TfOH-catalyzed formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles: Synthesis of tetrafunctionalized 2-imidazolines

Article abstract of DOI:10.1016/j.tetlet.2019.151576

We developed an efficient method for synthesis of tetrafunctionalized 2-imidazolines using TfOH-catalyzed formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles. This is the first report of C–N bond cleavage of N-tosylaziridine dicarboxylates catalyzed by Br?nsted acid and the reaction worked well over wide scope of substrates in good to excellent yields under mild conditions. The method has the potential to be applied to pharmaceutical design and synthesis of tetrafunctionalized 2-imidazolines.

Full text of DOI:10.1016/j.tetlet.2019.151576

Journal Pre-proofs
TfOH-Catalyzed Formal [3+2] Cycloaddition of N-tosylaziridine dicarboxy-
lates and Nitriles: Synthesis of Tetrafunctionalized 2-imidazolines
Qinglu Zuo, Zhichao Shi, Feng Zhan, Zhe Wang, Jin-Shun Lin, Yuyang Jiang
PII:
S0040-4039(19)31375-9
DOI:
https://doi.org/10.1016/j.tetlet.2019.151576
TETL 151576
Reference:
Tetrahedron Letters
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Revised Date:
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30 October 2019
21 December 2019
27 December 2019
Please cite this article as: Zuo, Q., Shi, Z., Zhan, F., Wang, Z., Lin, J-S., Jiang, Y., TfOH-Catalyzed Formal [3+2]
Cycloaddition of N-tosylaziridine dicarboxylates and Nitriles: Synthesis of Tetrafunctionalized 2-imidazolines,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151576
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Tetrahedron Letters
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TfOH-Catalyzed Formal [3+2] Cycloaddition of N-tosylaziridine dicarboxylates and
Nitriles: Synthesis of Tetrafunctionalized 2-imidazolines
Qinglu Zuoa, b, 1 , Zhichao Shia, b, Feng Zhana, b, Zhe Wanga, b, Jin-Shun Lina, b, *, Yuyang Jiangb, c, *
aDepartment of Chemistry, Tsinghua University, Beijing 100084, China.
bThe State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua
University, Shenzhen 518055, China.
cSchool of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
*E-mail address: jiangyy@sz.tsinghua.edu.cn (Yuyang Jiang); lin.jinshun@sz.tsinghua.edu.cn (Jin-Shun Lin).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We developed an efficient method for synthesis of tetrafunctionalized 2-imidazolines using TfOH-
catalyzed formal [3+2] cycloaddition of N-tosylaziridine dicarboxylates and nitriles. This is the first
report of C-N bond cleavage of N-tosylaziridine dicarboxylates catalyzed by Brønsted acid and the
reaction worked well over wide scope of substrates in good to excellent yields under mild conditions.
The method has the potential to be applied to pharmaceutical design and synthesis of
tetrafunctionalized 2-imidazolines.
Available online
Keywords:
TfOH
2019 Elsevier Ltd. All rights reserved.
N-tosylaziridine dicarboxylates
Nitrile
Tetrafunctionalized 2-imidazoline
1. Introduction
However, there still remain challenges in this field such as
difficult availability of precursors and the use of complex
reagents including transition metal salts. Hence, a novel and
efficient synthesis approach to the potentially bioactive
heterocycles is still valuable.
The synthesis of tetrafunctionalized 2-imidazolines has
received considerable attention due to their common use as
bioactive molecules,1-7 organocatalysts8 and ligands for
asymmetric synthesis9,10 (Figure 1). For example, Nutlin-3, which
is based on a tetrasubstituted 2-imidazoline scaffold, efficiently
disrupted the interaction between p53-MDM2 for cancer
treatment.5,6 Several approaches are known to synthesize
A. Previous work: Lewis acids-catalyzed functionalization of N-tosyl aziridines
C-C bond cleavage
dicarboxylates with diverse nucleophiles(
)
tetrafunctionalized
2-imidazolines,
involving
multistep
Ts
OR1
Ts
Lewis
acids
cyclization of 1,2-diamines11-15 or -amino alcohols,16 the metal-
N
N
CO2R1
CO2R1
O
catalyzed or metal-free protocols for multicomponent reactions17-
+ Nu
M
Azaheterocycles
Ar
Ar
O
OR1
25
or formal [3+2] annulation,26-30 and the transformations of the
Nu
protected α, β-diamino esters31, unsymmetrical imidazolines32,33
or imidoyl chlorides with aziridines.34
Nu: imines, aldehydes, indoles, alkynes, alkenes, ketenimines,
isocyanides, cyclopropanes et al. except nitriles
O
CN
H
B. Previous work: Brønsted acid-catalyzed [3+2] cycloaddition of cyclopropane
Cl
Cl
H3C
O
N
NH
N
nitriles C-C bond cleavage
( )
1,1-diesters or oxiranyldicarboxylates with
Bn
F
Ph
N
N
N
N
N
OiPr
X
R2
R3
CO2R1
CO2R1
X
Ph
TfOH
N
N
CR4
R2
R3
CO2R1
CO2R1
+
N
EtO2C
iPrO
Ph
N
R4
F
X
O, CH
2
=
Neuropeptide Y Y5
receptor antagonist
Nutlin-3
Ph
TCH-013
NF-kB inhibitor
C. This work: Brønsted acid-catalyzed [3+2] cycloaddition of N-tosylaziridines
nitriles (C-N bond cleavage)
dicarboxylates with
Ph
R1
R1
N
N
N
p-Tol
N
p-Tol
R2O2C
R2O2C
Bn
Bn
Ts
OH
N
N
N
N
TfOH
CO2R2
N
CR3
Br
N
Ph
Ph
Ph
+
Ph
Pd
R3
N
N
N
N
N
CO2R2
Ar
Br
N
Ph
CH3
Ph
Ph
Ph
Ph
Ar
Tetrafunctionalized 2-imidazoline
Br
Pybim
Chiral Bis(imidazoline) NCN Pincer
Pd(II) Bromide Complexes
IAP
Scheme 1. Different cleavage ways of aziridines.
Figure 1. Representative products containing 2-imidazoline cores in different
areas.

2
Tetrahedron
The formal [3+2] annulations of N-tosylaziridine dicarboxylates
Table 1. Initial Exploration of Reaction Conditions a
(donor–acceptor aziridines) with diverse nucleophiles has
emerged as a potentially powerful approach for convenient
access to structurally complex five-membered azaheterocycles
via Lewis acid-catalyzed/mediated C-C bond cleavage of donor–
acceptor (DA) aziridines (Scheme 1A).35-48 Although most
nitriles are known to be poor dipolarophiles for [3+2]
cycloaddition reactions, the groups of Zhong & Zeng49 and
Wang50 have independently demonstrated that TfOH-catalyzed
cycloaddition of oxiranes dicarboxylates or donor-acceptor
cyclopropane and nitriles successfully via C-C bond cleavage of
oxiranes or cyclopropanes (Scheme 1B).
Ts
N
Ts
EtOOC
EtOOC
Catalyst.
Temp.
N
COOEt
COOEt
+
PhC
N
N
1a
2a
3a
Entry
Catalyst (equiv)
Solvent
T (oC)
yield (%)b
1c
2c
3c
4c
5
Sc(OTf)3
Sc(OTf)3
DCM
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
50
0
decompose
decompose
decompose
decompose
N. R.
N. R.
N. R.
N. R.
N. R.
N. R.
89
Cu(OTf)2
DCM
Cu(OTf)2
TFA (1.0)
PTSA (1.0)
HCl (1.0)
Inspired by the above achievements and based on our
interest in developing antitumor heterocycles and potentially
bioactive azaheterocycles, we envisioned that the formal
[3+2] cycloaddition of N-tosylaziridine dicarboxylates and
nitriles to provide tetrafunctionalized 2-imidazolines.
Herein, we describe the first example of the development of
6
7
8
HNO3 (1.0)
TFAH (1.0)
Ac2O (1.0)
Tf2O (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (0.5)
TfOH (0.2)
TfOH (0.1)
TfOH (0.5)
TfOH (0.5)
9
a
remarkably mild TfOH-catalyzed formal [3+2]
cycloaddition of N-tosylaziridine dicarboxylates and nitriles,
providing facile and step-economical access to
10
11d
12
13
14
15
16
17
18
a
94
tetrafunctionalized 2-imidazolines bearing ester functional
groups, which serve as key building blocks in the potent NF-
κB inhibitor TCH-013 (Scheme 1C).51,52 Of particular note is
the fact that Brønsted acid have been not exploited in
annulation reaction of DA aziridines with diverse
nucleophiles or electron-rich reaction groups, though the
similar catalytic process has been reported to prepare
trifunctionalized 1H-imidazoles using nitriles and common
aziridines in the presence of TfOH via Ritter reaction,53
where the electronic nature of common aziridines were
different from DA aziridines. In this light, DA aziridines
inherently favour C-C bond cleavage, which was supported
by density functional theory (DFT) studies54 and the
experimental results showed that Lewis acids catalyzed C-C
bond heterolysis of DA aziridines.
DCM
trace
95
80
70
64
45
aReaction conditions: N-tosylaziridinedicarboxylate 1a (0.025 mmol),
benzonitrile 2a (0.2 mL, analytical-reagent grade), and the nitrile also served
b
as the solvent. Isolated yields based on 1a were given. N.R. stands for no
reaction, decompose means 1a was decomposed and the product 3a was not
c
detected. The reaction was conducted at 0.05 mmol scale and 20% catalyst
was added. dThe transformation could be also catalyzed by TfOH which
generated from Tf2O in benzonitrile with trace amounts of water after strictly
controlling the absence of water.
2. Results and Discussion
ester groups resulted in a decrease in yields, such as, the reaction
did not progress in the presence of the tert-butyl ester. (see Table
S1 in ESI for more details). We also explored various aryl groups
with electron-withdrawing (Cl, I, NO2) or electron-donating
groups (Me) of aziridines (3f-3i) and found that p-methylphenyl
substitution on aziridine 1i performed better and gave the product
3i in 72% yield. The N-substitution on aziridine dicarboxylates
had little influence on the reactivity generally (3a, 3c, 3j-3e) and
N-trifluoromethyl phenyl sulfonyl aziridines 1l reacted with 2a to
provide the desired 2-imidazolines 3l in 80% yield. The
configuration of 3e was determined by X-ray crystallographic
analysis (see Figure S1 in ESI).
We started to test our hypothesis by reacting 3-phenyl-1-
tosylaziridine dicarboxylates 1a and benzonitrile 2a as model
substrates in DCM using Sc(OTf)3 as a conventional Lewis acid
(Table 1, entry 1).55-57 Unfortunately, we found 1a was
decomposed and no identifiable products could be isolated.58 And
the same result was observed when excess nitrile was served as
the solvent without DCM (entry 2) and in the presence of
Cu(OTf)2 with or without DCM as solvent (entries 3-4).
Inspired by the above achievement,49,50 we next turned our
attention to Brønsted acids. On account of possible protonation of
nitriles by Brønsted acid, excess 2a was needed to complete the
reaction. Several Brønsted acids and acid anhydrides were
screened (entries 5-13), and only Tf2O and TfOH could promote
the reaction to give the [3+2] cycloaddition product 3a in more
than 85% yield when excess nitrile was served as the solvent due
to their strong proton-donating properties. When the amount of
TfOH was decreased to 10%, the yield decreased to 70% (entries
12, 14-16). The reaction performed not well at higher or lower
temperature (entries 17-18). As suggested above, the optimal
reaction condition was selected as 0.5 equiv of TfOH, 30 oC and
excess nitriles as solvent.
We next turned to investigate the scope of substituents on
nitriles 2 (Table 2B). Results of the cycloaddition of 1a with
various nitriles were delightful. Various alkyl nitriles, including
acetonitrile, isobutyronitrile, and butyronitrile gave the
corresponding product 3m-3o in 77-95% yields while
trimethylacetonitrile didn’t reacted with aziridines. The numbers
of -H to these nitriles varies from each other, and we proposed
that these protons could affect the process. Those nitriles with
vinyl groups also gave an excellent result to obtain the product
3p-3q in 72-75% yields. It is worth mentioning that the terminal
C=C bond of but-3-enenitrile has been transferred to the internal
place during the cycloaddition process and it gave the product 3p
in 75% yield. We also explored that when changing the number
of carbons between the imidazoline skeleton and the aryl group,
With the optimal reactions established, we next investigated
the substrate scope on N-tosylaziridine dicarboxylates 1 (Table
2A). We first examined the effect of the ester moieties on
reaction outcome. The ethyl (3a, 3c) and methyl ester (3b, 3d)
were also compatible but increasing the steric hinderance of the

Table 2. Substrate Scope for N-tosylaziridine dicarboxylates and nitriles a,b
enantiopurity erosion could probably be the partial
decomposition60 or racemization61 of the chiral aziridine (R)-1a,
which indicated that nucleophilic attack of the nucleophilic nitrile
2 could proceed through a SN2 model.
R1
R2OOC
R1
N
R2OOC
N
R3
COOR2
COOR2
TfOH (0.5 equiv)
R3C
N
+
N
30 o
C
Ts
1
2
3
Ts
N
X
X
EtOOC
TfOH (0.5 equiv.) EtOOC
N
COOEt
COOEt
PhCN
A. Scope for substituents on different N-tosylaziridine dicarboxylates
30 o
C
Ph
Ph
90%, 50% ee
N
Ph
3a,
Ts
N
R2OOC
R2OOC
EtOOC
EtOOC
SO2Ph
N
R2OOC
R2OOC
Ts
N
1a
(R)- , 99% ee
2a
chiral
N
N
N
Scheme 2. The formal [3+2] cycloaddition of (R)-1a with benzonitrile 2a
X
2 = Et, 94% (2 h)
3c,
3d,
3f,
X = Cl, 28% (12 h)
On the basis of the above observations and previous studies.53
The reaction pathway for this cycloaddition reaction is proposed
(Scheme 3). Initially, a proton from TfOH is coordinated to the
nitrogen of the aziridine and one of the carbonyl groups to
enhance the electrophilicity of the adjacent carbon of DA
aziridines, followed by the nucleophilic attack of the nitrile 2 to
the aryl-substituted C2 atom of the activated DA aziridines in a
SN2-type fashion to form a Ritter process intermediate 5 via C-N
bond cleavage. Finally, the following nucleophilic attack of the
TsNH on the nitrile carbenium affords tetrafunctionalized 2-
imidazolines 3. This proposed mechanism is similar to that of
[3+2] cycloaddition of oxiranes dicarboxylates with aldehydes
via C-O bond cleavage.62
R
2 = Et, 77% (1 h)
3a,
3b,
R
R
2 = Me, 97% (4 h)
R
2 = Me, 88% (1 h)
3g,
3h,
3i,
X = I,
X = NO2, 41% (12 h)
X = Me, 72% (3 h)
49% (4 h)
R1
Ms
N
EtOOC
EtOOC
O
S
N
EtOOC
EtOOC
O
N
N
3e,
94% (4 h)
3e
3j,
3k,
3l,
R
1 = NO2, 57% (12 h)
R
1 = Cl, 88% (12 h)
1 = CF3, 80% (12 h)
R
B. Scope for substituents on different nitriles
Ts
Ts
Ts
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
EtOOC
N
R3
N
N
H
R3
Ts
n
H
N
Ts
Ts
Ts
N
EtO2C
EtO2C
OEt
O
O
N
N
N
N
H
N
N
-H
Ar
Ar
R
C
OEt
CO2Et
R
N
OEt
CO2Et
O
H
H
Ar
H
H
3 = Me, 90% (1 h)
R
3 = 4-Me,80% (1 h)c
EtO
O
Ar
3t,
R C N
3r,
3m,
3n,
3o,
3p,
3q,
n = 1, 78% (2 h)
n = 2, 55% (2 h)
R
R
3 = 2-F, 76% (12 h)
3 = 3-F, 66% (12h)
3u,
3v,
3s,
2
4
3
R
3 = iPr, 77% (4 h)
3
5
1
95% (12 h)c
R
R
=
Ts
EtOOC
EtOOC
R3 = 4-F, 67% (12 h)c
R3
R3
=
75% (3 h)
72% (3 h)
3w,
N
Ph
=
CH3
N
Ts
N
EtOOC
Scheme 3. Proposed mechanism
Ts
EtOOC
EtOOC
3y,
33% (1 h)
Cl
N
S
CH3
The further synthetic application of tetrafunctionalized 2-
imidazolines has been showcased by the transformation of 3n,
which gave NH free 2-imidazoline 6 in 83% yield easily in the
presence of LiCl at 160 °C in DMSO by the remove of Ts group
and one ester group (Scheme 4).63
N
N
e
d
3z
, 20%, dr 6:1, (12 h)
3x,
54% (3 h)
3y
aReaction conditions: N-tosylaziridine dicarboxylate 1 (0.2 mmol), nitrile 2
(0.3 mL), and TfOH (8.8 mL, 0.1 mmol) at 30 oC, the excess nitrile also
Ts
H
N
EtOOC
EtOOC
EtOOC
N
N
LiCl, DMSO
160 oC, 2 h
b
c
N
served as the solvent. Isolated yields based on 1 were given. The reaction
was conducted at 35 oC . dThe reaction was conducted at 0 oC. eUsing ethyl 3-
phenyl-1-tosylaziridine-2-carboxylate 1o as the aziridine substrate.
3n
6, 83%
Scheme 4. Synthetic application
the cycloaddition still performed well to give the product 3r-3s in
77-88% yields. Electron-donating group (Me) and different
positions of electron-withdrawing group (F) on the aryl moiety of
the aromatic nitriles are amenable, affording the desired product
3t-3w in 66-80% yields. Unfortunately, electron-rich nitrile with
p-methoxyphenyl group didn’t reacted with N-tosylaziridine 1a
with or without solvent (see Table S2 in ESI for more details). It
is noteworthy that thiophene-substituted nitrile was well-tolerated
in the presence of strong acid TfOH to furnish 3x in 54% yield.
Furthermore, the 2,2′-diester N-tosyl-aziridine bearing 4-Cl
substituent at aryl moiety could react with acetonitrile to give the
corresponding cycloaddition product 3y (confirmed by X-ray
study, Figure S2 in ESI). Additionally, it is noteworthy that the
similar transformation observed with N-tosylaziridine bearing
only one ester, afforded the corresponding product 3z in 20%
yield with 6:1 dr.
3. Conclusions
To sum up, we developed a novel and efficient route to
synthesize tetrafunctionalized 2-imidazolines using TfOH-
catalyzed formal [3+2] cycloaddition of N-tosylaziridine
dicarboxylates and nitriles. This is the first report of C-N bond
cleavage of N-tosylaziridine dicarboxylates catalyzed by
Brønsted acid and the method has the potential to be applied to
pharmaceutical design and synthesis of tetrafunctionalized 2-
imidazolines. Further study on biological activity is under
investigation in our laboratory.
Acknowledgments
The authors would like to thank the financial supports from
the Shenzhen Development and Reform Committee (Nos.
20151961 and 2019156) and Department of Science and
Technology of Guangdong Province (No. 2017B030314083).
To gain some insight into the reaction mechanism, we have
explored the cycloaddition of the chiral aziridine59 (R)-1a with
benzonitrile 2a. The reaction proceeded smoothly to afford the
corresponding chiral product 3a in 90% yield with 50% ee under
the otherwise identical reaction conditions (Scheme 2). The

4
Tetrahedron
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Supplementary Material
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Graphical Abstract

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template box below.
TfOH-Catalyzed Formal [3+2] Cycloaddition
of N-tosylaziridine dicarboxylates and
Nitriles: Synthesis of Tetrafunctionalized 2-
imidazolines
Leave this area blank for abstract info.
Qinglu Zuoa, b, 1 , Zhichao Shia, b, Feng Zhana, b, Zhe Wanga, b, Jin-Shun Lina, b, *, Yuyang Jiangb, c, *
R2
R2
O
S
R1O2C
R1O2C
O
O
S
O
N
TfOH
N
3
R3
+
N C
R
CO2R1
CO2R1
30 oC, 1-12 h
N
Ar
Ar
Tetrafunctionalized
2-imidazolines
N-tosylaziridine
dicarboxylates
Nitriles
[3+2]
mild condition
25 examples
C-N bond cleavage
azaheterocycles
(up to 97% yield)
Highlights
 TfOH-catalyzed
cycloaddition
of
N-
tosylaziridine dicarboxylates and nitriles gave
tetrafunctionalized 2-imidazolines.
 The method features mild conditions and wide
scope of substrates.
 First example of C-N bond cleavage of N-
tosylaziridine dicarboxylates catalyzed by
Brønsted acid.
 A SN2 process.