Copper(I)-Catalyzed Ketenimine Formation/Aza-Claisen Rearrangement Cascade for Stereoselective Synthesis of α-Allylic Amidines

Article abstract of DOI:10.1021/acs.orglett.0c01012

A copper-catalyzed three-component reaction of terminal alkynes, TsN₃, and tertiary allylic amines is developed toward the one-pot synthesis of α-allylic amidines. The product was synthesized on gram scale under 1 mol % of catalyst loading. Transformations of products into alkenyl amine and other nitrogen-containing compounds are demonstrated without any loss of stereochemical information.

Full text of DOI:10.1021/acs.orglett.0c01012

pubs.acs.org/OrgLett
Letter
Copper(I)-Catalyzed Ketenimine Formation/Aza-Claisen
Rearrangement Cascade for Stereoselective Synthesis of α‑Allylic
Amidines
Cheng-Gang Wang, Rui Wu, Ting-Peng Li, Tao Jia, Yang Li, Dongmei Fang, Xiaozhen Chen,
Yuanji Gao, Hai-Liang Ni, Ping Hu, Bi-Qin Wang, and Peng Cao*
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sı Supporting Information
ABSTRACT: A copper-catalyzed three-component reaction of terminal alkynes,
TsN , and tertiary allylic amines is developed toward the one-pot synthesis of α-
3
allylic amidines. The product was synthesized on gram scale under 1 mol % of
catalyst loading. Transformations of products into alkenyl amine and other
nitrogen-containing compounds are demonstrated without any loss of stereo-
chemical information.
he multicomponent reaction (MCR) represents one of
Scheme 1. CuAAC-Ketenimine Formation and Reaction
with Amines
T
the powerful tools to assemble complex molecules to
1
reach high efficiency and operational simplification. MCRs are
also particularly practical for the rapid construction of
successive stereocenters in total synthesis and drug develop-
2
ment. For example, Cu-catalyzed azide−alkyne cycloaddition
(
CuAAC) and triazole coupling cascade has become an
important strategy for the synthesis of important triazole
3
derivatives. When azides containing a strong electron-
withdrawing group (e.g., sulfonyl) at the N1 atom, the triazolyl
copper intermediate facilely undergoes a ring-opening
rearrangement/nitrogen-release process and the resultant
4
electrophilic ketenimine intermediate could couple with
various nucleophilic reagents to produce carbonyl derivative,
5
6
7
8
such as amides, amidines, ketones, imines, and N-
9
6a,b
containing heterocycles. In Chang’s pioneering work,
the
Cu-catalyzed three-component reaction of alkynes, N-Ts
azides, and primary/secondary amines provided a direct access
to amidines (Scheme 1a). In this context, the ketenimine
addition of secondary (homo)allylic amines, followed by an
oxidative carbanion cyclization, was demonstrated toward
10
cyclopropane-fused cyclic amidines (Scheme 1b). Recently,
the ketenimine addition of 4-nitrobenzenesulfonamides and
Truce−Smile rearrangement cascade was reported to construct
1
1
α-aryl amidines (Scheme 1c). However, the ketenimine
addition of tertiary amines remain challenging. The related
coupling reaction of trialkyl amines and N-sulfonyl ketenimine
not only enables the step- and atom-economic synthesis of
functionalized amidines but also generates multiple carbon
12
only gave dealkylation products.
In past decades, the Claisen rearrangement has become one
Received: March 19, 2020
of most powerful methods for the C−C bond formation and
13
stereoselective synthesis of α-allylic carbonyl derivatives. We
envisioned that the coupling of an allylic substituted tertiary
amine and the N-Ts ketenimine might form the zwitterion
intermediate that is allowed to undergo the aza-Claisen
rearrangement (Scheme 1d). Such a three-component reaction
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01012
A
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
stereocenters. Although Xu and Shen et al. demonstrated an
elegant Cu-mediated amino enyne cyclization/aza-Claisen
rearrangement cascade to construct cyclic α-allylic amidines,
Scheme 3. Scope of Terminal Alkynes
14
the intermolecular ketenimine addition/Claisen rearrangement
is still unknown. Herein, a Cu-catalyzed three-component
coupling reaction of tertiary allylic amines, alkynes, and azides
15
is reported to provide access to acyclic α-allylic amidines.
To test the feasibility, several allylic tertiary amines were
chosen to react with ethynylbenzene (1a) and TsN in the
3
presence of CuI (10 mol %) (Scheme 2). Pleasingly, cinnamyl
Scheme 2. Initial Attempts
a
All reactions were performed under argon using 1 (0.3 mmol), TsN3
0.3 mmol), 2a (0.2 mmol), and Cu(CH CN) PF (0.02 mmol) in
.0 mL of MeCN for 12h. Isolated yield. Determined by H NMR
(
1
3
4
6
b
c
1
of the crude product.
3
ba-3ea in high yields (73−85%). The electron-deficient
arylalkynes gave moderate to good yields. For example, p-F, p-
CF and p-COOMe substituted ethynylbenzenes were readily
transformed into 3fa (63%), 3ja (80%) and 3la (60%) in good
yields, while the three-component reaction with p-Cl-, p-Br-, o-
pyrrolidine (2a) was able to couple with the in situ generated
ketenimine and transformed into the rearrangement product
3
(
3aa) as single diastereomeric isomer. The syn configuration of
aa was confirmed by the X-ray diffraction analysis and the
observed stereochemical outcome is consistent with that of the
Br-, and p-NO -substituted ethynylbenzenes gave moderate
3
2
yields. In particular, 3,4-dichloro-4-ethynylbenzene and 3-
ethynylpyridine were allowed to undergo the three-component
reaction, providing 3ma (62%) and 3na (83%) in good yields
with excellent diastereoselectivities. In the next investigation,
hex-1-yne- or OAc/OBoc-tethered alkynes were reactive to
undergo the Cu-catalyzed cascade, affording α-alkyl-substi-
tuted homoallylic amidines (3oa−3ra) in high yields (71−
1
3c
ketene−Claisen reaction.
condition optimization, 3aa was obtained in excellent yield
94%) in the presence of Cu(CH CN) PF (10 mol %) with
During the further reaction
(
3
4
6
CH CN as the solvent at 35 °C for 12 h (Table 1, entry 1).
3
The yield was slightly decreased when any reaction parameter
was changed (entries 2−7). None of the target was observed in
the absence of copper salt (entry 8).
96%) with moderate diastereoselectivities. The low stereo-
selectivities for products (3oa−3ra) might result from their
less sterically hindered R group that leading the ketenimine
reacts less selectively with the allylic amine 2a between path a
and b; thus, the formed mixture of E- and Z-ethene-1,1-
diamine intermediates undergo the stereospecific rearrange-
ment and produce two diastereoisomers less selectively (Figure
With the optimal conditions in hand, the scope of terminal
alkynes was evaluated. A broad range of arylalkynes, depicted
in Scheme 3, reacted with TsN and cinnamyl pyrrolidine to
3
form homoallylic amidines with excellent stereoselectivities.
Electron-rich arylalkynes, bearing a p-Me, p-OMe, o-OMe, or
t
p- Bu substituent, were quite reactive and transformed into
1
).
a
Table 1. Reaction Conditions Evaluation
b
c
entry
changes of reactions conditions
none
CuI instead of Cu(CH CN) PF
yield (%)
dr
1
2
3
4
5
6
7
8
94
80
74
62
87
80
81
0
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
3
4
6
Cu(OTf) instead of Cu(CH CN) PF
2
3
4
6
THF instead of CH CN
Figure 1. Proposed mechanism.
3
DCM instead of CH CN
3
25 °C instead of 35 °C
45 °C instead of 35 °C
without copper
The next investigation was focused on the scope of allylic
tertiary amines. (Table 2) The electronic properties of aryl
groups on cinnamyl pyrrolidine substrates (2b−2h) has little
effect on reactivity and stereoselectivity of the reaction.
Electron-deficient cinnamyl amines bearing a F, Cl, Br, or
a
All reactions were performed under argon using 1 (0.3 mmol), TsN3
0.3 mmol), 2a (0.2 mmol), catalyst (10 mol %) in 1 mL of the
(
b
c
1
solvent. The isolated yield. Determined by H NMR of the crude
product.
NO substituent reacted smoothly to form 3ad−3ag in high
2
yields (82−99%). The furan-derived allylic amine (2i) was
B
https://dx.doi.org/10.1021/acs.orglett.0c01012
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a
Table 2. Scope of Allylic Amines
Scheme 4. Gram-Scale Synthesis and Transformations of
aa
3
16
reduction to afford 6. It is worth noticing that all products
were obtained without any loss of diastereoselectivities.
In conclusion, a new approach toward the synthesis of α-
allylic amidines was accomplished by merging Cu-catalyzed
ketenimine formation/aza-Claisen rearrangement cascade.
Allylic tertiary amines were employed and successfully
incorporated into α-allylic amidines bearing tertiary/quater-
nary carbon centers. The method features good tolerance of
functional groups, easy scale-up, and easy operation. The
research on asymmetric synthesis of functionalized amidines is
currently ongoing.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01012.
a
All reactions were performed under argon using 1a (0.3 mmol),
TsN (0.3 mmol), 2 (0.2 mmol), and Cu(CH CN) PF (0.02 mmol)
Experimental procedures, spectroscopic data, and NMR
spectra of all products (PDF)
3
3
4
6
b
c
1
in 1.0 mL of MeCN for 12h. Isolated yield. Determined by H
NMR of the crude product.
Accession Codes
CCDC 1940552 and 1945363 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
smoothly transformed into syn-homoallylic amidines (3ai).
Divinyl and crotyl pyrrolidines (2j and 2k) also showed high
reactivities as well as excellent stereoselectivities. (Table 2,
entries 4 and 5) Allylic amines with trisubstituted olefinic
groups (2l−2n) were exposed to the catalytic system and
reacted smoothly to produce expected three-component
adducts (3al−3an) with excellent drs. Yields were slightly
eroded (65−73%) owing to the partial decomposition of
zwitterionic 1,5-diene intermediates.
AUTHOR INFORMATION
Corresponding Author
■
Peng Cao − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China; orcid.org/
0000-0001-8199-0015; Email: cao_peng@outlook.com
To demonstrate the application of this Cu-catalyzed MCR,
the scale-up reaction with 2.5 mmol of the allylic amine (2a)
was performed. The reaction proceeded smoothly under 1 mol
Authors
%
of catalyst loading, giving 1.06 g of 3aa (92% yield) (Scheme
Cheng-Gang Wang − College of Chemistry and Materials
Science, Sichuan Normal University, Chengdu 610068, China
Rui Wu − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China
4
). Some transformations of the product were carried out to
construct N-containing molecules. For example, the selective
reduction of 3aa to olefinic amine (4) with LiAlH proceeded
4
smoothly in good yield (83%). The selective transformation of
olefinic group by a sequential hydroboration and oxidation was
successful to give a multifunctionalized amidine (5) in 88%
yield. And the N-Ts group of 3aa was readily removed by SmI2
Ting-Peng Li − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Tao Jia − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China
C
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Letter
Yang Li − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China
Dongmei Fang − Natural Products Research Center, Chengdu
Institute of Biology, Chinese Academy of Sciences, Chengdu
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6
10041, China
Xiaozhen Chen − Natural Products Research Center, Chengdu
Institute of Biology, Chinese Academy of Sciences, Chengdu
6
10041, China
Yuanji Gao − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Hai-Liang Ni − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Ping Hu − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China
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Bi-Qin Wang − College of Chemistry and Materials Science,
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(b) Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.;
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dichotomy via a common pathway. J. Org. Chem. 2008, 73, 5520.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01012
Notes
(c) Yao, B.; Shen, C.; Liang, Z.; Zhang, Y. Copper-catalyzed reaction
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the NSFC (Nos. 21572218, 21901176, and
1901177) for financial support.
2
1
,6-enyne-derived ketenimine: an efficient construction of strained
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E
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