Synthesis of five-membered cyclic nitrones based on the Lewis acid-catalysed [3+2]-annulation reaction of donor-acceptor cyclopropanes with 1,4,2-dioxazoles

Article abstract of DOI:10.1039/C8CC04656E

A novel synthesis of five-membered cyclic nitrones has been developed based on the Lewis acid-catalysed [3+2]-annulation reaction of D-A cyclopropanes with 1,4,2-dioxazoles. Broad substrate scope and generally good yield make this reaction useful in the p

Full text of DOI:10.1039/C8CC04656E

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Synthesis of five-membered cyclic nitrones based
on the Lewis acid-catalysed [3+2]-annulation
reaction of donor–acceptor cyclopropanes with
1,4,2-dioxazoles†
Cite this:DOI: 10.1039/c8cc04656e
Received 11th June 2018,
Accepted 11th August 2018
Zhe-Hao Wang, Huan-Huan Zhang,* Peng-Fei Xu
and Yong-Chun Luo
*
DOI: 10.1039/c8cc04656e
rsc.li/chemcomm
A novel synthesis of five-membered cyclic nitrones has been developed nitrones based on the [3+2]-annulation reaction between D–A
based on the Lewis acid-catalysed [3+2]-annulation reaction of D–A cyclopropanes and 1,4,2-dioxazoles 214 (Fig. 2(b)).
cyclopropanes with 1,4,2-dioxazoles. Broad substrate scope and
At the outset of our work, we investigated the model reaction
generally good yield make this reaction useful in the preparation of of dimethyl 2-phenylcyclopropane-1,1-dicarboxylate 1a with
nitrones. When a suitable 1,4,2-dioxazole was used, nitrone and dioxazole 2a under various conditions, and the results are
tetrahydrofuran could be prepared in one pot with high atom summarized in Table 1. Under the catalysis of Ni(ClO4)2Á6H2O,
economy.
cyclopropane 1a and dioxazole 2a reacted smoothly in 1,2-dicloro-
ethane at 60 1C and gave the expected product 3a in 30% yield
The synthesis of heterocycles has always been a hot spot of (Table 1, entry 1). The structure of 3a was determined by X-ray
organic synthesis.1 In recent years, donor–acceptor cyclo- crystallographic analysis.15 Then, the screening of Lewis acids
propanes (D–A cyclopropanes) have been emerging as a kind was carried out (Table 1, entries 2–7), and these results demonstrated
of versatile building block for the synthesis of heterocycles.2 For that Yb(OTf)3 is the optimal catalyst, which gave the product 3a in
the construction of nitrogen-containing heterocycles, the annula- 66% yield (Table 1, entry 7). Next, to further improve the yield, the
tion reactions of D–A cyclopropanes with compounds bearing reaction concentration was doubled and the reaction was performed
a carbon–nitrogen multiple bond were very useful. For example, under reflux. After 5 hours, the starting material 2a was fully
under the catalysis of Lewis acids, the imines3 and nitriles4 give exhausted, and the desired product 3a was obtained in 90% yield
five-membered heterocycles via [3+2]-annulation reactions, and (Table 1, entry 8). When toluene was used as the solvent, the yield
the nitrones,5 oximes,6 hydrazones,7 azides,8 and nitronates9 give decreased to 68% (Table 1, entry 9). Therefore, we continued to
six-membered heterocycles via [3+3]-annulation reactions (Fig. 1). optimize the reaction conditions in 1,2-dichloroethane. Furthermore,
In addition, some rearrangement reactions of D–A cyclopropanes reducing the catalyst loading to 5 mol%, after 12 hours, the product
have also been developed for the synthesis of heterocycles.2d,e,10 was obtained in 74% yield (Table 1, entry 10). Finally, to improve the
As far as we know, the synthesis of cyclic nitrones from D–A economy of this reaction, the molar ratio of cyclopropane 1a to
cyclopropanes has not been developed.
dioxazole 2a was reduced from 1.5 to 1.2, but the reaction efficiency
Cyclic nitrones are very useful 1,3-dipoles, which play an was unchanged (Table 1, entry 11). Thus, the conditions in entry 11
important role in the construction of polycyclic compounds.11 (Table 1) were determined to be the optimal.
At present, the cyclic nitrones are usually synthesized via two
main approaches (Fig. 2(a)). One is the oxidation of a cyclic
secondary amine or a hydroxylamine,11a,12 the other is the
intramolecular condensation between a hydroxylamine and a
carbonyl group.11a,13 However, using the intermolecular annulation
reaction to synthesise cyclic nitrones has rarely been reported.
Herein, we report a new method for the synthesis of five-membered
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, P. R. China.
E-mail: zhanghh@lzu.edu.cn, luoych@lzu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 1821163 and
Fig. 1 Lewis acid-catalysed annulation reactions of D–A cyclopropanes
with compounds containing a carbon–nitrogen multiple bond.
1857538. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c8cc04656e
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Table 2 Investigation of the scope of D–A cyclopropanes
Fig. 2 Synthesis of five-membered cyclic nitrones.
Table 1 Optimization of the reaction conditionsa
Entry Lewis acid
Solvent
Temperature Time Yielde (%)
1
2
3
4
5
6
7
Ni(ClO4)2Á6H2O DCE
60 1C
60 1C
60 1C
60 1C
60 1C
60 1C
60 1C
Reflux
30
30
30
30
30
30
30
5
30
28
6
Cu(OTf)2
La(OTf)3ÁxH2O
Zn(OTf)2
AlCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
20
Trace
63
66
90
68
74
90
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
8b
9b
10c
11d
Toluene Reflux
DCE
DCE
12
12
5
Reflux
Reflux
a
Reaction conditions: 1a (1.5 equiv., 0.30 mmol), 2a (1.0 equiv., 0.20 mmol),
Lewis acid (10 mol%, 0.02 mmol), solvent (C = 0.1 M, 2 mL), 4 Å molecular
sieve (200 mg). b Solvent (C = 0.2 M, 1 mL). c 5 mol% of Yb(OTf)3 was used.
d 1a (1.2 equiv., 0.24 mmol), 2a (1.0 equiv., 0.20 mmol). e Isolated yield.
With the optimal conditions in hand, the scope and limitations
of the reaction were explored. The scope of cyclopropanes was first
investigated using dioxazole 2a as the reaction partner under
the optimal conditions. The results are summarized in Table 2.
For most of the 2-arylcyclopropane 1,1-diesters, the electronic
and steric effects of the substituents on the aryl groups have
little influence on this reaction. Whether electron-deficient F,
Cl, or Br, or electron-rich methoxy was installed on the para- or
meta-position of the aryl group, the cyclopropanes always gave
the desired products in moderate to excellent yields (Table 2,
Scheme 1 The preparation of cyclic nitrone 3a in gram-scale.
According to the previous reports on the Lewis acid-catalysed
3a–3d and 3f–3j). However, the 2-(2-bromophenyl)cyclopropane annulation reactions of D–A cyclopropanes with carbonyl
1,1-diester gave the product 3e (Table 2) only in 45% yield. The compounds,16,22 it is possible that the byproduct ketone generated
alkyl or vinyl substituted cyclopropanes afforded the products in in our reaction could react with cyclopropane 1 continuously. As
lower yield than the aryl substituted ones (Table 2, 3k–3m). For expected, when dioxazole 2h reacted with 2.0 equivalents of
the cyclopropanes bearing different ester groups, the allyl ester cyclopropane 1a under the catalysis of Sc(OTf)3, nitrone 3a and
and benzyl ester also furnished the corresponding products tetrahydrofuran 4h were obtained in one pot with 86% and 30%
in moderate yields (Table 2, 3n and 3o). Next, the scope of yields (Scheme 2).
dioxazoles was also investigated using several dioxazoles under
Next, we attempted to develop a multi-component reaction
the optimal conditions. Except for the 2-phenylvinyl substituted involving the [3+2]-cycloaddition of nitrone with an alkyne
dioxazole 2f, others were tolerated well in this reaction and gave (Scheme 3(a)). When dioxazole 2a, cyclopropane 1a and dimethyl
the product in good yields (Table 2, 3p–3u, 3w and 3x). Finally, to acetylenedicarboxylate 5 reacted in DCE,17 oxazole 6 was isolated
test the practicability of this method for the preparation of cyclic as the major product, and the cyclopropane 1a was almost
nitrones, a gram-scale reaction was conducted in standard quantitatively recycled. Seeking to understand the formation
conditions. Cyclic nitrone 3a was obtained in 88% yield (Scheme 1). pathway of oxazole 6, the reaction of nitrone 3a with alkyne 5
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Scheme 2 Lewis acid-catalysed cascade annulation reactions of D–A
cyclopropanes with 1,4,2-dioxazole.
Scheme 5 Derivatization of cyclic nitrone 3a.
Scheme 6 The reaction of enantioenriched cyclopropane (S)-1a.
nitrone 3a was readily achieved by concentrated HCl in methanol.
The obtained nitrone 8 could react with methyl propionate
smoothly and gave the cycloadduct 9.18,19 Under the irradiation of
ultraviolet light, nitrone 3a was transformed into oxaziridine 10.18,20
Finally, reduction of nitrone 3a with LiAlH4 afforded cyclic
hydroxylamine 11.18,21
Finally, we explored the stereospecificity of this reaction
with enantioenriched (99% ee) cyclopropane (S)-1a22 (Scheme 6).
Dioxazole 2a reacted with (S)-1a with high stereospecificity, giving
(R)-3a23 with 91% ee. To interpret this result, a possible mechanism
for this reaction was proposed (Scheme 7). This reaction went
through two stages, the stepwise annulation of cyclopropane
(S)-1a with dioxazole 2a and the decomposition of annulation
product III. During the annulation, a SN2 like nucleophilic
attack of dioxazole 2a on the activated cyclopropane (S)-1a led
to the ring-opening and the configuration inversion of the
stereocenter in (S)-1a. Then, the intramolecular cyclization of
zwitterion II finished the annulation. Finally, the annulation
product III decomposed into nitrone (R)-3a and acetone.24
In conclusion, a novel synthesis of five-membered cyclic
nitrones has been developed based on the Lewis acid-catalysed
[3+2]-annulation reaction of D–A cyclopropanes with 1,4,2-
dioxazoles. A broad substrate scope and generally good yield
were observed. Derivatization of the product demonstrated that
this method is useful for the synthesis of some nitrogen-
containing heterocycles. It is noteworthy that using this method
nitrone and tetrahydrofuran can be prepared in one-pot with
high atom economy when a suitable 1,4,2-dioxazole was used.
Scheme 3 Multi-component reactions involving the [3+2]-cycloaddition
of nitrone with alkyne.
was conducted (Scheme 3(b)). This reaction also offered oxazole
6 and cyclopropane 1a in high yields. At that moment, we suspected
that oxazole 6 may be formed by the decomposition of the
cycloadduct 7. To prove this assumption, we prepared cycloadduct
7
18 in 8% yield at 60 1C (Scheme 3(c)). Then, refluxing the solution
of cycloadduct 7 in DCE offered oxazole 6 and cyclopropane 1a
(Scheme 3(d)). So far, these results fully confirmed that oxazole 6
was generated from the decomposition of cycloadduct 7.
Based on the understanding of the above transformation, we
developed a D–A cyclopropane and Lewis acid co-catalysed
reaction for the synthesis of oxazole 6 (Scheme 4). In this
reaction, D–A cyclopropane 1a plays the role of transferring
nitrile oxide from dioxazole 2a to oxazole 6 circularly.
To further explore the reactivity of 3a, some transformations
were carried out (Scheme 5). The decarboxylation of cyclic
Scheme 4 Lewis acid/D–A cyclopropane co-catalysed annulation reactions
of dimethyl acetylenedicarboxylate with 1,4,2-dioxazole.
Scheme 7 Proposed reaction mechanism.
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