-H. Li, T.-Y. Wang, Z.-Y. Han, L.
Zhang, L.-Z. Gong, Org. Lett. 2016, 18, 4178; f) S. K. Pawar, R. L. Sahani,
R.-S. Liu, Chem. Eur. J. 2015, 21, 10843; g) L. Zhu, Y. Yu, Z. Mao, X.
Huang, Org. Lett. 2015, 17, 30; for an Ag-catalyzed cyclization of azide-
tethered electron-deficient alkynes, see: h) H. Su, M. Bao, J. Huang, L.
Qiu, X. Xu, Adv. Synth. Catal. 2019, 361, 826.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · metal carbene · alkynes •
cyclization · heterocycles
[12] For gold-catalyzed intermolecular reaction of azides with ynamides via α-
imino gold carbenes, see: a) C. Shu, C.-H. Shen, Y.-H. Wang, L. Li, T. Li,
X. Lu, L.-W. Ye, Org. Lett. 2016, 18, 4630; b) C. Shu, Y.-H. Wang, C.-H.
Shen, P.-P. Ruan, X. Lu, L.-W. Ye, Org. Lett. 2016, 18, 3254; c) 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.
[1] For recent selected reviews on the generation of metal carbenes from
alkynes, see: a) L. Chen, K. Chen, S. Zhu, Chem 2018, 4, 1208; b) W. Zi,
F. D. Toste, Chem. Soc. Rev. 2016, 45, 4567; c) R. J. Harris, R. A.
Widenhoefer, Chem. Soc. Rev. 2016, 45, 4533; d) Z. Zheng, Z. Wang, Y.
Wang, L. Zhang, Chem. Soc. Rev. 2016, 45, 4448; e) M. Jia, S. Ma,
Angew. Chem. Int. Ed. 2016, 55, 9134; f) R. Dorel, A. M. Echavarren,
Chem. Rev. 2015, 115, 9028; g) Y. Wang, M. E. Muratore, A. M.
Echavarren, Chem. Eur. J. 2015, 21, 7332; h) D. Qian, J. Zhang, Chem.
Soc. Rev. 2015, 44, 677; i) H.-S. Yeom, S. Shin, Acc. Chem. Res. 2014,
47, 966; j) L. Fensterbank, M. Malacria, Acc. Chem. Res. 2014, 47, 953; k)
C. Obradors, A. M. Echavarren, Acc. Chem. Res. 2014, 47, 902; l) Y.-M.
Wang, A. D. Lackner, F. D. Toste, Acc. Chem. Res. 2014, 47, 889; m) L.
Zhang, Acc. Chem. Res. 2014, 47, 877; n) A. S. K. Hashmi, Acc. Chem.
Res. 2014, 47, 864.
[13] For recent reviews on ynamide reactivity, see: a) B. Zhou, T.-D. Tan, X.-Q.
Zhu, M. Shang, L.-W. Ye, ACS Catal. 2019, 9, 6393; b) G. Evano, C.
Theunissen, M. Lecomte, Aldrichimica Acta 2015, 48, 59; c) X.-N. Wang,
H.-S. Yeom, L.-C. Fang, S. He, Z.-X. Ma, B. L. Kedrowski, R. P. Hsung,
Acc. Chem. Res. 2014, 47, 560; d) K. A. DeKorver, H. Li, A. G. Lohse, R.
Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064; e) G.
Evano, A. Coste, K. Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840.
[14] For selected examples by our group, see: a) F.-L. Hong, Y.-B. Chen, S.-H.
Ye, G.-Y. Zhu, X.-Q. Zhu, X. Lu, R.-S. Liu, L.-W. Ye, J. Am. Chem. Soc.
2020, 142, 7618; b) Z.-S. Wang, Y.-B. Chen, H.-W. Zhang, Z. Sun, C. Zhu,
L.-W. Ye, J. Am. Chem. Soc. 2020, 142, 3636; c) F.-L. Hong, Z.-S. Wang,
D.-D. Wei, T.-Y. Zhai, G.-C. Deng, X. Lu, R.-S. Liu, L.-W. Ye, J. Am.
Chem. Soc. 2019, 141, 16961; d) Y. Xu, Q. Sun, T.-D. Tan, M.-Y. Yang, P.
Yuan, S.-Q. Wu, X. Lu, X. Hong, L.-W. Ye, Angew. Chem. Int. Ed. 2019,
58, 16252; e) B. Zhou, Y.-Q. Zhang, K. Zhang, M.-Y. Yang, Y.-B. Chen, Y.
Li, Q. Peng, S.-F. Zhu, Q.-L. Zhou, L.-W. Ye, Nat. Commun. 2019, 10,
3234; f) 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; g) B. Zhou, L. Li, X.-Q.
Zhu, J.-Z. Yan, Y.-L. Guo, L.-W. Ye, Angew. Chem. Int., Ed. 2017, 56,
4015; h) L. Li, X.-M. Chen, Z.-S. Wang, B. Zhou, X. Liu, X. Lu, L.-W. Ye,
ACS Catal. 2017, 7, 4004.
[15] Previous generations of α-imino copper carbenes are from diazo and
triazole precursors. For selected examples on the generation of α-imino
copper carbenes from diazos see: a) G. Sheng, S. Ma, S. Bai, J. Mao, P.
Lu, Y. Wang, Chem. Commun. 2018, 54, 1529; b) L. Wang, Y. Wu, Y.
Liu, H. Yang, X. Liu, J. Wang, X. Li, J. Jiang, Org. Lett. 2017, 19, 782; c)
C. Zhang, S. Chang, L. Qiu, X. Xu, Chem. Commun. 2016, 52, 12470; d)
E. Lourdusamy, L. Yao, C.-M. Park, Angew. Chem. Int. Ed. 2010, 49,
7963; for selected examples on the generation of α-imino copper
carbenes from triazoles see: e) R. Shen, C. Dong, J. Yang, L.-B. Han, Adv.
Synth. Catal. 2018, 360, 4252; f) V. Helan, A. V. Gulevich, V. Gevorgyan,
Chem. Sci. 2015, 6, 1928.
[2] For reviews, see: a) E. Aguilar, J. Santamaría, Org. Chem. Front. 2019, 6,
1513; b) X.-R. Song, Y.-F. Qiu, X.-Y. Liu, Y.-M. Liang, Org. Biomol. Chem.
2016, 14, 11317; c) P. W. Davies, M. Garzón, Asian J. Org. Chem. 2015,
4, 694.
[3] For selected examples, see: a) X. Tian, L. Song, K. Farshadfar, M.
Rudolph, F. Rominger, T. Oeser, A. Ariafard, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2020, 59, 471; b) Z. Zeng, H. Jin, M. Rudolph, F. Rominger,
A. S. K. Hashmi, Angew. Chem. Int. Ed. 2018, 57, 16549; c) Z. Zeng, H.
Jin, K. Sekine, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem.
Int. Ed. 2018, 57, 6935; d) H. Jin, B. Tian, X. Song, J. Xie, M. Rudolph, F.
Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 55, 12688; e) H.
Jin, L. Huang, J. Xie, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2016, 55, 794; f) B. D. Mokar, P. D. Jadhav, Y. B. Pandit,
R.-S. Liu, Chem. Sci. 2018, 9, 4488; g) S. S. Giri, R.-S. Liu, Chem. Sci.
2018, 9, 2991; h) P. D. Jadhav, X. Lu, R.-S. Liu, ACS Catal. 2018, 8, 9697;
i) R. L. Sahani, R.-S. Liu, Angew. Chem. Int. Ed. 2017, 56, 12736; j) R. L.
Sahani, R.-S. Liu, Angew. Chem. Int. Ed. 2017, 56, 1026; k) W.-B. Shen,
X.-Y. Xiao, Q. Sun, B. Zhou, X.-Q. Zhu, J.-Z. Yan, X. Lu, L.-W. Ye, Angew.
Chem. Int. Ed. 2017, 56, 605; l) 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.
[4] For selected examples, see: a) M. Garzón, P. W. Davies, Org. Lett. 2014,
16, 4850; b) E. Chatzopoulou, P. W. Davies, Chem. Commun. 2013, 49,
8617; c) H.-H. Hung, Y.-C. Liao, R.-S. Liu, J. Org. Chem. 2013, 78, 7970;
d) P. W. Davies, A. Cremonesi, L. Dumitrescu, Angew. Chem. Int. Ed.
2011, 50, 8931; e) C. Li, L. Zhang, Org. Lett. 2011, 13, 1738.
[5] For a review, see: a) X. Tian, L. Song, A. S. K. Hashmi, Chem. Eur. J.
2020, 26, 3197; for selected examples, see: b) X. Tian, L. Song, M.
Rudolph, F. Rominger, T. Oeser, A. S. K. Hashmi, Angew. Chem. Int. Ed.
2019, 58, 3589; c) X. Tian, L. Song, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Org. Lett. 2019, 21, 4327; d) X. Tian, L. Song, C. Han, C. Zhang,
Y. Wu, M. Rudolph, F. Rominger, A. S. K. Hashmi, Org. Lett. 2019, 21,
2937; e) X. Tian, L. Song, M. Rudolph, Q. Wang, X. Song, F. Rominger, A.
S. K. Hashmi, Org. Lett. 2019, 21, 1598.
[6] For the generation of α-imino metal carbenes via Rh-catalyzed
metallonitrene-initiated alkyne oxidation, see: a) N. Mace, A. R. Thornton,
S. B. Blakey, Angew. Chem. Int. Ed. 2013, 52, 5836; b) A. R. Thornton, V.
I. Martin, S. B. Blakey, J. Am. Chem. Soc. 2009, 131, 2434; c) A. R.
Thornton, S. B. Blakey, J. Am. Chem. Soc. 2008, 130, 5020; for relevant
Rh-catalyzed allene amination, see: d) A. H. Stoll, S. B. Blakey, Chem.
Sci. 2011, 2, 112; e) A. H. Stoll, S. B. Blakey, J. Am. Chem. Soc. 2010,
132, 2108; for relevant Rh-catalyzed asymmetric cyclization, see: f) K.
Hong, H. Su, C. Pei, X. Lv, W. Hu, L. Qiu, X. Xu, Org. Lett. 2019, 21, 3328;
for the use of 1-propargyl-1H-benzotriazoles as nitrene transfer reagents,
see: g) D. Allegue, J. González, S. Fernández, J. Santamaría, A.
[16] For details, see the Supporting Information (SI).
[17] Y. Liao, Q. Lu, G. Chen, Y. Yu, C. Li, X. Huang, ACS Catal. 2017, 7, 7529.
[18] CCDC 1970123 (2k), 1970124 (4m), 1974960 (6a), 2003044 (2av) and
1970125 ((-)-2aw) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[19] For recent selected examples on the cyclization of N-propargyl ynamides,
see: a) B. Prabagar, R. K. Mallick, R. Prasad, V. Gandon, A. K. Sahoo,
Angew. Chem. Int. Ed. 2019, 58, 2365; b) S. Dutta, R. K. Mallick, R.
Prasad, V. Gandon, A. K. Sahoo, Angew. Chem. Int. Ed. 2019, 58, 2289.
[20] For this tricyclic skeleton found in a variety of bioactive compounds, see for
examples: a) B. Liu, X. Yuan, B. Xu, H. Zhang, R. Li, X. Wang, Z. Ge, R.
Li, Eur. J. Med. Chem. 2019, 170, 1; b) K. K. Deibler, R. K. Mishra, M. R.
Clutter, A. Antanasijevic, R. Bergan, M. Caffrey, K. A. Scheidt, ACS Chem.
Biol. 2017, 12, 1245; c) A. R. Saundane, R. Kalpana, Med. Chem. Res.
2015, 24, 1681; d) M. Zhang, D. Liu, B. Lu, PCT Int. Appl. WO
2014043296A1, 2014; e) G. Van Baelen, S. Hostyn, L. Dhooghe, P.
Tapolcsányi, P. Mátyus, G. Lemière, R. Dommisse, M. Kaiser, R. Brun, P.
Cos, L. Maes, G. Hajós, Z. Riedl, I. Nagy, B. U. W. Maes, L. Pieters, Biorg.
Med. Chem. 2009, 17, 7209; f) G. Van Baelen, G. L. F. Lemière, R. A.
Dommisse, B. U. W. Maes, ARKIVOC 2009, vi, 174; g) H.-H. Ha, J. S.
Kim, B. M. Kim, Bioorg. Med. Chem. Lett. 2008, 18, 653.
6
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10.1002/anie.202007206
Angewandte Chemie International Edition
[21] This chiral ligand was first reported by our group, see: X.-Q. Zhu, Z.-S.
Wang, B.-S. Hou, H.-W. Zhang, C. Deng, L.-W. Ye, Angew. Chem. Int. Ed.
2020, 59, 1666.
[22] a) J. P. Parrish, D. B. Kastrinsky, D. L. Boger, Org. Lett. 2003, 5, 2577; b)
J. P. Parrish, D. B. Kastrinsky, I. Hwang, D. L. Boger, J. Org. Chem. 2003,
68, 8984.
[23] Attempts to oxidize the benzylic methylene group of these tetracyclic
cyclopropanes 2 into the carbonyl group have been unsuccessful to date.
[24] The reaction of ynamide 1at bearing an electron-deficient alkene failed to
deliver the desired cyclopropanation product. Please see SI for full details.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202007206
Angewandte Chemie International Edition
Asymmetric Catalysis
Xin Liu, Ze-Shu Wang, Tong-Yi Zhai,
Chen Luo, Yi-Ping Zhang, Yang-Bo
Chen, Chao Deng,* Rai-Shung Liu, and
Long-Wu Ye* Page – Page
Copper-Catalyzed
Azide-Ynamide
Cyclization for Generation of α-Imino
Copper Carbenes: Divergent and
Enantioselective
Access
to
Polycyclic N-Heterocycles
An efficient copper-catalyzed cascade cyclization of azide-ynamides via α-imino
copper carbene intermediates is disclosed, enabling divergent synthesis of
polycyclic N-heterocycles in generally good to excellent yields with broad substrate
scope and excellent diastereoselectivities (d.r. > 20/1), which represents the first
generation of α-imino copper carbenes directly from alkynes. Moreover, such an
asymmetric azide-ynamide cyclization has been achieved with high
enantioselectivities (up to 98:2 e.r.), which constitutes the first asymmetric azide-
alkyne cyclization.
8
This article is protected by copyright. All rights reserved.