One-pot synthesis of isoxazoles from enaminones: An application of Fe(II) as the catalyst for ring expansion of 2H-azirine intermediates

Article abstract of DOI:10.1016/j.tetlet.2013.08.079

We report an application of FeCl₂ as an inexpensive, nontoxic, and efficient catalyst in a clean ring expansion reaction of 2H-azirine derivatives, an intermediate formed through the PhI(OAc)₂-mediated azirination of readily availabl

Full text of DOI:10.1016/j.tetlet.2013.08.079

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
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One-pot synthesis of isoxazoles from enaminones: an application
of Fe(II) as the catalyst for ring expansion of 2H-azirine
intermediates
a,
Yunhui Zheng a, Chao Yang a, Daisy Zhang-Negrerie a, Yunfei Du a,b, , Kang Zhao
⇑
⇑
a Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
b Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an application of FeCl2 as an inexpensive, nontoxic, and efficient catalyst in a clean ring expan-
sion reaction of 2H-azirine derivatives, an intermediate formed through the PhI(OAc)2-mediated azirina-
tion of readily available enaminones. An alternative one-pot protocol for the synthesis of various
substituted isoxazoles from their corresponding enaminones has been further established based on this
reaction, and herein described.
Received 9 June 2013
Revised 1 August 2013
Accepted 20 August 2013
Available online xxxx
Ó 2013 Published by Elsevier Ltd.
Keywords:
One-pot synthesis
Isoxazoles
Enaminones
FeCl2-catalyzed ring expansion
2H-Azirine
Isoxazole skeleton, ubiquitous in natural products and pharma-
ceuticals, is a key heterocyclic motif that is responsible for a broad
spectrum of biological and pharmacological activities, and has
become a key substructure in drug design.1 The biological activi-
ties’ studies on the agents containing functionalized isoxazole
and derivatives have stimulated a significant interest in developing
novel synthetic methods for their syntheses. Among versatile
diverse strategies ranging over numerous reaction types and
starting materials,2 ring expansion of 2H-azirine compounds via
rearrangement has been considered as a unique and attractive
approach to access this important class of heterocycles.3
path a
hν (334 nm)
path c
O
O
Ph
O
H
metal catalyst
N
N
N
R
nonhydroxylic
Ru, Mo, Rh
Ph solvents, 200 o
C
Ph
Ph
A1
A2
(R = Ph)
(R = H)
B1
B2
path b
Scheme 1. Existing methods for rearrangement of 2H-azirines into isoxazoles or
isoxazoles to 2H-azirines.
application of rhodium acetate dimer (Rh2(OAc)4) in nonpolar sol-
vents could realize the conversion of 2H-azirine A2 to isoxazoles
B2 (Scheme 1, path c). Considering the cost and toxicity of the above
metal catalysts, it is evidently much desired to identify cheaper and
less or nontoxic transition metal catalysts for realizing the same rear-
rangement of 2H-azirines into isoxazoles. In this Letter, we report the
discovery of an one-pot protocol, where the commonly known Fe(II)
salt served as an efficient catalyst in carrying out the ring expansion
reaction of the 2H-azirine intermediates to form their corresponding
isoxazoles in a controlled and specific manner (Scheme 2, path a).
It is worth pointing out that this process is indeed the reverse
reaction of Auricchio’s work,8 in which a FeCl2-catalyzed isomeri-
zation of isoxazole B3 to azirine A3 was realized (Scheme 2, path
b). It is apparent that the substrate type we have applied thermo-
dynamically favors the rearrangement of azirine into isoxazole.9
In our previous studies, we reported that, upon treatment with
hypervalent iodine reagent, that is, phenyliodine (III) diacetate
(PIDA), enaminone 20 underwent azirination to give 2H-azirine
In 1972, Singh et al.4 reported the photo rearrangement of 2H-azi-
rines which afforded isoxazoles or oxazoles, depending on the
wavelength applied. For example, irradiation of 2-benzoyl-3-phe-
nyl-2H-azirine A1 with 334 nm light afforded almost exclusively
its corresponding isoxazole B1 (Scheme 1, path a). The same conver-
sion of 2H-azirines to isoxazoles could also be achieved via the ther-
mal rearrangement in nonhydroxylic solvents at high temperature.
For example, on heating in nonhydroxylic solvents at 200 °C,
2H-azirine A1 produced its corresponding isoxazole B1 in 30% yield
(Scheme 1, path b).5 The rearrangement of 2H-azirines into
isoxazoles could also be mediated by some metal catalysts such as
6
Grubbs’ ruthenium–carbene complexes,3(b,c) or Mo(CO)6
(Scheme 1, path c). Recent findings by Ray et al.7 revealed that the
⇑
Corresponding authors. Tel.: +86 022 27404031; fax: +86 022 27404031.
E-mail addresses: duyunfeier@tju.edu.cn (Y. Du), kangzhao@tju.edu.cn (K. Zhao).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.08.079
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2
Y. Zheng et al. / Tetrahedron Letters xxx (2013) xxx–xxx
a. FeCl2-catalyzed isomerization of azirines to isoxazoles
O
O
O
R1
O
FeCl2 (20 mol %)
THF, 60 oC, N2
53%
O
N
N
FeCl2
N
N
R1
solvent
R2
Ph
A6
Ph
N
R3
R2
R3
H
C1
1a
A
This work
1
Scheme 5. The discovery of rearrangement of 2H-azirine A6 into isoxazole 1a.
b. FeCl2-catalyzed isomerization of isoxazoles to azirines
O
O
MeO
FeCl2 4H2O
MeCN, rt
N
N
MeO
Ph
Ph
Table 1
B3
Auricchio's work
A3
Condition optimization of one-pot synthesis of isoxazole 1a from enaminone 2aa
Scheme 2. Substituent-dependant FeCl2-mediated isomerization between 2H-
Azirines and isoxazoles.
O
NH2
O
1) PhI(OAc)2
2) FeCl2, N2
N
Ph
Ph
2a
1a
O
O
PhI(OAc)2
DCE, 0 oC - rt
N
Entry Additive
(equiv)
Base
(equiv)
Solvent
Temp
(°C)
Timeb
(h)
Yieldc
(%)
NH2
R
R
R = Ph, p-OMeC6H4, p-NO2C6H4
2'
A4
1
2
3
FeCl2 (1.0)
FeCl2 (1.0)
FeCl2 (1.0)
—
—
—
MeOH
DCE
1,4-
rt
rt
rt
24
24
24
10
Trace
Trace
Scheme 3. PIDA-mediated azirination of enaminones previously reported (our
previous work).
Dioxane
1,4-
Dioxane
1,4-
Dioxane
1,4-
Dioxane
4
FeCl2 (1.0)
FeCl2 (1.0)
FeCl2 (1.0)
FeCl2 (1.0)
FeCl2 (1.0)
FeCl2 (0.5)
FeCl2 (0.2)
FeCl2 (0.5)
—
—
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
2
21
5
Na2CO3
(2.0)
NaOH
(2.0)
2
77
A4 (Scheme 3).10 In 2009, Zheng et al.11 described the FeCl2-cata-
lyzed ring opening of 2H-azirines A5 to form 2,3-disubstituted in-
doles C (Scheme 4).
6
2
62
7
NEt3 (2.0) 1,4-
Dioxane
DBU (2.0) 1,4-
Dioxane
1,4-
24
2
Trace
0
Inspired by these results, we set out to investigate the conver-
sion of the 2H-azirine intermediate A6, obtained through the aziri-
nation of enaminone 2a, to its corresponding indole product C1
using the conditions described by Zheng. Unexpectedly, the prod-
uct was found to consist of exclusively the isoxazole 1a, in 53%
of yield, upon treatment of A5 with FeCl2 in THF at 60 °C under a
nitrogen atmosphere, with no formation of the expected indole
product C1 (Scheme 5). Although unexpected, this finding opened
the door for us to establish an alternative protocol to access a vari-
ety of isoxazoles via the FeCl2-catalyzed ring expansion of their
corresponding 2-acyl-2H-azirine compounds.
8
9
Na2CO3
(2.0)
Na2CO3
(2.0)
Na2CO3
(1.0)
Na2CO3
(2.0)
5
83
Dioxane
1,4-
Dioxane
1,4-
Dioxane
1,4-
dioXane
10
11
12
8
43
6
71
24
Trace
a
General conditions: (1) enamine (1.0 mmol), PIDA (1.2 mmol) in solvent (5 mL)
0.2 h; (2) FeCl2 added after the reaction mixture was cooled to rt.
Our next focus was on developing a one-pot protocol for the
synthesis of isoxazoles 1 from enaminones 2 through the azirina-
tion reaction of 2 mediated by PhI(OAc)2 followed by Fe(II)-cata-
lyzed ring expansion of the generated 2H-azirines. The main task
naturally involved the identification of a suitable solvent which
would allow high yields for both steps. Substrate 2a was used to
further screen the optimal reaction conditions (Table 1). Among
the solvents being screened, DCE and MeOH were found to be
the best ones for the azirination step, but unfortunately unsuitable
for the second step of ring opening of the generated 2H-azirine
intermediate (Table 1, entry 1). Only trace amounts of the products
were observed when both steps were carried out in DCE or 1,4-
dioxane at room temperature (Table 1, entries 2 and 3). Further
studies showed that carrying out both reactions under reflux in
1,4-dioxane, provided the desired isoxazole 1a in 21% yield
(Table 1, entry 4). Delightedly, we found that the introduction of
some bases, such as sodium carbonate or sodium hydroxide greatly
b
Reaction time for the second step.
Isolated yields.
c
improved the product yield, possibly because the acetic acid re-
leased by PhI(OAc)2during the first reaction got neutralized (Ta-
ble 1, entries 5 and 6). However, the replacement of inorganic
bases with NEt3 or DBU led to a complex mixture of unidentified
byproducts in each case (Table 1, entries 7 and 8). The best result
was obtained when enaminone 2a was subjected to the PhI(OAc)2-
mediated azirination in the presence of 2.0 equiv of sodium car-
bonate, followed by addition of 0.5 equiv of FeCl2 to mediate the
ring opening of the generated 2H-azirines, with both steps occur-
ring in 1,4-dioxane as the solvent and at the reflux temperature
(Table 1, entry 9). Reducing the dosage of either FeCl2 or Na2CO3
afforded lower yields of isoxazole (Table 1, entries 10 and 11). It
is worth noting that when no FeCl2 was applied, the reaction only
provided trace amount of its corresponding isoxazole product (Ta-
ble 1, entry 12), which was probably due to the thermal rearrange-
ments of the generated 2H-azirine intermediate. This result clearly
implies that FeCl2 plays an indispensable role in the rearrangement
of 2H-azirine intermediate into isoxazole 1a.
R'
R'
R''
THF, 70 oC, N2, 24 h
5 mol % FeCl2
X
R''
N
X
N
H
With the optimized reaction conditions obtained, the generality
and substituent scope of this one-pot synthesis of isoxazoles was
investigated. The results are summarized in Table 2. The analogous
enaminone derivatives 2b–c, both bearing electron-donating
A5
C
Scheme 4. FeCl2-catalyzed rearrangement of 2H-azirines into indoles (Zheng’s
work).
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Y. Zheng et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 2
One-pot synthesis of isoxazoles 1 from enaminones 2 mediated by PIDA and Fe(II)a
O
NH2
R2
1) PIDA, Na2CO3
1,4-dioxane, reflux
R1
O
N
R1
2) FeCl2, reflux, N2
R3
R3
R2
2
1
Entry
Enamine 2
Isoxazole 1
Time (h)
0.2/5
Yieldb (%)
O
NH2
O
N
1a
2a
1
83
1a
2a
2b
O
NH2
O
N
1b
2b
2
0.2/5
80
1b
O
O
NH2
O
N
1c
2c
3
0.2/5
82
MeO
OMe
2c
1c
NH2
O
N
1d
60c
2d
4
0.2/16
O2N
NO2
2d
1d
O
NH2
O
O
O
O
N
N
N
N
2e
46d
1e
5
6
0.3/10
2e
1e
O
O
NH2
NH2
NH2
2f
n-Bu
1f
0.3/8
60
n-Bu
2f
1f
2g
Bn
63c
1g
7
8
0.3/24
0.3/8
Bn
2g
1g
O
2h
1h
81
Bn
Bn
1h
2h
a
General conditions: (1) enamine (1.0 mmol), PIDA (1.2 mmol), Na2CO3 (2.0 mmol) in 1,4-dioxane (5 mL) under reflux; (2) FeCl2 (0.5 mmol), stirred under reflux, under N2
unless otherwise stated.
b
Isolated yields.
Another portion of FeCl2 (0.5 mmol) was added after 8 h.
1.0 mmol of FeCl2 was used.
c
d
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4
Y. Zheng et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Core Faculty of Tianjin University (2013XR-0144), and the Innova-
tion Foundation of Tianjin University (2013XJ-0005) for financial
support.
Fe
N
O
NH2
R2
O
N
Fe2+
O
PIDA
R1
R1
R1
R2
R2
R2
R3
2
R3
R3
D
Supplementary data
A
Fe
N
Fe
N
Supplementary data (list of new compounds along with their
yield and copies of 1H and 13C NMR spectra) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.08.079. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
R1
O
O
- Fe2+
N
O
R1
R2
R3
R2
R3
R1
R3
F
1
E
Scheme 6. Proposed mechanistic pathways.
substituents on the benzene ring, can be converted into their
corresponding isoxazoles 1b–c in very good yields. However, with
the nitro group as the substituent in 2d, the yield of the desired
isoxazole 1d was drastically lowered, due to the formation of some
unidentified byproducts during the rearrangement process. But to
our delight, this one-pot protocol was also found to be applicable
References and notes
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to the enaminones bearing
a-alkyl substituents, such as methyl,
n-butyl, and benzyl groups, which extends this method to the syn-
thesis of 4-alky isoxazoles 1e–h. However, these isoxazoles were
obtained in comparably low yields due to the formation of more
unidentified byproducts in both the azirination and rearrangement
process.
Based on the mechanism Zheng described for the FeCl2-cata-
lyzed ring opening of 2H-azirines, we propose a plausible mecha-
nistic pathway for the above one-pot synthesis of isoxazole 1
(Scheme 6). Initially, the starting enaminone 2 was conveniently
converted into 2H-azirine A via the PhI(OAc)2-mediated azirina-
tion.10 Then the coordination of Fe(II) to the nitrogen atom of
2H-azirine A produced the iron-azirine complex D,11 which was
converted into iron vinyl nitrene complex E. Subsequent 6p-elec-
tron electrocyclization12 of E afforded isoxazole 1 through the
intermediate F. Due to the presence of an adjacent carbonyl group
in the substrate, the five-centered 6
p electrocyclization preferen-
tially occurred between the vinyl nitrene moiety and the C@O
bond, the result of which furnished the oxazole products, rather
than the indole products in Zheng’s work.11
In summary, we have described here an alternative synthetic
methodology to form the biologically important isoxazoles from
their corresponding enaminone compounds, based on our
discovery of a FeCl2-mediated rearrangement of 2H-azirines into
isoxazoles. Other than the importance of the product, the conve-
nience of the one-pot procedure, the specificity of the reaction,
and the low cost of the environmentally benign Fe(II) catalyst
are among the highlighted characteristics of the method herein
reported.
7. Brahma, S.; Ray, J. K. J. Heterocycl. Chem. 2008, 45, 311–317.
8. Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A. Tetrahedron 1997, 53,
10911–10920.
9. Auricchio has concluded that in the presence of the metal, the 2H-azirine A3
and isoxazole B3 is in equilibrium and this is shifted to the isoxazole or the
azirine depending on the nature of the substituents on the ring. For his work
describing this, see Ref.
10. Li, X.; Du, Y.; Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643–2646.
11. Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N. Org. Lett. 2010, 12, 3736–3739.
12. Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6, 743–746.
8
.
Acknowledgments
Y.D. acknowledges the National Natural Science Foundation of
China (#21072148), Foundation (B) for Peiyang Scholar–Young
Please cite this article in press as: Zheng, Y.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.08.079