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Synthesis of chiral pyridine-oxazolines via a

Cite this: Org. Chem. Front., 2022, 9,
catalytic asymmetric Heine reaction of meso-
1531 N-(2-picolinoyl)-aziridines†
Yi Li, Wang-Yuren Li, Xiaoxue Tang, Xiaohua Liu * and Xiaoming Feng *

Received 21st December 2021,
Accepted 26th January 2022
DOI: 10.1039/d1qo01900g
rsc.li/frontiers-organic
An asymmetric Heine reaction of (meso)-N-(2-picolinoyl)-aziridines catalyzed by a chiral ytterbium(III)–
N,N’-dioxide complex was established. A novel library of pyridine-oxazolines was obtained with decent
yields and enantioselectivities, which show potential as chiral ligands and Lewis base catalysts. Besides,
based on the control experiments, a possible work mode was proposed.

Introduction recent years. Various nucleophiles, such as phosphites,6 alco-

hols or water,12a hydroxylamines,7 tetrazoles8 or pyrazoles,12b
Chiral pyridine-oxazoline (Pyox) ligands were first used by TMSNCS9 and different carbon-based nucleophiles,10 have
Brunner and coworkers in enantioselective monophenylation been used for desymmetrization by intermolecular ring-
in 1986,1 and these ligands have been reemployed in a wider opening and cycloadditions11 of meso-2-( picolinoyl)-aziridines
range of catalytic asymmetric reactions in recent years. Due to (Scheme 1c), delivering useful chiral β-functional amine
the pull–push feature of Pyox-type ligands (Scheme 1a), they derivatives with vicinal stereocenters. Encouraged by Morgan’s
have shown excellent catalytic behaviour in many different elegant work5 and our previous works on the desymmetriza-
reactions, such as Heck-type reactions, Wacker-type reactions, tion of aziridines,12 we envisioned that meso-N-(2-picolinoyl)-
carboamination, arylboration, coupling reactions and others.2 aziridine could undergo the asymmetric Heine reaction for the
Besides, Pyox-type compounds themselves can act as chiral direct synthesis of optically active Pyox-type ligands
Lewis base catalysts to promote asymmetric hydrosilyation of (Scheme 1d). Herein, we report our strategy for the construc-
ketones and ketimines.3 Typically, enantioenriched Pyox and tion of Pyox compounds as well as their potential applications.
other oxazolines are prepared from optically pure 1,2-amino
alcohols (Scheme 1a). Methods for the catalytic enantio-
selective synthesis of oxazolines from achiral starting materials
are rare, and the strong coordination abilities of Pyox-type
ligands to metal salts can lead to poisoning of the metal cata-
lysts, making the highly catalytic enantioselective synthesis of
Pyoxes by metal catalysis more difficult.
The Heine reaction, an effective method for the construc-
tion of oxazolines from N-acylaziridines, has been widely used
in organic synthesis.4 In 2016, the Morgan group achieved the
first catalytic asymmetric Heine reaction using a palladium(II)-
diphosphine complex for the synthesis of a series of isoxazole-
oxazoline compounds from meso-N-(3-isoxazol)-aziridines.5
Meso-N-(2-picolinoyl)-aziridines are also important synthons
which have received a tremendous amount of attention in

Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of

Chemistry, Sichuan University, Chengdu 610064, China. E-mail: liuxh@scu.edu.cn,
xmfeng@scu.edu.cn; Fax: +86 28 85418249
† Electronic supplementary information (ESI) available. CCDC 2084388 and
2094394. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1qo01900g Scheme 1 Background information and proposal.

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Research Article Organic Chemistry Frontiers

Results and discussion
We initially chose meso-N-(2-picolinoyl)-aziridine 1a as a
model substrate to optimize the suitable chiral catalysts
(Fig. 1) in CHCl3 (0.1 M) at 35 °C (Table 1). A chiral catalyst of
BINAP with Pd(OTf )2, which showed excellent catalytic ability
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was advantageous for the enantioselectivity (entry 6 vs. entries
5 and 7), and substitution at the para-position was unfavorable
(entry 8). Using L3-RaEt2 as the optimal ligand, most of the
lanthanide metal triflate complexes promoted the reaction
efficiently (for details, see ESI Table S5†). The metal ions
bearing similar ionic radii to Y(III) could afford almost equally

in previous work,5 yielded a trace amount of the targeted Pyox
product 2a (entry 1). Several classic Lewis acid catalysts
without detailed optimization, such as Box/Cu(OTf )2, PyBox/
Cu(OTf )2 and PyBox/Yb(OTf )3, provided a moderate yield with
poor enantioselectivity (entries 2–4). Next, a range of Lewis
acids were examined by complexing with Feng N,N′-dioxide
ligands. A tetradentate ligand complex L3-RaPr2/Y(OTf )3 could
accelerate the rearrangement to give Pyox 2a in 80% yield and
89% ee (entry 5). Evaluation of the peripheral amide subunits
indicated that moderate steric hindrance at 2,6-substitutions
high enantioselectivities (85–96% ee with 87–98% yield), and
the best results (98% yield and 96% ee) were obtained by
using Yb(OTf )3 as the metal precursor (entries 11–13), whereas
La(OTf )3 and Ce(OTf )3 with larger ionic radii decreased the
enantioselectivity and reactivity dramatically (entries 9 and
10). Finally, the enantioselectivity was further improved (98%
ee) with a slightly decreased yield by lowering the reaction
temperature to 10 °C (entry 14).
Both substituents on the pyridine ring and oxazoline ring
have critical influence on the reactivity and enantioselectivity
in the Pyox/metal salt catalyzed asymmetric reaction through
adjusting the redox ability and steric hindrance of the metal
catalysts. As can be surmised from the data in Table 2, our
investigations into the generality revealed that the Heine reac-
tion occurred readily where either substituted-pyridines or

Table 2 The substrate scopea

Fig. 1 Selected chiral ligands tested in the study.

Table 1 Optimization of the reaction conditionsa

Entry Ligand Metal salt Yieldb (%) eec (%)

1d BINAP Pd(OTf)2 Trace —

2d iPrBox Cu(OTf)2 50 0
3d Py-Box Cu(OTf)2 67 0
4d Py-Box Yb(OTf)3 69 7
5 L3-RaPr2 Y(OTf)3 80 89
6 L3-RaEt2 Y(OTf)3 80 94
7 L3-RaMe2 Y(OTf)3 85 90
8 L3-RaEt2Me Y(OTf)3 80 87
9 L3-RaEt2 La(OTf)3 37 18
10 L3-RaEt2 Ce(OTf)3 49 68
11 L3-RaEt2 Pr(OTf)3 87 85
12 L3-RaEt2 Eu(OTf)3 97 92
13 L3-RaEt2 Yb(OTf)3 98 96
14e L3-RaEt2 Yb(OTf)3 94 98
a
Unless otherwise noted, the reactions were carried out with 1a
(0.1 mmol) and the preformed catalyst {ligand : metal salt (1.05 : 1, a
Unless otherwise noted, the reactions were carried out with 1
10 mol%)} in CHCl3 (0.1 M) at 35 °C under an N2 atmosphere. (0.1 mmol) and the preformed catalyst L3-RaEt2/Yb(OTf)3 (1.05 : 1,
b
Isolated yields. c ee values were determined by UPC2. d Ligand/metal 10 mol%) in CHCl3 (0.1 M) at the corresponding temperature. Isolated
salt (1.2 : 1, 10 mol%). e At 10 °C. yields. The ee values were determined by UPC2. b L3-PrEt2.

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aziridines are tolerable. A wide range of meso-aziridines 2b–2l

bearing different substitutions on the N-picolinoyl unit were
evaluated. The electronic properties of the substituents had an
influence on the reactivity and ee value. Substitutions at the
C4-position (2a–2f ), especially electron-withdrawing ones,
afforded excellent enantioselectivity (88–98% ee with 77–94%
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yield), with the methoxy group as the exception (73% ee with

40% yield), but a good ee value (93% ee) could be obtained by
using the ligand L3-PrEt2 instead (Fig. 1). A methyl substituent
at the C5-position afforded the desired product 2i with a
slightly higher ee value than electron-withdrawing substi-
tutions (2g and 2h). A methyl substituent at the C-3 position
also afforded the desired product (2j) with a good yield and ee
value. When isoquinoline was incorporated into the acyl
moiety, the desired isoquinoline-oxazoline 2k could be
obtained in 90% yield and 72% ee. In addition, the aziridine
unit can be modified with various substituents which pro-
duced a range of chiral Pyox products with variation at the oxa-
zoline unit (2l–2q). Substrates bearing five-, six- and seven-
membered rings underwent the reaction smoothly, delivering
the corresponding products 2l–2o in good yields (70–90%) and Scheme 2 a) The gram-scale experiment and the X-ray structures of
enantioselectivity (89–91% ee). The acyclic meso-aziridine 1p 2a-CuCl2 and iPrPyox-CuCl2; application of 2a in (b) hydrosilylation and
was also a valuable substrate, affording the corresponding 2p (c) conjugation addition.
in 60% yield and 90% ee in the presence of L3-PrEt2. But
diaryl substituted aziridine yielded a formal intramolecular
[3 + 3] product in a high yield (see the ESI† for more infor-
mation). Notably, the exo-bridged aziridine 1q delivered the
desired Pyox 2q with a bridge ring in an excellent yield (95%)
and up to 99% ee in the presence of the chiral metal complex
catalyst.
To show the synthetic utility of the current catalytic system,
a scale-up synthesis of 2a was carried out under the optimized
reaction conditions. As shown in Scheme 2a, the reaction at
the 6 mmol scale efficiently yielded Pyox 2a with 91% yield
(1.098 g) and 98% ee. Next, we obtained a single crystal of the
2a-CuCl2 complex14 and the absolute configuration of 2a was
determined to be (3aS,7aR) by X-ray analysis. In comparison
with the copper complex of iPrPyox,15 both complexes adopt a
distorted square planar geometry via two-nitrogen coordi-
nation. The N–Cu–N angle of 2a is slightly smaller than that of
iPrPyox (79.8° vs. 80.6°), and the two superimposed crystal
structures manifest an analogous and steric bias between the
cyclic and acyclic oxazoline units. Encouraged by these results,
Pyox 2a was evaluated as a Lewis base catalyst in asymmetric
hydrosilylation of (naphthalen-1-yl)ethenone 3 (Scheme 2b).3
The desired reduced product 4 was obtained in 98% yield and
62% ee. Additionally, Pyox 2a can also be used as a ligand
coordinating with Pd(TFA)2 in the conjugation addition reac-
tion of nitroalkene and 4-methylphenylboronic acid
(Scheme 2c),16 and the desired product 5 was obtained with
81% yield and 75% ee. These results indicated that the cata-
lytic products have potential as chiral ligands and catalysts in
asymmetric catalysis.
With the goal of identification of the mechanism, we
carried out the reaction of disubstituted aziridine 1r. As shown
in Scheme 3a, the Pyox product 2r with 5,5-disubstitutions as Scheme 3 Mechanism studies.

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Research Article
well as the related enamine 6r rather than 2r′ with 4,4-disubsti-
tutions were isolated as the major products under the standard
reaction conditions, although the enantioselectivity was out of
control. This indicates that the reaction might proceed via an
SNi mechanism, which occurs via heterolysis ( path a) to gene-
rate a relatively stable intermediate. In comparison, the
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racemic reaction of 1a proceeded well with the assistance of
NaI, which is proposed via an SN2 mechanism (Scheme 3b).
However, the reaction did not occur when bridged 1q was
mixed with NaI, which might be due to the fact that the steric
hindrance of the bridge ring is disadvantageous for the substi-
tution of iodide (Scheme 3c). The chiral catalyst promoted
reaction of 1q proceeded well, implying that the SNi mecha-
nism is dominant, and the anion-involved SN2 mechanism
could be ruled out in this system,17 and it is also different
from previous intermolecular desymmetric processes.6–13
Based on the absolute configuration of the product 2a and
the single-crystal structure of the catalyst L3-RaEt2/Yb(OTf )3,18
possible work modes to unveil the enantiocontrol are provided
in Scheme 3d. Initially, the chiral Yb(III) catalyst bonds 2-picoli-
noyl-aziridine 1a with the two nitrogens, and the pyridine ring
is located above the bicyclic ring of the ligand where CH–π inter-
action could stabilize the state to extend based on our previous
study.18 The mode in the left was unfavorable due to the block
raised from the lower left amide substitution of the ligand with
the ring of 1a. Alternatively, the orientation of the substrate in
the right mode has priority where the cyclic backbone of aziri-
dine toward the groove between the downward amide and the
bicyclic ring of the ligand. Therefore, the desired (3aS,7aR)-
product 2a can be produced via an SNi mechanism and is
released from the catalyst after dissociation.
Conclusions
In summary, we demonstrated an asymmetric Heine reaction
of meso-N-(2-picolinoyl)-aziridines catalyzed by a chiral Yb(III)–
N,N′-dioxide complex. It produces a highly enantioenriched
pyridine-oxazoline library in decent yields across a series of
structural modifications. The catalytic products also show
potential as both Lewis base catalysts and ligands in asym-
metric catalysis. Based on the X-ray crystal structure of the
catalyst as well as the product and primary control experi-
ments, a possible catalytic mode was proposed. Further efforts
to apply the catalyst system to other transformations are
underway.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (21890723 and 21921002) for financial support.
1534 | Org. Chem. Front., 2022, 9, 1531–1535
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