Synthesis of 1,2,4-oxadiazolidines via [3+2] cycloaddition of nitrones with carbodiimides

Article abstract of DOI:10.1039/c9nj00030e

An efficient [3+2] cycloaddition of nitrones and carbodiimides has been developed. This 1,3-dipolar cycloaddition features high regioselectivity, mild and metal-free conditions, excellent functional group compatibility, and a broad substrate scope. The X-ray structures of two regio-isomers confirmed the regioselectivity of this transformation.

Full text of DOI:10.1039/c9nj00030e

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DOI: 10.1039/C9NJ00030E
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Synthesis of 1,2,4-Oxadiazolidines via [3+2] Cycloaddition of
Nitrones with Carbodiimides
Received 00th January 20xx,
Accepted 00th January 20xx
Yuan Chen,a, † Liuting Fuyue,a, † Gangqiang Wang,a, † Hang Wang,a Chun Lu,a Haibing Guo,a Chiara
St. Amant,b Shaofa Sun *a and Yalan Xing *b
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient [3+2] cycloaddition of nitrones and carbodiimdes has reaction of nitrones and carbodiimides for the synthesis of a
been developed. This 1,3-dipolar cycloaddition features high substituted quinolone.7 These examples from the literature
regioselectivity, mild and metal-free conditions, excellent suffer poor selectivity, harsh conditions, and
a limited
functional group compatibility, and a broad substrate scope. X-ray substrate scope. Herein, we report our systematic studies on
structures of two regio-isomers confirmed the regioselectivity of the [3+2] cycloaddition reaction of nitrones and carbodiimides
this transformation.
from the highly regioselective synthesis of 1,2,4-
oxadiazolidines in high yields and mild conditions.
Scheme 1. [3+2] cycloaddition of nitrones with carbodiimides
Introduction
The 1,3-dipolar cycloaddition reaction is one of the most
important methods for generating heterocyclic structures of
different sizes, ranging from three-membered to macrocyclic
rings.1 1,3-Dipolar cycloaddition reactions of nitrones with
different dipolarophiles are well-studied reactions in synthetic
organic chemistry.2 Our research team has a long-standing
interest for the development of novel cycloaddition reactions
for the synthesis of heterocycles.3 Recently, we reported
highly efficient [3+3] cycloaddition reactions of in situ
generated aza-oxyallyl cations with nitrones (Scheme 1).4
As part of our continuous effort of developing efficient
syntheses of bio-active heterocyclic compounds, we decided to
explore 1,3-diploar cycloaddition reactions of nitrones and
carbodiimides. Carbodiimides have been utilized as
dipolarophiles for different cycloaddition reactions.5 However,
studies on cycloaddition of nitrones and carbodiimides is very
limited. In 1972, Komatsu described a cycloaddition reaction of
nitrones with diphenylcarbodiimide yielding a mixture of three
products oxadiazolidine, triazolidinone, and amidine (Scheme
1).6 In 1998, Mekheimer published a 1,3-dipolar cycloaddition
a. Non-power Nuclear Technology Collaborative Innovation Center, School of
Nuclear Technology and Chemistry & Biology, Hubei University of Science and
Technology, Xianning 437100, ChinaAddress
Results
b. Department of Chemistry, William Paterson University of New Jersey, 300
Pompton Road, Wayne, NJ 07470, US
c. † These three authors contributed equally to the work
We began our investigation of the [3+2] cycloaddition of
nitrones
with
carbodiimides
using
(Z)-N-methyl-1-
phenylmethanimine oxide 1a and diphenylmethanediimine 2a
as model substrates (Table 1). First, we utilized acetonitrile as
the solvent and tested the reaction under different
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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o
temperatures (50, 60, 80 and 110 C) for 4 hours (entry 1-4). R2 group on nitrones to a methyl substituent, and then varied
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We then decreased the reaction temperature to room different R1 groups. Nitrones with aromaDtiOcIs: u10b.1s0ti3t9u/eCn9tNsJ0o0n0t3h0eE
temperature and increase the reaction time to 24 hours (entry R1 position gave good to excellent yields (3a-3k, 80-90%). In
5). It was found that the best yield (89%) was achieved at 60 oC general, electron-donating groups such as methyl and methoxy
(entry 4). We then screened many different solvents such as on the phenyl ring of R1 gave slightly higher yields (3b
toluene, DMF, DMSO, 1,4-dioxane, ethanol, methanol, ethyl 3d) of the cycloaddition products than electron-withdrawing
acetate, DCM, THF, and TFIP under different reaction groups such as halogens and nitro groups (3c 3e 3f 3h 3i,
, 3g, and
,
,
,
,
temperatures and times (entry 6-15). However, they all gave a and 3j). Substituents on different positions of the phenyl rings
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lower yield than the optimal conditions found using did not produce significantly different yields. Heteroaromatic
acetonitrile. Therefore, using acetonitrile as solvent at 60 C groups at R1 also generated the desired product in excellent
for 4 hours was identified as the optimal conditions for this yield (3k). Additionally, when the aliphatic substituent propyl
o
transformation.
group was on R1 of nitrone, the reaction gave slightly lower
yield (3l, 75%) compared to the aromatic substituents. The
reaction yield was dropped when a benzyl group was on the R2
nitrone (3m, 70%).
Table 1. Optimization of reaction conditions
Scheme 2. Substrate scope for nitrones
Entry a
Solvent
CH3CN
T/oC
110
80
T/h
4
Yield b
40%
56%
89%
64%
24%
50%
<5%
<5%
69%
1
2
3
4
5
6
7
8
9
CH3CN
4
CH3CN
60
4
CH3CN
50
4
CH3CN
r.t.
60
24
24
24
24
4
Toluene
DMF
60
DMSO
60
1,4-dioxane
60
10
11
12
13
14
15
CH3CH2OH
CH3OH
CH3CO2Et
DCM
60
r.t.
r.t.
r.t.
r.t.
r.t.
24
24
24
24
24
24
<5%
<5%
<5%
<5%
<5%
<5%
THF
TFIP
a. Reaction conditions: a mixture of 1a (1.5 mmol), 2a (1.0 mmol) in solvent
(2 mL) was stirred at the setting temperature for a certain period of time.
b. Yield of isolated product.
Next, we investigated the substrate scope and the limitation of
carbodiimides, and found that this cycloaddition reaction gave
excellent regioselectivity when asymmetric carbodiimides
were utilized. Aromatic rings bearing different substitutions
were chosen as the R3 and R4 groups of carbodiimides. To our
delight, substrates with either electron-donating or electron-
withdrawing groups all gave good to excellent yields for the
cycloaddition products. More importantly, electron-
withdrawing and donating groups on carbodiimines gave
With the optimal conditions in hand, we explored the
substrate scopes and functional group compatibility of both
nitrones and carbodiimides. As shown in Scheme 2, the
substrate scope of nitrone was studied based on the [3+2]
cycloaddition of various nitrones and diphenylmethanediimine
2a under the optimal conditions. We found that this
cycloaddition reaction had a very broad substrate scope and
an excellent functional group compatibility. We first fixed the
different regio-isomers (4a, 4b and 4i vs. 4c, 4d, 4f, 4g and 4h)
in excellent selectivity. This regioselectivity follows the general
rule of regiochemistry of nitrone-olefin [3+2] cycloadditions
and was controlled by the frontier molecular orbitals on the
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nitrones (the dipole) and the carbodiimides (dipolarophile).8 synthesis of heterocycles are under development in our research
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We believe steric effect also plays a critical role in this team and will be reported in due course.
DOI: 10.1039/C9NJ00030E
cycloaddition reaction. When both electron-donating and
electron-withdrawing groups are on the same phenyl ring, the
bulkier phenyl group with two substituents is added to the less
hindered side of the nitrone in good yield (4j). We also see the
steric effect on substrate 4i, where the bulkier naphthalenyl
group is added to the less hindered side of nitrone.
Additionally, a highly sterically hindered dipolarophile was also
Scheme 4. X-ray structures of 4a and 4f
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tolerated in this reaction and gave a good yield (4k
, 66%).
Scheme 3. Substrate scope for carbodiimides
Acknowledgments
This work was supported by the Hubei Provincial Natural Science
Foundation of China (2017CFC859) and the National Students,
Platform for Innovation and Entrepreneurship Training Program
(201810927008) are greatly appreciated. This research was
supported by a grant from the Center for Research, College of
Science and Health, William Paterson University of New Jersey.
The authors are also grateful to the ART program, College of
Science and Health, and Chemistry Department of William
Paterson University.
Notes and references
To confirm the structure of the cycloaddition products and the
regioselectivity of this transformation, we obtained the X-ray
crystallography structures of both 4a and 4f. As shown in
Scheme 4, the electron donating group (methyl group on 4a) and
the electron withdrawing group (fluoro group on 4f) cause
different regio-isomers.
1 a) A. A. Tabolin, A. Y, Sukhorukov, S. L. Ioffe, A. D. Dilman.
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Conclusion
In summary,
a highly regioselective synthesis of 1,2,4-
oxadiazolidines has been achieved via a [3+2] cycloaddition of
nitrones and carbodiimides in good to excellent yields. X-ray
crystallography confirmed the structure assignment and Synthesis. 2017, 49, 2819-2851. d) B. Bdiri, B-J. Zhao, Z. M. Zhou,
regioselectivity of this cycloaddition. This reaction features mild
and metal-free reaction conditions, excellent functional group
compatibility, and a broad substrate scope. This method also
provides an efficient approach for the synthesis of heterocyclic
oxadiazolidines. More novel cycloaddition reactions for the
Tetrahedron: Asymmetry. 2017, 28, 876-899.
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R2
N
R2
R2
O
CH3CN
60oC
R1
N
O
+
R3 N C N R4
N
R4
N
R3
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Mild conditions
Excellent regioselectivity
High yields