Catalytic Asymmetric Hydroacyloxylation/Ring-Opening Reaction of Ynamides, Acids, and Aziridines

Article abstract of DOI:10.1021/acs.orglett.1c00631

A highly enantioselective three-component reaction of ynamides with carboxylic acids and 2,2′-diester aziridines has been realized by using a chiral N,N′-dioxide/Ho(OTf)3 complex as a Lewis acid catalyst. The process includes the formation of an α-acyloxyenamide intermediate through the addition of carboxylic acids to ynamides and the following enantioselective nucleophilic addition to in-situ-generated azomethine ylides induced by the chiral catalyst. A range of amino acyloxyenamides are delivered in moderate to good yields with good ee values. In addition, a possible catalytic cycle with a transition model is proposed to elucidate the reaction mechanism.

Full text of DOI:10.1021/acs.orglett.1c00631

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Letter
Catalytic Asymmetric Hydroacyloxylation/Ring-Opening Reaction of
Ynamides, Acids, and Aziridines
Xiangqiang Li, Hongkun Zeng, Lili Lin,* and Xiaoming Feng*
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ABSTRACT: A highly enantioselective three-component reaction of ynamides with carboxylic acids and 2,2′-diester aziridines has
been realized by using a chiral N,N′-dioxide/Ho(OTf)3 complex as a Lewis acid catalyst. The process includes the formation of an α-
acyloxyenamide intermediate through the addition of carboxylic acids to ynamides and the following enantioselective nucleophilic
addition to in-situ-generated azomethine ylides induced by the chiral catalyst. A range of amino acyloxyenamides are delivered in
moderate to good yields with good ee values. In addition, a possible catalytic cycle with a transition model is proposed to elucidate
the reaction mechanism.
ortho-hydroxybenzyl alcohols by developing a chiral N,N′-
dioxide/Sc(III) complex catalytic system.6
ulticomponent reactions are attractive for their rapid
Mgeneration of molecules with broad chemical diversity
and molecular complexity from three or more materials in a
highly efficient, economic, and environmentally friendly one-pot
manner.1 One difficulty that lies in the catalytic asymmetric
multicomponent one-pot reactions is the competitive inter-
action among reactants as well as the catalyst.2 Because of the
activation by the nitrogen atom, the CC bond in the ynamides
is strongly polarized and shows a good differentiation between
the two carbon atoms.3,4 Recently, Cui’s group reported BF3-
promoted multicomponent reactions (MCRs) of ynamides,
organic acids with aldehydes,5a imines,5b and ortho-quinone
methides,5c giving racemic β-acyloxyamide, β-amino amide, and
diarylpropanamide products. These MCRs relied on acylox-
yenamide intermediates derived from ynamides and carboxylic
acids (Scheme 1, path ii). Our group realized the first catalytic
asymmetric three-component cascade reaction of ynamides and
On the contrary, aziridines are widely used synthetic
precursors for synthesizing chiral nitrogenous compounds.7
Because 2,2′-diester (D-A type) aziridines can undergo C−C
bond cleavage to generate azomethine ylides8 in the presence of
a Lewis acid under mild conditions,9 we assessed that 2,2′-
diester aziridines could also be employed as an electrophile to
capture the acyloxyenamide intermediates formed by the
hydroacyloxylation of ynamides with carboxylic acids (Scheme
1, paths ii and v). The possible challenge arises from the high
reactivity of azomethine ylides because they might be readily
hydrolyzed in the presence of carboxylic acids and engaged in a
two-component reaction with ynamides or carboxylic acids
(Scheme 1, paths i and iii). Although difficulties might exist, the
resulting chiral amino acyloxyenamides are multifunctional and
have a potential use in drug syntheses.10 Herein we developed a
chiral N,N′-dioxide/Ho(OTf)3 complex catalytic system for the
asymmetric three-component hydroacyloxylation/ring opening
of ynesulfonamides, carboxylic acids, and 2,2′-diester aziridines,
generating chiral amino acyloxyenamides in one pot (Scheme 1,
path iv).11
Scheme 1. Three-Component Reactions of Ynamides,
Aziridines, and Acids
Received: February 22, 2021
Published: March 26, 2021
https://doi.org/10.1021/acs.orglett.1c00631
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2954−2958
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Initially, the 2,2′-diester aziridine 1b, para-nitrobenzoic acid
2a, and N-Ts ynamide 3a were employed to explore the reaction
conditions (Table 1). The L3-PiPr3/Sc(III)/LiNTf2 catalyst,
To reduce the impact of the erosion of diester aziridine under
Lewis acidic conditions, the amount of 1b was increased to 1.5
equiv, and the amount of 4 Å molecular sieve, which can slow
down the hydrolysis of azomethine ylides, was increased from 50
to 130 mg, and thus the desired 4b was obtained in 51% yield
with 95% ee (entry 7). Moreover, the yield could be increased to
74% with the ee value reduced to 86% (entry 8) when N-
methanesulfonyl protecting diester aziridine 1d was used as the
substrate, probably because the N-methanesulfonyl protecting
group enhances the stability of the azomethine ylides formed in
situ from 2,2′-diester aziridines. It was surprising that a small
excessive amount of metal salt (L3-PiEt2Br/Ho(OTf)3 = 1/1.1)
could further increase the reactivity with maintained enantio-
selectivity (entry 9, 86% yield, 87% ee). Under the current
reaction conditions, the two-component [3 + 2] cycloaddition
product 5d could be isolated with ∼10% yield. However, when
2,2′-diester aziridine 1c and ynamide 3a were mixed under
optimized conditions, [3 + 2] cycloaddition occurred and
delivered the tetra-substituted 3-pyrroline 5c in 50% yield
without enantioselectivity (eq 1). In addition, we surveyed other
ligands. Superior Box and BINOL did not give any
enantioselectivity (entries 10−12).
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
meal salt
ligand
solvent
yield (%)
ee (%)
1
2
3
4
5
6
Sc(OTf)3
La(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
Ho(OTf)3
L3-PiPr2
L3-PiPr2
L3-PiPr2
L3-PiEt2
L3-PiEt2Br
L3-PiEt2Br
L3-PiEt2Br
L3-PiEt2Br
L3-PiEt2Br
tBu-Box
toluene
toluene
toluene
toluene
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
trace
11
28
13
28
34
51
74
86
28
15
25
53
57
74
82
90
95
86
87
0
Next, we turned our attention to the substrate generality
under optimal reaction conditions. First, diester aziridines 1a−
1m were investigated. As shown in Scheme 2, 1a−1d with an N-
d
7
e
8
ef
,
9
a
ef
,
Scheme 2. Substrate Scope of 2,2′-Diester Aziridines
10
11
12
ef
,
iPr-Pybox
(S)-BINOL
0
0
ef
,
a
Unless otherwise noted, all reactions were carried out with ligand/
metal salt/LiNTf2 (1:1:1.5, 10 mol %), 1b (0.10 mmol), 2a (1.0
equiv), 3a (1.0 equiv), and 4 Å molecule sieve (50 mg) in solvent (1.0
b
mL) under a N2 atmosphere at 35 °C for 24 h. Isolated yield.
c
d
Determined by chiral HPLC analysis. 1b (1.5 equiv), 4 Å molecule
e
sieves (130 mg), and CHCl3 (2.0 mL) were used. 1d (1.5 equiv), 4 Å
molecule sieves (130 mg), and CHCl3 (2.0 mL) were used. Ligand/
f
metal salt 1:1.1.
which was efficient in the three-component reaction of ortho-
hydroxybenzyl alcohols with ynamides and carboxylic acid,6 is
inoperative in this reaction (entry 1). Next, various metal salts
were screened by complexing with L3-PiPr2 (entries 2 and 3).
The rare-earth metal complex of Ho(OTf)3 could provide the
desired product 4b in 28% yield with 57% ee (entry 3). The low
yield was caused by the hydrolysis of aziridine 1b and the
generation of the byproduct 3-pyrroline 5, which was produced
by the [3 + 2] cycloaddition of aziridine 1b and ynamide 3a
(Scheme 1, path i and eq 1). Then, an examination of the steric
a
All reactions were carried out with L3-PiEt2Br/Ho(OTf)3/LiNTf2
(1:1.1:1.5, 10 mol %), 1 (1.5 equiv), 2a (0.10 mmol), 3a (1.0 equiv),
and 4 Å molecule sieve (130 mg) in CHCl3 (2.0 mL) under a N2
atmosphere at 35 °C for 24 h.
hindrance of the ligands was conducted, and a significant
influence on the enantioselectivity was exhibited. L3-PiEt2 with a
decreased steric hindrance improved the ee value to 74%, but the
yield decreased (Table 1, entry 4). L3-PiEt2Br with a bromo
atom at the para position of phenyl ring further improved the ee
to 82% ee with the yield remaining low (entry 5). When the
reaction was carried out in CHCl3, the yield could be increased
to 34%, and the enantioselectivity increased to 90% ee (entry 6).
methylsulfonyl protecting group or N-phenylsulfonyl protecting
group could afford the corresponding products 4a−4d in
moderate yields with good ee values (53−86% yield, 87−94%
ee). 1d−1i bearing different substituent groups, such as Me−,
F−, Cl−, Br−, and phenyl−, on the para position of the Ar1 ring
could be transformed to the corresponding products 4d−4i in
moderate to good yields with good ee values (43−86% yield,
87−94% ee). When 2-naphthyl-substituted diester aziridine 1j
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was applied, the product 4j could be obtained in 81% yield with
62% ee. Moreover, aziridines 1k−1m with dipropyl, diisopropyl,
or dibutyl esters were also tolerated in this three-component
process and furnished the corresponding products 4k−4m in
moderate yields with good ee values. Aziridines with strong
electron-donating groups in Ar1 were not suitable. The reaction
mixtures were complex, and only trace amounts of the desired
products could be detected. The reason might be that the
corresponding azomethine ylides are unstable. The absolute
configuration of the product 4b was determined to be (S) by X-
ray single-crystal analysis. To show the synthetic utility of the
methodology, a gram-scale synthesis of 4b was performed.
Under the optimized reaction conditions, 1b (3.75 mmol), 2a
(2.50 mmol), and 3a (2.50 mmol) reacted smoothly, affording
1.22 g of the product 4b in 60% yield with 90% ee. (See the
details in the Supporting Information (SI).)
acyloxyenamide intermediates are unstable (eq 2 vs eq 3). The
stability of intermediate 6 under L3-PiEt2Br/Ho(OTf)3
conditions was conducted in CHCl3, and nearly no decom-
position occurred. Nevertheless, under the same conditions, the
electron-donating-group-substituted enamide 7 partially de-
composed. To get insight into the more mechanistic
implications, the reaction between enamide 6 and 2,2′-diester
aziridine 1d was carried out under the optimal conditions (eq 4),
and the product 4d was delivered in 45% yield with 87% ee,
which means that the acyloxyenamide intermediate should be
the actual intermediate.
Subsequently, the carboxylic acids 2 and ynamides 3 were
varied. As shown in Scheme 3, carboxylic acids 2b−2d with
Scheme 3. Substrate Scope of Carboxylic Acids and
a
Ynamides.
Different ynamides were also surveyed under the optimized
conditions. Ynamides bearing different N-alkyl groups (such as
allyl, 3-butenyl, or benzyl groups) performed well under the
optimized reaction conditions, delivering the corresponding
products 4v−4x in moderate yields with good ee values (57−
58% yields, 78−88% ee). Ynamide 3e with N-methanesulfonyl
group was also suitable, and the desired product 4y was obtained
in 51% yield with 86% ee. The absolute configurations of the
products 4a−4y were also determined to be (S) by comparing
the circular dichroism spectra with that of 4b. (See the details in
the SI).
On the basis of the experimental phenomena, the
determination of the absolute configuration of the products,
and our previous works,6 a plausible catalytic cycle with a
transition-state model is proposed. As shown in Scheme 4, the
tetradentate L3-PiEt2Br coordinates to Ho(OTf)3, forming the
Scheme 4. Proposed Reaction Mechanism
a
All reactions were carried out with L3-PiEt2Br/Ho(OTf)3/LiNTf2
(1:1.1:1.5, 10 mol %), 4 Å molecule sieve (130 mg), 1d (1.5 equiv), 2
(0.10 mmol), and 3 (1.0 equiv) in CHCl3 (2.0 mL) under a N2
atmosphere at 35 °C for 24 h.
O2N, F3C, or NC groups at the meta or para position of the
phenyl ring furnished this three-component reaction well and
provided the corresponding products 4n−4p in 57−67% yield
with 80−82% ee. Next, a range of nitrobenzoic acids 2e−2h
substituted by halogen atoms at the three- or four-position of the
phenyl ring were investigated, and the corresponding products
4q−4t were obtained in 37−48% yields with 64−80% ee. 2,4,6-
Trichlorobenzoic acid 2i produced product 4u in 57% yield with
48% ee. Benzoic acids with electron-donating groups caused the
reaction mixture to be complex, which might be because the α-
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L3-PiEt2Br/Ho(III) complex. Meanwhile, the azomethine ylide
intermediate A is generated through the cleavage of the carbon−
carbon bond in aziridines 1d under the assistance of LiNTf2.
Because of the strong bidentate coordination of two ester groups
to the metal center, the chiral L3-PiEt2Br/Ho(III) complex can
readily catch the azomethine ylide to form intermediate B. The
coordination is also supported by the high-resolution electro-
spray ionization mass spectrometry (ESI-HRMS) analysis of the
mixture of L3-PiEt2Br, Ho(OTf)3, and 1d, as the characteristic
signal of [L3-PiEt2Br-Ho3+-2(OTf−)-1d]+ m/z = 1568.1588
(m/z calcd 1568.1606) was found. The Re face of azomethine
ylide intermediate B is strongly shielded by the neighboring 2,6-
diethyl-4-bromo group of the ligand L3-PiEt2Br. As a result, the
N-Ts iminium carbon of intermediate B is attacked by the
acyloxyenamide 6 from B’s Si face, delivering the intermediate
C. Finally, the intermediate C undergoes a 1,4-proton shift and
furnishes the desired product (S)-4d.
In summary, the catalytic asymmetric three-component
cascade hydroacyloxylation/ring-opening reaction of aziridines
with ynamides and carboxylic acids has been realized by using a
chiral N,N′-dioxide/Ho(OTf)3 complex as the chiral Lewis acid
catalyst. This protocol provides a facile and efficient access to
chiral amino acyloxyenamides under mild reaction conditions.
Moreover, a plausible catalytic cycle has been proposed to
explain the reaction mechanism. Further development of
asymmetric multicomponent reactions (AMCRs) is ongoing
in our group.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00631
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the financial support from the National Natural
Science Foundation of China (nos. 21890723 and 21871188).
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00631.
Experimental procedures, full spectroscopic data for all
new compounds, and copies of 1H, 13C{1H}, and 19F{1H}
NMR and HPLC spectra (PDF)
Accession Codes
CCDC 2021534 and 2060367 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.
AUTHOR INFORMATION
Corresponding Authors
■
Lili Lin − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China; orcid.org/0000-
0001-8723-6793; Email: lililin@scu.edu.cn
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478; Email: xmfeng@scu.edu.cn
Authors
Xiangqiang Li − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Hongkun Zeng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
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