Synthesis of ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate via regioselective dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2012.05.089

Efforts to prepare ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5- carboxylate (1) by developing a regioselective 1,3-dipolar cycloaddition between phenyl nitrile oxide and various 4,4,4-trifluoromethyl crotonates are described. The substitution at the C2-position of crotonate dipolarophile 4 significantly influenced the regiochemistry and yield of the cycloaddition. Enol and enol ether-based crotonates underwent regioselective cycloadditions with phenyl nitrile oxide to provide 4-trifluoromethyl isoxazoles in good yields.

Full text of DOI:10.1016/j.tetlet.2012.05.089

Tetrahedron Letters 53 (2012) 3994–3997
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Tetrahedron Letters
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Synthesis of ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate via
regioselective dipolar cycloaddition
Michael A. Schmidt a, , Kishta Katipally a, Antonio Ramirez a, Omid Soltani a, Xiaoping Hou b,
⇑
Huiping Zhang b, Bang-Chi Chen b, Xinhua Qian a, Rajendra P. Deshpande a
a Chemical Development, R&D, Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, NJ 08903, United States
b Discovery Chemistry, R&D, Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Efforts to prepare ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (1) by developing a regiose-
lective 1,3-dipolar cycloaddition between phenyl nitrile oxide and various 4,4,4-trifluoromethyl croto-
nates are described. The substitution at the C2-position of crotonate dipolarophile 4 significantly
influenced the regiochemistry and yield of the cycloaddition. Enol and enol ether-based crotonates
underwent regioselective cycloadditions with phenyl nitrile oxide to provide 4-trifluoromethyl isoxaz-
oles in good yields.
Received 27 April 2012
Revised 15 May 2012
Accepted 19 May 2012
Available online 26 May 2012
Keywords:
Heterocycles
Ó 2012 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition
Regioselective
Fluorine
3-Substituted 4-(trifluoromethyl)isoxazole-5-carboxylates have
been utilized in a number of biologically active molecules in both
agricultural1a,e and pharmaceutical industries1b–d,f as fungicides
or potential therapeutics. Despite their usefulness, there are lim-
ited reports of the regioselective synthesis of trisubstituted isoxaz-
oles. Typically, two options are considered for synthesizing
trifluoromethylated isoxazoles such as 1: (1) appending the 4-tri-
fluoromethyl group to a 3,5-disubstituted isoxazole; or (2) by con-
structing the heterocycle using trifluoromethyl containing starting
materials.2 The modification of a preexisting heterocycle generally
requires harsh conditions and/or undesirable reagents. On the
other hand, building the heterocycle from trifluoromethylated
precursors may circumvent the difficulties of fluorination or triflu-
oromethylation. Nevertheless, there are few reports of the regiose-
lective synthesis of isoxazoles with the substitution pattern of 1.
This is first due to limited availability of trifluoromethylated
precursors, and possibly also due to the unique nature of the tri-
fluoromethyl group which can significantly alter chemical behav-
ior thus complicating the chemistry.2a,3
tion between 3 and bromoalkene 64e generate the undesired regio-
isomer as the major product (Scheme 1). Moreover, the yields from
such cycloaddition reactions are usually low due to the competing
Michael-type reaction between the nitrile oxide (or variant) and
the highly electrophilic alkyne 5.4f Thus far, there are no reported
regiospecific methods to synthesize 3-phenyl-4-(trifluoro-
methyl)isoxazole-5-carboxylates 7.
Early efforts4g,h focused on examining the 1,3-dipolar cycloaddi-
tion between nitrile oxide precursor 3 and various alkynes (Fig. 1).
First, we investigated the use of magnesium salts to improve the
regioselectivity of the cycloaddition5 between chlorooxime 3 and
alkyne 5, but without success. The observed poor selectivities
could be due to the presence of the trifluoromethyl group which
polarizes the alkyne in the opposite direction to that of the ester
group. Next, we explored the use of hindered ortho ester 9 as a
dipolarophile, which afforded a ꢀ3:1 ratio of cycloadducts favoring
the undesired 5-trifluoromethyl isoxazole. It has been previously
reported that the less hindered butynol 10, however, afforded the
desired 4-trifluoromethyl isoxazole alcohol in a ꢀ9:1 ratio.4g,h This
ratio was unaffected by varying the bases or by addition of Lewis
acids. The moderate regioisomer ratio, coupled with the difficulty
in preparing pure 10, and the necessity of an additional oxidation
step in downstream chemistry led us to consider alternative ap-
proaches to prepare 1.
As part of a recent program in our laboratories, we required an
efficient synthesis of ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-
5-carboxylate (1). A review of the methods to construct the trisub-
stituted 4-trifluoromethyl isoxazole 1 revealed both the 1,3-dipolar
cycloaddition between phenyl nitrile oxide precursor 3 and methyl
4,4,4-trifluoromethylbut-2-ynoate (5)4b,f,g as well as the cycloaddi-
To increase our understanding of the reaction with the goal of
improving the desired regioselectivity of the cycloaddition, we uti-
lized computational methods to evaluate the viability of crotonates
substituted at the C2-position as alkyne surrogates. We analyzed
⇑
Corresponding author.
E-mail address: Michael.Schmidt@bms.com (M.A. Schmidt).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.089

M. A. Schmidt et al. / Tetrahedron Letters 53 (2012) 3994–3997
3995
CO2Me
O
OH
Cl
N
F3C
F3C
N
5
CO2R
Et3N
or
N
O
CO2R
CF3
CO2R
CF3
3
Br
7
8
6
(Minor)
1 : 4-9
(Major)
Scheme 1. Reported approaches to similar isoxazoles.4b,e–h
Me
Table 2
1,3-Dipolar cycloaddition
CO2Me
O
O
OH
F3C
O
5
OH
O
O
F3C
N
N
N
11-17
F3C
CO2Et
9
10
CF3
+
Mg+2
Cl
Base
CF3
CO2Et
Figure 1. Alkynes studied in the cycloaddition.
3
1
2
the molecular orbitals of phenyl nitrile oxide and a variety of
methyl 4,4,4-trifluoromethyl crotonates using DFT calculations
(see Table S1).6 The results indicated that the preferred molecular
orbital interactions engage the phenyl nitrile oxide HOMO and the
LUMO of crotonates. In addition, the nitrile oxide HOMO is concen-
trated at the O-atom indicating that it is the nucleophilic terminus
of the 1,3-dipole.7 A simple ground state FMO prediction of the reg-
ioselectivities was impeded however, by the insensitivity of the
crotonate LUMO coefficients of C2 and C3 substitutions. Alterna-
tively, examination of the natural bond orbital (NBO) charges8 of
crotonates (Table S2) showed dramatic changes in the polarization
of the C2–C3 bond: the most inductively electron-withdrawing
groups (X = OH, F) would induce positive charge at the C2 and neg-
ative charge at the C3 position, whereas less electronegative sub-
stituents (X = H, Br) sustain negative charge at the C2 and the C3
positions (Table S2). Since the nitrile oxide bears negative charge
at the O-terminus and positive charge at the C-atom, electron-
withdrawing groups in the crotonate would provide a better elec-
trostatic match for the cycloaddition and therefore promote high
regioselectivity. This argument was also supported by calculations
of regioisomeric transition states on the selected 1,3-dipolar cyc-
loadditions (Table 1).
Following the computational findings, we investigated the cyc-
loadditions between chlorooxime 3 and 4,4,4-trifluoromethylcrot-
onates with electron-withdrawing groups at the C2-position.
Gratifyingly, the treatment of readily available vinyl bromide9 11
(Table 2) with chlorooxime 3 in the presence of dibasic sodium
phosphate (4.0 equiv) led to a ꢀ9:1 ratio of the desired 4-trifluoro-
methyl isoxazole 1 in 70% isolated yield.10 Screening of various
inorganic and tertiary amine bases, solvents, and reaction temper-
atures did not provide better selectivity. Throughout the reaction
Dipolarophile
Br
Conditionsa
Yieldb (ratio 1:2)
F3C
F3C
F3C
A
75% (90:10)
CO2Et
11
O
Bc
Bd
B
55% (>99:1)
79% (>99:1)
29% (>99:1)
22% (>99:1)
CO2Et
12
OEt
CO2Et
13
14
15
OAc
F3C
F3C
F3C
CO2Et
OBz
A
CO2Et
OTs
A
16% (>99:1)
35% (>99:1)f
CO2Et
16
17
NHCBz
F3C
Ae
CO2Me
a
Condition A: 4 equiv Na2HPO4, EtOAc, 50 °C. Condition B: 2 equiv Et3N, DMA,
60 °C.
b
Yields determined by HPLC against a calibrated standard.
c
d
e
Run at À20 °C.
An additional charge of 1 equiv chlorooxime and 2 equiv base added after 24 h.
After consumption of the starting material, BF3OEt2 was added, then the methyl
ester was hydrolyzed with LiOH.
f
The carboxylic acid was isolated.
Table 1
Calculated DDGà values for regioisomeric transition states
O
N
N
O
N
N
N
N
O
O
O
N
O
H
CO2Me
H
CO2Me
O
3
2
F3C
F3C
X
X
CO2Et
F3C
TS-I
TS-II
18
19
20
Entry
X
DDGà (TSII–TSI)a
Figure 2. Byproducts observed in the cycloaddition.
1
2
3
H
Br
OH
+1.1
+3.1
+4.1
optimization, the major byproducts consistently observed were ni-
a
trile oxide dimers 18 and 19 (Fig. 2).
kcal/mol.

3996
M. A. Schmidt et al. / Tetrahedron Letters 53 (2012) 3994–3997
O
N
OH
Cl
O
CO2H
N
Br
Na2HPO4
EtOAc
N
H
N
H
F3C
CF3
22
CO2H
3
21
23
Scheme 2. Cycloaddition between 3 and 21.
In an attempt to obtain better regioselectivity, we next consid-
ered enol-based dipolarophiles generated from -ketoester 12
to afford the isoxazole. A subsequent treatment with 1.0 equiv
BF3ÁOEt2 was required to achieve elimination. The crude mixture
was then hydrolyzed with LiOH to afford the acid 22 in 35% overall
yield with no detectable amounts of the undesired regioisomer.
It is noteworthy that 2-bromo-4,4,4-trifluorocrotonic acid (21,
94:6 Z:E)18 was also a highly selective dipolarophile, yielding the
desired 4-trifluoromethyl isoxazole acid 22 in approximately 30%
yield (Scheme 2). A major side product found in this reaction
was diphenylurea (23), which presumably was formed by the ni-
trile oxide (or chlorooxime 3) undergoing a Beckmann rearrange-
ment mediated by the carboxylate of 21 to from phenyl
isocyanate, which can react further to form 23.19
In summary, a regioselective synthesis of ethyl 3-phenyl-4-(tri-
fluoromethyl)isoxazole-5-carboxylate 1 was developed. A key find-
ing in this study involves the achievement of high regioselectivity
in a 1,3-dipolar cycloaddition by introduction of an enol ether at
the C2-position of crotonate 4. The 2-alkoxy crotonate provided a
stable dipolarophile relative to the highly sensitive 4,4,4-trifluoro-
methyl enolate and circumvented the formation of dioxazole side
products. DFT computational studies supported the critical role
of inductively electron-withdrawing substituents at the C2-posi-
tion in guiding regioselectivities of the 1,3-dipolar cycloaddition.
a
(Table 1, entry 3). As predicted, the cycloaddition between 1211
and chlorooxime 3 in the presence of triethylamine (2 equiv) in
DMA at À20 °C afforded exclusively the desired 4-trifluoromethyl
isoxazole 1 in 55% yield. The moderate yield was attributed to
byproduct formation and decomposition of 12 (Fig. 2) via a cascade
elimination of the fluoride under basic conditions.12 The byproduct
distribution could be controlled by changing reaction conditions.
Using less polar solvents (dichloromethane, toluene) and/or inor-
ganic bases (sodium and potassium phosphates, carbonates, and
hydroxides) led to the formation of adduct 20 as the major product
with various amounts of nitrile oxide dimers 18 and 19. We attri-
bute these results to the unsuccessful generation of the corre-
sponding enol of 12. We found that temperature and base
strength affected the rate of decomposition of substrate 12 pre-
sumably via its unstable enol form. Running the reaction at
À20 °C, we achieved the best yield of product 1. When a stronger
amine base such as DBU was used, however, only trace amounts
of product were formed. Clearly, our expectation of using the elec-
tron withdrawing ester functionality in 12 to circumvent the
known E1cB-type of elimination of fluoride12 was not completely
successful.
Although using a-ketoester 12 as the dipolarophile led to exclu-
Acknowledgements
sive formation of the desired 4-trifluoromethylisoxazole 1, the low
throughput resulting from the instability of the substrate ham-
pered its practical application. To address this issue, we decided
to explore ethyl enol ether 13 as a dipolarophile. The Z-ethyl enol
ether 13 was prepared via a Wittig reaction between (1,2-dieth-
oxy-2-oxoethyl)triphenylphosphonium chloride and 1-ethoxy-
2,2,2-trifluoroethanol in 44% unoptimized yield.13 The cycloaddi-
tion between enol ether 13 and chlorooxime 3 (2.0 equiv) in the
presence of triethylamine in DMA at 60 °C afforded the desired
4-trifluoromethyl isoxazole 9 as a single regioisomer in 79% yield.
While adduct 20 was not observed in this reaction, significant
amounts of nitrile oxide dimers 18 and 19 were observed due to
the use of excess chlorooxime. To minimize the dimerization, chlo-
rooxime 3 was added in portions over 8 h at 60 °C. The slow addi-
tion led to greatly lowered levels of dimers 18 and 19, however at a
noticeable expense of product yield (70%). Interestingly, the E-enol
ether of 1314 was unreactive under the reaction conditions, possi-
bly due to the development of 1,3-allylic strain in the
cycloaddition.15
We thank Drs David Kronenthal, Robert Waltermire, David Con-
lon, Martin Eastgate, and Lopa Desai for assistance reviewing the
manuscript.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.089.
References and notes
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isoxazoline adduct. This species did not eliminate benzyl carbamate

M. A. Schmidt et al. / Tetrahedron Letters 53 (2012) 3994–3997
3997
6. All calculations were performed with Gaussian 98 using the B3LYP method. The
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