Magnesium Catalysis Mediated Tetrazoles in Desymmetrization Reaction of Aziridines

Article abstract of DOI:10.1021/acs.orglett.7b01333

A magnesium-catalyzed asymmetric ring-opening reaction of aziridines with substituted tetrazoles is reported. The current protocol proceeds smoothly and gives the corresponding desymmetrization products in high yields and good enantioselectivities. A new

Full text of DOI:10.1021/acs.orglett.7b01333

Letter
pubs.acs.org/OrgLett
Magnesium Catalysis Mediated Tetrazoles in Desymmetrization
Reaction of Aziridines
Dan Li, Kezhou Wang, Linqing Wang, Yuan Wang, Pengxin Wang, Xin Liu, Dongxu Yang,*
and Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A magnesium-catalyzed asymmetric ring-open-
ing reaction of aziridines with substituted tetrazoles is
reported. The current protocol proceeds smoothly and gives
the corresponding desymmetrization products in high yields
and good enantioselectivities. A new chiral ligand was
synthesized from azetidine and (R)-BINOL and was employed
in the current in situ generated magnesium catalyst. The
Mg(II)-mediated desymmetrization reaction could be per-
formed on gram scale under mild conditions and was
transformed to chiral alkyl amines by a deprotection process.
itrogen-containing heterocycles and their derivatives are
Nwidely distributed in numerous naturally occurring
compounds, many of which exhibit significant biological
properties.1 In this regard, substituted tetrazoles are valuable
nitrogen-containing heterocycles to medicinal chemistry and
often act as key pharmacophores in many drugs, such as losartan
and valsartan, antagonists of angiotensin II receptor.2 As such,
the introduction of tetrazoles into more complex skeletons is
meaningful for discovering of pharmaceutical candidates,3 and it
would be highly desirable to construct enantioenriched
structures while equipping substituted tetrazoles in one single
step. However, to date, there are limited examples established for
substituted tetrazoles in asymmetric reactions. In the docu-
mented methods, catalytic asymmetric reactions concerning
substituted tetrazoles is narrow, often restricted to asymmetric
conjugate reactions to different acceptors by metal or organo-
catalysis methods since the seminal work accomplished by
Jacobsen and co-workers in 2005.4,5 Very recently, Piotrowski
and co-workers reported an interesting three-component
reaction between substituted azoles, aldehydes, and different
acylation reagents in the presence of Lewis base catalysts. This
reaction could be used to synthesize valuable substituted
tetrazoles by capping of the equilibrating azole-aldehyde
adducts.6 Considering our ongoing works on ring-opening
reactions of three-membered rings7 and inspired by the well-
documented studies on asymmetric reactions of aziridines,8,9
herein we report the participation of substituted tetrazoles in the
desymmetrization reaction of aziridines for the first time.
transformation proceeded smoothly in the presence of these
magnesium catalysts under mild conditions (Table 1, entries 1−
4; Scheme 1, L1−L4). Next, we examined chiral ligands derived
from BINOL by introduction of C2-symmetric Brønsted bases on
the naphthol rings, and it was observed that these ligands (L5−
L8) gave more potential results when amine groups were
equipped on the phenol ligands. We supposed heterocyclic rings
on the ligands should act not only as steric hindrance groups, but
also as Brønsted bases to activate tetrazoles during the ring-
opening process. We then wondered it would be helpful to
reduce the members of the heterocyclic rings, letting tetrazoles
be activated via hydrogen bond function but not stemmed by the
heterocyclic rings’ structure during the coordination process. To
our delight, a new ligand L9 synthesized from (R)-BINOL and
azetidine showed superior ability in introducing high level of
enantioselectivities compared with other chiral ligands by simply
reducing the heterocyclic rings’ cubage (Scheme 2). On the other
hand, the ligand L10 synthesized from imidazole did not give
higher enantioselectivities, perhaps owing to its relatively weaker
basicity.
Next the detailed conditions were further optimized. Solvent
screening to others, such as xylenes, PhCl, THF, DCM, and
ether, did not give more favorable results as shown in Table 1,
and it was observed that polarity solvents dramatically decreased
the enantioselectivities of the reaction, which might be due to the
solvent’s coordination effects (Table 1, entries 11−16). Other
magnesium salts such as Mg(OTf)2 or Mg(OAc)2 would lead to
low selectivities. Further optimization progress found the
introduction of molecular sieves into the reaction led to higher
er values (Table 1, 19−22).11
On the basis of our recent efforts to investige magnesium
catalysis in asymmetric synthesis,10 the initial experiment began
by evaluating a series of chiral ligands in the Mg(II)-mediated
desymmetrization of aziridine 1a with tetrazole 2a. The initial
trial of oxazoline−OH ligand L1 and some simple BINOL
derivatives did not give more promising er values, although the
Received: May 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01333
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Organic Letters
Letter
Table 1. Optimization of the Tetrazole-Involved
Desymmetrization Reaction
Scheme 2. Synthesis Process of Ligand L9
a
b
crystallographic analysis of 3i with a halogenated protected
entry
ligand
solvent
additives
er
group.12
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
tol
54:46
60:40
2
tol
Scheme 3. Substrate Scope and X-ray Crystallographic
Analysis of the Desymmetrization Product
3
tol
51.5:48.5
53:47
4
tol
5
tol
65:35
6
tol
69:31
7
tol
62.5:37.5
65:35
8
tol
9
tol
90:10
10
11
12
13
14
15
16
17
18
19
20
21
22
tol
63.5:36.5
87.5:12.5
87.5:12.5
70:30
xylene
o-xylene
PhCl
DCM
THF
ether
tol
60:40
59:41
50:50
c
62.5:37.5
56.5:43.5
94.5:5.5
97.5:2.5
97:3
d
tol
tol
3 Å MS
4 Å MS
5 Å MS
13x MS
tol
tol
tol
87.5:12.5
a
Reactions were performed with aziridine (1a, 0.10 mmol) and
tetrazole (2a, 0.12 mmol) in toluene (1.0 mL) in the presence of
b
Bu2Mg (20 mol %) and L (20 mol %). The er value of 3a was
c
analyzed by chiral stationary-phase HPLC. Using Mg(OTf)2 instead
d
of Bu2Mg. Using Mg(OAc)2·4H2O instead of Bu2Mg.
Scheme 1. Chiral Ligands Prepared for the Reaction
Then a series of substituted tetrazoles were synthesized and
participated in the desymmetrization reaction. Aryl groups with
different electronic effects were tolerable but led to the
corresponding ring-opening products with different enantiose-
lectivities. Introduction of alkyl groups into the azole’s ring did
not affect the reaction’s efficiency and resulted in moderate or
higher er values, which might depend on the steric hindrance
effects (Scheme 4).
With these optimized conditions, we explored the scope of this
Mg(II)-mediated tetrazole-involved desymmetrization reaction.
First, meso-aziridines with cyclic and acyclic structures were
combined with phenyl-substituted tetrazole 2a after the ring-
opening process mediated by the in situ generated bifunctional
magnesium catalyst, leading to the desired enantioenriched
heterocyclic products in high yields and moderate to excellent er
values (Scheme 3). The absolute configuration of the
desymmetrization products was determined by the X-ray
Furthermore, the tetrazole-involved desymmetrization reac-
tion was carried out on gram scale by utilization of 10 mol % in
situ generated magnesium catalyst, leading to the ring-opening
B
DOI: 10.1021/acs.orglett.7b01333
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Substrate Scope of the Tetrazole-Involved
Desymmetrization Reaction
Scheme 5. Gram-Scale Synthesis and Further
Transformations of the Desymmetrization Products
products in 3a in an excellent yield and enantioselecitivity. The
deprotection process proceeded smoothly by treating 3 with
NaOH at 90 °C, generating the chiral amine 5 and 6 in almost
quantitive yield (Scheme 5).
Finally, a proposed mechanism is proposed in Figure 1. The N-
heterocyclic ring on phenol ligand L9 is supposed to act as a C2-
symmetric Brønsted base that could coordinate with tetrazoles
by a hydrogen bond. Thus, use of these N-heterocyclic rings
would have more positive effects on introduction of high levels of
enantioselectivity. The in situ generated magnesium catalysts
from this type of ligands are highly effective via the bifunctional
catalysis route.
Figure 1. Proposed mechanism of the Mg(II)-mediated desymmetriza-
In summary, we have reported a desymmetrization reaction of
meso-aziridines with substituted tetrazoles mediated by a newly
developed magnesium catalyst.13 A series of enantioenriched
heterocyclic compounds relying on the successful development
of a bifunctional chiral ligand L9 were generated. The catalytic
desymmetrization reaction could be performed on gram scale,
and the protection group is smoothly removed to generate chiral
alkyl amines. Further investigation of bifunctional magnesium
catalysts will be undertaken in our future work.
tion reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01333.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
C
DOI: 10.1021/acs.orglett.7b01333
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Crystallographic data of 3a (CIF)
Letter
(c) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Wang, R. Angew.
Chem., Int. Ed. 2015, 54, 2185. (d) Wang, L.; Yang, D.; Li, D.; Wang, R.
Org. Lett. 2015, 17, 3004. (e) Li, D.; Wang, L.; Yang, D.; Zhang, B.;
Wang, R. ACS Catal. 2015, 5, 7432. (f) Wang, L.; Li, D.; Yang, D.; Wang,
K.; Wang, J.; Wang, P.; Su, W.; Wang, R. Chem. - Asian J. 2016, 11, 691.
(g) Li, D.; Wang, Y.; Wang, L.; Wang, J.; Wang, P.; Wang, K.; Lin, L.;
Liu, D.; Jiang, X.; Yang, D. Chem. Commun. 2016, 52, 9640. (h) Li, D.;
Yang, D.; Wang, L.; Liu, X.; Jiang, X.; Wang, R. Chem. - Eur. J. 2016, 22,
17141.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yangdx@lzu.edu.cn.
*E-mail: wangrui@lzu.edu.cn.
ORCID
(9) For more representative examples on asymmetric ring-opening
reactions of aziridines utilization of magnesium salts, see: (a) Nakamura,
S.; Hayashi, M.; Kamada, Y.; Sasaki, R.; Hiramatsu, Y.; Shibata, N.; Toru,
T. Tetrahedron Lett. 2010, 51, 3820. (b) Della Sala, G. Tetrahedron 2013,
69, 50. (c) Li, J.; Liao, Y.; Zhang, Y.; Liu, X.; Lin, L.; Feng, X. Chem.
Commun. 2014, 50, 6672.
(10) (a) Yang, D.; Wang, L.; Han, F.; Zhao, D.; Zhang, B.; Wang, R.
Angew. Chem., Int. Ed. 2013, 52, 6739. (b) Yang, D.; Wang, L.; Han, F.;
Zhao, D.; Wang, R. Chem. - Eur. J. 2014, 20, 8584. (c) Wang, L.; Yang,
D.; Li, D.; Liu, X.; Zhao, Q.; Zhu, R.; Zhang, B.; Wang, R. Org. Lett. 2015,
17, 4260. (d) Yang, D.; Wang, L.; Kai, M.; Li, D.; Yao, X.; Wang, R.
Angew. Chem., Int. Ed. 2015, 54, 9523. (e) Wang, L.; Yang, D.; Li, D.;
Wang, P.; Wang, K.; Wang, J.; Wang, R. Chem. - Eur. J. 2016, 22, 8483.
(11) Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Chem. Rev. 2016,
116, 4006.
Rui Wang: 0000-0002-4719-9921
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21432003, 81473095,
21602091), the Program for Chang-jiang Scholars and
Innovative Research Team in University (PCSIRT: No.
IRT_15R27), Special Research Found for the Doctoral Program
of Higher Education (20130211130005), and the Fundamental
Research Funds for the Central Universities (lzujbky-2015-282,
lzujbky-2016-ct01).
(12) CCDC 1544156 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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DOI: 10.1021/acs.orglett.7b01333
Org. Lett. XXXX, XXX, XXX−XXX