Hexafluoroantimonic acid catalysis: Formal [3+2+2] cycloaddition of aziridines with two alkynes

Article abstract of DOI:10.1002/anie.201310944

A practical method for the synthesis of azepine derivatives, a typical seven-membered heterocyclic ring system, was developed and involves the use of hexafluoroantimonic acid to catalyze a formal [3+2+2] cycloaddition of aziridines with two alkynes. This method was applicable to two of the same or different terminal alkynes for the [3+2+2] cycloaddition with unactivated aziridines, and furnished the corresponding azepine derivatives in good yields with good levels of chemo- and regioselectivity. The mechanism was also discussed according to the results of the in situ HRMS and ¹H NMR analysis. Superacid powers: The title reaction of unactivated aziridines with two of the same or different terminal alkyne components has been developed, thus opening a new access to seven-membered heterocyclic ring systems. This transformation is experimentally simple while furnishing azepine derivatives in good yields (up to 78%) with good levels of chemo- and regioselectivity. Ts= 4-toluenesulfonyl.

Full text of DOI:10.1002/anie.201310944

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Angewandte
Communications
DOI: 10.1002/anie.201310944
Heterocycles
Hexafluoroantimonic Acid Catalysis: Formal [3+2+2] Cycloaddition
of Aziridines with Two Alkynes**
Ming-Bo Zhou, Ren-Jie Song, and Jin-Heng Li*
Dedicated to Professor Ming-Cai Chen on the occasion of his 60th birthday
Abstract: A practical method for the synthesis of azepine
derivatives, a typical seven-membered heterocyclic ring system,
was developed and involves the use of hexafluoroantimonic
acid to catalyze a formal [3+2+2] cycloaddition of aziridines
with two alkynes. This method was applicable to two of the
same or different terminal alkynes for the [3+2+2] cyclo-
addition with unactivated aziridines, and furnished the corre-
sponding azepine derivatives in good yields with good levels of
chemo- and regioselectivity. The mechanism was also discussed
1
according to the results of the in situ HRMS and H NMR
analysis.
Scheme 1. The cycloaddition of aziridines. Ts=4-toluenesulfonyl.
T
he cycloaddition reaction has proven to be a powerful and
straightforward synthetic tool for the atom-economical con-
struction of cyclic compounds in modern organic chemis-
try.[1–4] In the cycloaddition field, an important strategy
involving the use of the ring-openings of small strained
rings as a key step, fascinates numerous researchers because it
can be used to meet the synthetic demand of making bioactive
natural products containing hererocyclic rings.[1–3] These
cycloaddition processes allow the ring-opening of small
strained rings and subsequent reaction with 2p components
to construct various rings, specifically five- and six-membered
rings, through [3+2] or [4+2] modalities. Particularly, cyclo-
addition reactions involving ring-opening reactions of
strained aziridines have been widely applied in the construc-
tion of nitrogen-containing five-membered rings.[3] However,
methods for the selective construction of larger nitrogen-
containing rings, including nitrogen-containing seven-mem-
bered rings, are lacking.[4]
dipoles (A; in the presence of Lewis acids; Scheme 1) and
azomethine ylides (under irradiation or thermolysis) for
[3+2] cycloaddition with 2p components such as alkenes
and alkynes.[3] We reasoned that aziridines could undergo the
[3+2+2] cycloaddition with two 2p components when the
nucleophilicity of nitrogen anion in the intermediate B was
reduced, thus enabling a subsequent electrophilic addition to
another 2p component to form nitrogen-containing seven-
membered rings. Herein, we report a new strategy to access
the stable nitrogen anion in intermediate B using the super-
acid HSbF6, thus triggering a new formal [3+2+2] cyclo-
addition of unactivated aziridines to two of the same or
different terminal alkynes to construct azepine architectures
(Scheme 1b). Such a reaction would be particularly valuable
for the synthesis of azepine derivatives,[4,5] a typical seven-
membered heterocyclic ring system, which are synthetically
versatile compounds in synthesis and important skeletal units
found in numerous natural products, potent pharmaceuticals,
and peptidomimetics.[6]
Generally, aziridines, a class of strained small hetero-
cycles, are used as the precursors for both zwitterionic 1,3-
We first investigated the proposed [3+2+2] cycloaddition
reaction between 2-phenyl-1-tosylaziridine (1a) with phenyl-
acetylene to optimize the reaction conditions (Table 1).
Examination of a range of reaction temperatures, Brønsted
acids, and solvents (entries 1–11) revealed the combination of
the HSbF6 as the catalyst and CH2Cl2 as the solvent at 408C to
be most effective: treatment of 1a with phenylacetylene and
15 mol% HSbF6 in CH2Cl2 at 408C for 24 hours regioselec-
tively afforded the desired azepine 2 in 76% yield (entry 1).
The results demonstrated that the reaction temperature
affected the reaction: the yield of 2 was reduced to 60%
when the reaction was carried out at room temperature
(entry 2). Of the amounts of HSbF6 examined, it turned out
that 15 mol% of HSbF6 was perfect for the reaction
(entries 1, 3, and 4). Notably, the absence of HSbF6 resulted
in no detectable amounts of 2 (entry 5). Subsequently, several
[*] M.-B. Zhou, R.-J. Song, Prof. Dr. J.-H. Li
State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering
Hunan University, Changsha 410082 (China)
E-mail: jhli@hnu.edu.cn
Prof. Dr. J.-H. Li
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
[**] We thank the Natural Science Foundation of China (No. 21172060),
Specialized Research Fund for the Doctoral Program of Higher
Education (No. 20120161110041), and Hunan Provincial Natural
Science Foundation of China (No. 13JJ2018) for financial support.
M.-B.Z. also thanks the Hunan Provincial Innovation Foundation for
Postgraduate (CX2013B154).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310944.
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Table 1: Screening optimal reaction conditions.[a]
Table 2: HSbF6-catalyzed [3+2+2] cycloaddition of aziridines (1) with
two of the same terminal alkynes.[a]
Entry
Variation from the standard conditions
Yield [%][b]
1
2
3
none
76
60
58
at room temperature
HSbF6 (10 mol%)
4
HSbF6 (30 mol%)
61
5
without HSbF6
0
6
7
8
9
10
11
12[c]
HOTf instead of HSbF6
HOAc instead of HSbF6
HBF4 instead of HSbF6
CH2ClCH2Cl instead of CH2Cl2 for 48 h
toluene instead of CH2Cl2 for 48 h
MeNO2 instead of CH2Cl2 for 48 h
none for 72 h
12
trace
6
52
trace
14
73
[a] Reaction conditions: 1a (0.2 mmol), phenylacetylene (0.8 mmol),
HSbF6·6H2O (15 mol%), and CH2Cl2 (2 mL) at 408C under an argon
atmosphere for 24 h. [b] Yield of isolated product. [c] 1a (6 mmol,
1.638 g).
other Brønsted acids, such as HOTf, HOAc, and HBF4, were
tested (entries 6–8). Both HOTf and HBF4 could catalyze the
reaction, albeit in low yields after 24 hours (entries 6 and 8).
However, HOAc had no effect on the reaction (entry 7).
Screening revealed that the effect of solvents had a funda-
mental influence on the reaction (entries 1 and 9–11). While
CH2ClCH2Cl was still an efficient solvent for the reaction
(entry 9), both toluene and MeNO2 displayed lower activity
(entries 10 and 11). It is noteworthy that the reaction of
1.638 g (6 mmol) 1a proceeds in good yield (entry 12).
With the standard reaction conditions in hand, the scope
of this HSbF6-catalyzed [3+2+2] cycloaddition reaction, with
respect to aziridines reacting with two of the same terminal
alkynes, was first exploited (Table 2). The standard reaction
conditions were found to be compatible with a wide range of
terminal alkynes, including aryl, heteroaryl, and aliphatic
alkynes (3–11). Furthermore, several substituents, such as Me,
MeO, Cl, and Br, on the aryl ring of alkynes were well
tolerated (3–9). Alkynes having a para- or meta-methyl-
substituted aryl group underwent the reaction with 1a and
HSbF6 smoothly, thus providing the desired products 3 and 7
in 73 and 66% yield, respectively. Importantly, the halogens
Cl and Br were tolerated under the reaction conditions,
thereby facilitating additional modifications at the halogen-
ated positions (5, 6, and 8). When using a dimethyl-substituted
aryl alkyne, satisfactory yield was still achieved under the
same reaction conditions (9). We were pleased to find that this
[3+2+2] cycloaddition reaction was applicable to the prep-
aration of the thiophen-3-yl-containing azepine 10 in 67%
yield. Ethynylcyclopropane was also a suitable substrate for
the reaction (11).
[a] Reaction conditions: 1 (0.2 mmol), alkyne (0.8 mmol), HSbF6·6H2O
(15 mol%), and CH2Cl2 (2 mL) at 408C under argon atmosphere for
24 h. Yields are those of the isolated products.
discover that a number of substituents, Me, Br, Cl, and NO2,
at the para position of the 2-aryl moiety were perfectly
tolerated, thus resulting in the corresponding products 13–16
in moderate to good yields. Interestingly, the naphthalen-1-yl
group could be readily introduced into the azepine structure
(17). It was noted that 2-methyl-2-phenyl-1-tosylaziridine was
also viable for the formation of the azepine 18 in 67% yield.
In light of the results described above, we next decided to
examine the possibility of synthesizing azepines having
different substituents at the 5- and 7-positions by using two
different terminal alkynes (Table 3). As expected, the reac-
tion of 1a with two different terminal alkynes was successfully
performed, thus furnishing the desired azepines 19–27 in
moderate to good yields. For example, when 1a was treated
with phenylacetylene (the first alkyne) and 5 mol% HSbF6 in
CH2Cl2 at 08C for 15 minutes, with subsequent addition of 4-
methylphenylacetylene (the second alkyne) and 10 mol%
HSbF6 and an increase in the reaction temperature to 408C
for about 24 hours, 3,5-diphenyl-7-p-tolyl-1-tosyl-2,3-dihydro-
1H-azepine (19) was delivered in 78% yield. It was noted that
the same reaction conditions could be viable for the [3+2+2]
Gratifyingly, this catalyzed [3+2+2] cycloaddition proto-
col was subject to a variety of 1-tosylaziridines (1; Table 2, 12–
18). 2-(3-Chlorophenyl)-1-tosylaziridine, for instance, was
successfully reacted with phenylacetylene and HSbF6 to
afford the product 12 in 66% yield. We were delighted to
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Table 3: [3+2+2] Cycloaddition of 1a with two different terminal
alkynes.[a]
Scheme 2. Possible mechanism.
Consequently, the working mechanism outlined in
Scheme 2 was proposed on the basis of the present results
and the literature reports.[3,7,8] Initially, the zwitterionic 1,3-
dipole intermediate C is formed from the reaction of 1a with
HSbF6,[3,8] with subsequent electrophilic addition to phenyl-
acetylene to afford the intermediate D.[7,8] In this step, HSbF6
can also serve to stabilize the nitrogen anion. Subsequently, D
undergoes the second electrophilic addition to a second
molecule of phenylacetylene to give the intermediate E.[8]
Finally, dipolar cyclization of E gives the desired azepine 2.
In summary, we have developed the first HSbF6-catalyzed
formal [3+2+2] cycloaddition of 1-tosylaziridines with two
alkynes. This novel method provides a mild and general access
to the azepine architectures with both excellent functional-
group tolerance and good levels of selectivity control, thus
representing a new [3+2+2] cycloaddition transformation
using 1-tosylaziridines as zwitterionic 1,3-dipoles. Studies on
the mechanism and applications of this formal [3+2+2]
cycloaddition method in organic synthesis are currently
underway in our laboratory.
[a] Reaction conditions: a mixture of 1a (0.2 mmol), the first alkyne
(0.4 mmol), HSbF6·6H2O (5 mol%), and CH2Cl2 (2 mL) was stirred at
08C under an argon atmosphere. After 15 min, both the second alkyne
(0.4 mmol) and HSbF6·6H2O (10 mol%) were added and the mixture
was stirred at 408C for about 24 h. Yields are those of the isolated
products. [b] The mixture of 1a (0.2 mmol), the first alkyne (0.4 mmol),
HSbF6·6H2O (5 mol%), and CH2Cl2 (2 mL) was first stirred at 158C
under argon atmosphere for 30 min.
cycloaddition of 1a with phenylacetylene and another alkyne,
such as 2-methylphenylacetylene, 4-chlorophenylacetylene, 3-
bromophenylacetylene, (2-thienyl)acetylene, or 2-chloro-4-
methylphenylacetylene, thus leading to the corresponding
azepines 20–24, which have different substituents at the 7-
position, in moderate to good yields. Interestingly, the
substituent at the 5-position of the azepines could also be
varied simply by the use of different alkynes the first step.
Both phenylacetylene and 10 mol% HSbF6 were added after
4-methoxyphenylacetylene reacted with 1a and 5 mol%
HSbF6 in CH2Cl2 at 158C for 30 minutes, thus providing the
5-(4-methoxyphenyl)-substituted azepine 25 in 67% yield.
When using 4-methylphenylacetylene or (2-thienyl)acetylene
as the first alkyne, the corresponding 4-methylphenyl- and 4-
(2-thienyl)-substituted azepines 26 and 27, respectively, were
also obtained in good yields.
However, phenyl(2-phenylaziridin-1-yl)methanone (1b)
was unreactive for the [3+2+2] cycloaddition reaction
[Eq. (1)]. To understand the mechanism, the reaction of the
enyne 29 was carried out [Eq. (2)]. The results disclosed that
29 could not be converted into 2 under the standard reaction
conditions, thus suggesting that the current reaction does not
include an enyne intermediate.
Received: December 18, 2013
Revised: January 16, 2014
Published online: March 11, 2014
Keywords: alkynes · aziridines · cycloaddition · heterocycles ·
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superacidic systems
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Supporting Information. In addition, four other intermediates
were also observed by the in situ HRMS analysis:
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