Triflic Anhydride Mediated Ring-Opening/Recyclization Reaction of α-Carbamoyl α-Oximyl Cyclopropanes with DMF: Synthetic Route to 5-Aminoisoxazoles

Article abstract of DOI:10.1055/s-0035-1561437

A facile and efficient synthesis of fully substituted 5-amino-soxazoles was developed from α-cyclopropyl β-oximyl amides in the presence of triflic anhydride (Tf₂O) in DMF under very mild conditions. The process involves sequential ring-opening

Full text of DOI:10.1055/s-0035-1561437

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–E
A
special topic
M. Yu et al.
Special Topic
Synthesis
Triflic Anhydride Mediated Ring-Opening/Recyclization Reaction
of α-Carbamoyl α-Oximyl Cyclopropanes with DMF: Synthetic
Route to 5-Aminoisoxazoles
Mangfei Yua,b
Qian Zhangb
Jia Wangb
Peng Huangb
Pengfei Yan*a
Rui Zhangb
N
HO
R
N
O
O
H
O
Tf2O, DMF
40 °C
O
NHAr
R
NHAr
7 examples, 68–79 yield
one ring opened
one ring formed
one N–O bond formed
one C–O bond formed
Dewen Dong*b
a School of Chemistry and Materials Science, Heilongjiang University,
74 Xuefu Road, Harbin 150080, P. R. of China
yanpf@vip.sina.com
b Key Laboratory of Synthetic Rubber, Changchun Institute of Applied
Chemistry, Chinese Academy of Sciences, 5625 Renmin Street,
Changchun 130022, P. R. of China
dwdong@ciac.ac.cn
Received: 08.03.2016
Accepted after revision: 31.03.2016
Published online: 10.05.2016
actions. Therefore, some research efforts have been direct-
ed toward the development of efficient and elegant ap-
proaches for the synthesis of isoxazoles in a regioselective
manner by altering the electrophilicity of the terminal car-
bon atoms in the C3 units,8 controlling the reaction condi-
tions,9 or introducing leaving groups at the α-position of
α,β-unsaturated ketones to allow the transformation of the
initially formed isoxazolines into the aromatic isoxazoles.10
Nevertheless, the development of new methods for the effi-
cient synthesis of isoxazoles, in particular with a flexible
pattern, under mild conditions is still in high demand.
As part of our ongoing research directed to the develop-
ment of methods for the synthesis of heterocycles from β-
oxo amide derivatives, we prepared a series of α-carbamoyl
α-oximyl cyclopropanes 1, and achieved divergent synthe-
sis of 5-arylamino-4-haloethyl isoxazoles (paths A and
B),11,12 5-chloro-1H-pyrazoles (path C),11 and spiro-fused
pyrazolin-5-ones (paths D and E)12,13 under varied condi-
tions (Scheme 1). Very recently, we investigated the reac-
tion of α-aminopropenoyl α-carbamoyl cyclopropane in the
presence of triflic anhydride (Tf2O)/DMF, and developed a
facile and efficient synthesis of 2,3-dihydrofuro[3,2-c]pyri-
din-4(5H)-ones, in which Tf2O/DMF acted as a Vilsmeier
type reagent.14 In connection with these studies and our
continuing interest in the further synthetic potential of β-
oximyl amides 1, we investigated their reactivity towards
triflic anhydride under different conditions. As a result of
this study, we achieved a facile synthesis of fully substitut-
ed 5-amino isoxazoles 2 (Scheme 1, path F) under very mild
conditions. Herein, we wish to report our experimental re-
sults and present the proposed mechanisms involved.
DOI: 10.1055/s-0035-1561437; Art ID: ss-2016-c0166-st
Abstract A facile and efficient synthesis of fully substituted 5-amino-
isoxazoles was developed from α-cyclopropyl β-oximyl amides in the
presence of triflic anhydride (Tf2O) in DMF under very mild conditions.
The process involves sequential ring-opening and intramolecular cy-
clization reactions.
Key words cyclization, heterocycles, isoxazoles, ring-opening reac-
tion
In recent decades, isoxazoles and their analogues have
emerged as a very important class of heterocycles in areas
of natural product and pharmaceutical chemistry.1,2 Many
natural products and synthetic compounds based on the
isoxazole ring system have been found to have a wide range
of bioactivities, and some of them, such as valdecoxib, le-
flunomide and cloxacillin, have been clinically proven as
pharmaceutical drugs.3 In addition, isoxazoles are utilized
as key building blocks for the synthesis of natural products
and related structures.4 Their diverse biological activities
and synthetic utilities have stimulated substantial interest
in the construction of the skeleton of isoxazoles,5 including
either intermolecular [2+3] cycloadditions of 1,3-dipoles to
alkynes,6 or condensations of hydroxylamine with β-dike-
tone equivalent three-carbon 1,3-electronphilic units bear-
ing sp or sp2 carbon atoms, such as propargylic ketones,
enones, and α,β-unsaturated nitriles.7
However, the appealing generality of these methods
sometimes suffer in their versatility, convenience, yield, or
frequent formation of a regioisomeric mixture in these re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

B
M. Yu et al.
Special Topic
Synthesis
when the reaction of 1a and Tf2O (1.2 equiv) was conducted
in DMF at 40 °C for 40 minutes, whereby the yield of 2a
reached 71% (Table 1, entry 3).
Ar
N
O
N
O
N
N
NHAr
NHAr
Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Br
Table 1 Screening of Reaction Conditionsa
PPh3, CBr4 POCl3, DMF
POCl3, CH2Cl2
path A
N
HO
Cl
DMF
path B
path C
O
N
O
O
H
O
N
HN
Cl
H
HO
1a
2a
N
O
Entry
Reagent (equiv)
Temp (°C)
Time (min)
Yield (%)b
NHAr
1
2
3
4
5
6
7
Tf2O (1.0)
Tf2O (1.2)
Tf2O (1.2)
Tf2O (1.2)
Tf2O (1.5)
Ac2O (1.2)
TfOH (1.2)
r.t.
r.t.
40
65
40
40
40
70
50
40
25
35
60
60
54
62
71
69
70
14
n.r.c
PIFA, TFA
path E
Tf2O, DMF
path F
TsCl, KOH
path D
this work
Ar
N
–O
Ar
N
N
R
O
N+
N
O
O
H
O
O
a Reaction conditions: 1a (1.0 mmol), anhydrous DMF (10.0 mL).
NHAr
b Isolated yield.
c No reaction.
Scheme 1 The reactions of α-carbamoyl α-oximyl cyclopropanes 1 un-
der different conditions
Having established the optimal conditions for the ring-
opening/recyclization process, we aimed to determine its
scope with respect to the amide motif of α-carbamoyl α-
oximyl cyclopropanes 1. Thus, a series of reactions of sub-
strates 1 with Tf2O were carried out in DMF at 40 °C; the re-
sults are summarized in Table 2. It was observed that all the
reactions of α-cyclopropyl β-oximyl amides 1b–g bearing
electron-donating or electron-withdrawing aryl amide
groups proceeded smoothly to afford the corresponding
substituted 5-arylamino-isoxazoles 2b–g in good yields
(Table 2, entries 2–7). However, in the case of substrate 1h,
bearing a phenyl R, an inseparable complex mixture was
formed although a wide range of experimental conditions
was tested (Table 2, entry 8). It should be mentioned that
the structure of 2a was further confirmed by X-ray single
crystal analysis and by its spectral and analytical data (Fig-
ure 1). Therefore, we have provided a facile and novel syn-
thetic route to fully substituted 5-aminoisoxazoles 2.
The substrates, α-carbamoyl α-oximyl cyclopropanes 1,
were prepared by the reaction of α-acyl α-carbamoyl cyclo-
propanes with hydroxylamine (NH2OH·HCl) in the presence
of NaOAc in methanol at room temperature in high yields
(up to 95%).11 We then selected N-(4-chlorophenyl)-1-[1-
(hydroxyimino)ethyl]cyclopropane carboxamide (1a) as the
model compound and examined its behavior in the pres-
ence of triflic anhydride. Upon treatment of 1a with 1.0
equivalent of Tf2O in DMF at room temperature for one
hour, the reaction proceeded, as indicated by TLC, and fur-
nished a single product after workup and purification of
the resulting mixture by silica column chromatography.
The product was characterized as 2-{5-[(4-chlorophe-
nyl)amino]-3-methylisox-azol-4-yl}ethyl
formate
(2a)
based on its spectral and analytical data (Table 1, entry 1).
The optimization of the reaction conditions, including reac-
tion temperature, reaction time, and ratio of Tf2O to sub-
strate 1a, were then investigated. It was observed that an
increase of either the reaction temperature or the ratio of
Tf2O to substrate 1a reduced the reaction time and gave a
higher yield of 2a (Table 1, entries 2 and 3). However, fur-
ther increase of either reaction temperature or the ratio of
Tf2O to substrate 1a had no significant influence on the
yield of 2a (Table 1, entries 4 and 5). Interestingly, other re-
agents, such as acetic anhydride and triflic acid were em-
ployed in this reaction; the former was not effective (Table
1, entry 6) and the latter was even inert (Table 1, entry 7).
After a series of experiments, optimal results were obtained
Figure 1 ORTEP drawing of 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

C
M. Yu et al.
Special Topic
Synthesis
Table 2 Synthesis of 5-Aminoisoxazoles 2 from α-Carbamoyl α-Ox-
imyl Cyclopropanes 1a
molecular cyclization reaction to form an iminium inter-
mediate B,23 which is hydrolyzed during work-up to give
the final product, substituted 5-aminoisoxazole 2.23,24
In summary, a facile and efficient one-pot synthesis of
fully substituted 5-aminoisoxazoles 2 is developed through
triflic anhydride-mediated ring-opening and intramolecu-
lar cyclization reactions of readily available α-cyclopropyl
β-oximyl amides 1. The ready availability of substrates,
mild reaction conditions, simple execution, good yields,
and synthetic potential of the products make this novel
protocol very attractive. Further work on the mechanism of
the reactions and the utilization and extension of the scope
of the methodology, is under investigation in our laborato-
ry.
HO
N
R
N
O
O
O
H
Tf2O, DMF, 40 °C
O
R
NHAr
NHAr
1
2
Entry
1
Ar
4-ClC6H4
R
2
Yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Ph
2a
2b
2c
2d
2e
2f
71
3-ClC6H4
2-ClC6H4
2,4-Me2C6H3
4-MeC6H4
2-MeC6H4
Ph
68
70
79
76
73
All reagents were purchased from commercial sources and used with-
out treatment, unless otherwise indicated. 1H NMR spectra were re-
corded at 300 or 400 MHz with TMS as internal standard at 25 °C on a
Varian Inova-400 (or Bruker-300) spectrometer, and 13C NMR spectra
were recorded at 100 MHz at 25 °C on a Varian Inova-400 spectrome-
ter. IR spectra (KBr) were recorded on a Shimadzu FTIR-8400S spec-
trophotometer in the range of 400–4000 cm–1. Melting points are un-
corrected. All reactions were monitored by TLC with GF254 silica gel
coated plates. Chromatography was carried out on silica gel (300−400
mesh). Petroleum ether (PE) used was the fraction boiling in the
range 60–90 °C.
1g
1h
2g
2h
75
Ph
mixture
a Reaction conditions: 1 (1.0 mmol), anhydrous DMF (10.0 mL), Tf2O (1.2
mmol), 40 °C, 30–50 min.
b Isolated yield.
It is widely known that DMF is not only used as an effec-
tive polar solvent for various chemical reactions, but it also
acts as a multipurpose agent in chemistry,15 such as an ef-
fective ligand of metallic complexes,16 a dehydrating
agent,17 a reducing agent,18 a catalyst,19 or a component of
the Vilsmeier reagent.20 More importantly, the structural
features of DMF makes it suitable as either an electrophile
or a nucleophile in reactions.21 On the basis of our experi-
mental results described above, it is very clear that DMF
plays dual roles as solvent and reactant in the ring-open-
ing/recyclization reaction of α-carbamoyl α-oximyl cyclo-
propanes 1. Thus, a mechanism for the synthesis of 5-aryl-
aminoisoxazoles 2 is proposed as depicted in Scheme 2. In
the presence of Tf2O, α-carbamoyl α-oximyl cyclopropane 1
is transformed into intermediate A through a tosylation re-
action.22 The attack of DMF to the cyclopropane ring trig-
gers the tandem ring-opening of cyclopropane and intra-
Synthesis of 2a; Typical Procedure
To a round-bottom flask containing ice-cold anhydrous DMF (10 mL),
Tf2O (1.2 mmol) was added dropwise, and the solution was stirred for
5 min at 0 °C. Compound 1a (1.0 mmol) was added and the mixture
was heated to 40 °C under stirring for 40 min. The resulting mixture
was poured into brine (15 mL) and extracted with CH2Cl2 (3 × 10 mL).
The combined organic phase was washed with water (2 × 10 mL),
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography (silica gel; petroleum
ether–EtOAc, 8:1) to give 2a.
2-{5-[(4-Chlorophenyl)amino]-3-methylisoxazol-4-yl}ethyl For-
mate (2a)
Yield: 200 mg (71%); white solid; mp 129–130 °C.
IR (KBr): 3197, 3095, 2985, 1720, 1647, 1587, 1519, 1483, 1402, 1234,
1168, 1010, 958, 825 cm–1
.
TfO–
Tf2O
N
O
HO
TfO
N
O
N
O
NHAr
Me
Ar
Ar
N
N
N
O
H
H
+
B
Me
TfO–
Me
1
A
H2O
HNMe2
O
O–
O
+
N
Me
H
H
N
N
O
H
Me
Me
2
O
NHAr
Scheme 2 Plausible mechanism for the reaction of 1 with Tf2O in DMF
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

D
M. Yu et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 2.21 (s, 3 H), 2.64 (t, J = 6.7 Hz, 2 H),
4.21 (t, J = 6.7 Hz, 2 H), 6.71 (s, 1 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.25 (d, J =
8.8 Hz, 2 H), 8.05 (s, 1 H).
1H NMR (300 MHz, CDCl3): δ = 2.21 (s, 3 H), 2.30 (s, 3 H), 2.62 (t, J =
6.0 Hz, 2 H), 4.19 (t, J = 6.0 Hz, 2 H), 6.53 (s, 1 H), 7.06–7.09 (m, 4 H),
8.05 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 10.4, 21.4, 63.1, 92.9, 118.2, 127.2,
13C NMR (100 MHz, CDCl3): δ = 10.4, 20.6, 21.4, 63.2, 91.6, 117.5,
129.4, 138.5, 160.5, 160.9, 162.4.
129.9, 132.0, 137.1, 160.5, 160.9, 163.1.
Anal. Calcd for C13H13ClN2O3: C, 55.62; H, 4.67; N, 9.98. Found: C,
55.78; H, 4.70; N, 9.90.
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.43; H, 6.25; N, 10.85.
Colorless crystal; M = 280.06; monoclinic; P21/n; a = 5.5307(8) Å, b =
21.530(3) Å, c = 11.1271(15) Å, α = 90.00°, β = 96.547(2)°, γ = 90.00°;
V = 1316.3(3) Å3; Z = 17; T = 273(2) K; F000 = 663, R1 = 0.0996, wR2 =
0.2753. CCDC 1011915 contains the supplementary crystallographic
data for 2a. The data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/get-
structures.
2-{3-Methyl-5-[o-tolylamino]isoxazol-4-yl}ethyl Formate (2f)
Yield: 190 mg (73%); colorless semisolid.
1H NMR (300 MHz, CDCl3): δ = 2.14 (s, 3 H), 2.22 (s, 3 H), 2.53 (t, J =
6.6 Hz, 2 H), 4.10 (t, J = 6.6 Hz, 2 H), 6.25 (s, 1 H), 6.89 (t, J = 7.5 Hz,
1 H), 7.07–7.11 (m, 2 H), 7.20 (d, J = 9.0 Hz, 1 H), 7.95 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 10.4, 17.5, 21.3, 63.2, 92.9, 118.1,
122.8, 126.4, 126.9, 130.6, 138.0, 160.5, 160.7, 163.0.
2-{5-[(3-Chlorophenyl)amino]-3-methylisoxazol-4-yl}ethyl For-
mate (2b)
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.76; H, 6.14; N, 10.68.
Yield: 191 mg (68%); colorless semisolid.
1H NMR (400 MHz, CDCl3): δ = 2.19 (s, 3 H), 2.64 (t, J = 6.8 Hz, 2 H),
4.17 (t, J = 6.8 Hz, 2 H), 6.91 (dd, J = 8.0, 1.0 Hz, 1 H), 7.02–7.03 (m,
1 H), 7.13–7.17 (m, 2 H), 7.29 (s, 1 H), 8.01 (s, 1 H).
2-{3-Methyl-5-[phenylamino]isoxazol-4-yl}ethyl Formate (2g)
Yield: 185 mg (75%); white solid; mp 84–85 °C.
IR (KBr): 3217, 3116, 3051, 3004, 2962, 2933, 1712, 1650, 1591, 1529,
13C NMR (100 MHz, CDCl3): δ = 10.3, 21.1, 62.9, 93.5, 114.8, 116.6,
121.8, 130.2, 134.8, 141.2, 160.7, 160.9, 162.1.
1490, 1427, 1319, 1178, 1166, 1110, 973, 754, 688 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.21 (s, 3 H), 2.64 (t, J = 6.7 Hz, 2 H),
4.20 (t, J = 6.7 Hz, 2 H), 6.67 (s, 1 H), 7.00 (t, J = 7.2 Hz, 1 H), 7.17 (d, J =
7.8 Hz, 2 H), 7.26–7.31 (m, 2 H), 8.05 (s, 1 H).
Anal. Calcd for C13H13ClN2O3: C, 55.62; H, 4.67; N, 9.98. Found: C,
55.78; H, 4.61; N, 9.89.
13C NMR (100 MHz, CDCl3): δ = 10.4, 21.3, 63.0, 92.4, 117.0, 122.1,
129.3, 139.8, 160.6, 160.8, 162.7.
2-{5-[(2-Chlorophenyl)amino]-3-methylisoxazol-4-yl}ethyl For-
mate (2c)
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.23; H, 5.77; N, 11.44.
Yield: 196 mg (70%); white solid; mp 77–78 °C.
IR (KBr): 3375, 3153, 3033, 2972, 2960, 1726, 1643, 1593, 1523, 1469,
1458, 1425, 1309, 1176, 1035, 810, 756, 518 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.22 (s, 3 H), 2.66 (t, J = 6.0 Hz, 2 H),
4.24 (t, J = 6.0 Hz, 2 H), 6.90 (t, J = 7.6 Hz, 1 H), 7.12 (s, 1 H), 7.20 (t, J =
7.6 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 8.06 (s,
1 H).
Acknowledgment
Financial support of this research by the National Natural Science
Foundation of China (21172211 and 21542006) is greatly acknowl-
edged.
13C NMR (100 MHz, CDCl3): δ = 10.4, 21.3, 63.6, 95.2, 116.7, 120.7,
122.2, 128.0, 129.3, 136.6, 160.3, 160.5, 161.8.
Anal. Calcd for C13H13ClN2O3: C, 55.62; H, 4.67; N, 9.98. Found: C,
55.44; H, 4.72; N, 10.06.
Supporting Information
Supporting information for this article is available online at
2-{3-Methyl-5-[p-tolylamino]isoxazol-4-yl}ethyl Formate (2d)
http://dx.doi.org/10.1055/s-0035-1561437.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Yield: 217 mg (79%); colorless semisolid.
1H NMR (400 MHz, CDCl3): δ = 2.18 (s, 3 H), 2.24 (s, 3 H), 2.28 (s, 3 H),
2.55 (t, J = 6.5 Hz, 2 H), 4.13 (t, J = 6.5 Hz, 2 H), 6.26 (s, 1 H), 6.96 (d, J =
8.0 Hz, 1 H), 6.99 (s, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 8.00 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 10.4, 17.5, 20.6, 21.3, 63.2, 91.6, 119.3,
127.4, 131.4, 132.9, 135.1, 160.6, 160.8, 163.5.
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