1-Bromoethene-1-sulfonyl fluoride (1-Br-ESF), a new SuFEx clickable reagent, and its application for regioselective construction of 5-sulfonylfluoro isoxazoles

Article abstract of DOI:10.1039/c8cc00986d

A new fluorosulfonylation reagent 1-bromoethene-1-sulfonyl fluoride was developed (1-Br-ESF). This unique reagent possesses three addressable handles (vinyl, bromide, and sulfonyl fluoride) and has great potential to function as a tris-electrophile and as

Full text of DOI:10.1039/c8cc00986d

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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1-Bromoethene-1-Sulfonyl Fluoride (1-Br-ESF), a New SuFEx Clickable Reagent,
and the Application for Regioselective Construction of 5-Sulfonylfluoro
Isoxazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Jing Leng,a Hua-Li Qin * a
DOI: 10.1039/x0xx00000x
www.rsc.org/
5
A
new fluorosulfonylation reagent 1-bromoethene-1-sulfonyl desirable.
Herein, we report the development of 1-
6
fluoride was developed (1-Br-ESF). This unique reagent possesses bromoethene-1-sulfonyl fluoride (1-Br-ESF) as another SuFEx
three addressable handles (vinyl, bromide, and sulfonyl fluoride) clickable reagent and its utilization for regioselective
and has great potentiality to functionalize as a tris-electrophile construction of 5-sulfonylfluoro isoxazoles.
(1) SO2F2: Sharpless and coworkers 2014
and as a sulfur(VI) fluoride exchange (SuFEx) clickable material to
VI
enrich SuFEx tool cabinet. The application of this reagent for
regioselective synthesis of 5-sulfonylfluoro isoxazoles has been
realized through a [3+2] cycloaddition with N-hydroxybenzimidoyl
chloride. This practical protocol provides a general and direct
route to functionalized isoxazoles possessing sulfonyl fluoride
moieties.
R1
O
SO2F
SuFEx
SuFEx
OH
R1
SO2F2
VI
R2
R2 SO2F
NH
R3
N
R3
(2) Ethenesulfonyl fluoride (ESF): Sharpless, Qin and coworkers 2016, 2017
Sulfur(VI) fluoride exchange (SuFEx) is an emerging and widely
prevailing tool in click chemistry which enable the synthesis of
SVI covalently linked modules due to the special properties of
(hetro)Ar
X
VI
(hetro)Ar
SuFEx
SO2F
SO2F
X = N2BF4, I, B(OH)2
1
SVI-F compounds appearing in the nucleophilic substitutions.
(3) SOF4: Sharpless, Li and coworkers 2017
F
Recently, many SVI hub reagents have been developed and
R
NH2
N
widely used in the SuFEx field (Figure 1). Sulfuryl fluoride
2
(SO2F2), when reacted with oxygen or nitrogen nucleophiles
R
SVI
SuFEx
O
SF4
F
O
under appropriate condition provides fluorosulfates (or
fluorosulfonates) or fluorosulfonamides, which can
functionalize as robust click connecters for further nucleophilic
substitutions; ethenesulfonyl fluoride (ESF), 3 another excellent
SVI-F construction reagent, is a selectively addressable bis-
electrophile for SuFEx click chemistry; thionyl tetrafluoride
(4) This work
Br
Br
Br2, white light
r.t., DCM
Et3N
-50 oC, ether
a)
SO2F
SO2F
SO2F
Br
1
33 g
1'
2
41.4 g
73%
4
(SOF4), provides two SuFExable sites through a tetrahedral
R
NOH
Cl
imino sulfur (VI) link by the reaction of primary amino groups.
Therefore, design and synthesis of new highly connectable SVI-
F reagent to enrich SuFEx click chemistry tool cabinet for
further expanding the applications of click chemistry in the
fields of material science, drug discovery, chemical biology and
fine chemical industry is of great significance and rather
Br
R
N
O
b)
SuFEx
VI
SO2F
SO2F
Figure 1 Developments in Sulfur(VI) fluoride exchange (SuFEx)
click chemistry.
1-Bromoethene-1-sulfonyl fluoride (1-Br-ESF)
2, with a
bromide moiety connected directly to the vinyl group adjacent
to sulfonyl fluoride, is readily accessible from ethenesulfonyl
a.State Key Laboratory of Silicate Materials for Architectures; and School of
Chemistry, Chemical Engineering and Life Science, Wuhan University of
Technology, 205 Luoshi Road, Wuhan, Hubei Province, 430070, P. R. China; fluoride (ESF)
1
in 40-gram scale (Figure 1, 4a). As the unique
provides a vinyl
sulfonyl fluoride to act as excellent selectively
qinhuali@whut.edu.cn.
* Corresponding author: Hua-Li Qin
structure of ethenesulfonyl fluoride (ESF)
and
1
a
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
addressable bis-electrophile, the specifically designed 1-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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precursor, and 1-bromoethene-1-sulfonyl fluoride
the feasibility of formation of
2
to testify
3-(4-
bromoethene-1-sulfonyl fluoride (1-Br-ESF)
2 with one more
active site can be regarded as a tris-electrophile. In addition,
(benzyloxy)phenyl)isoxazole-5-sulfonyl fluoride 4b and 5b. To
our delight, the [3+2] cycloaddition occurred at room
temperature using Et3N as the base in toluene, providing the
desired isoxazole 4b in 16% yield selectively (entry 1). The
usage of other common solvents such as MeOH (entry 2), DMF
(entry 4) did not improve the yield of this transformation,
while the use of t-BuOH provided the desired product from
isolatable level to moderate yield (entry 3, 6). The relatively
weaker organic base tripropylamine performed the annulation
smoothly (entry 6), while the inorganic bases (entry 9-12) were
found unsuitable for this transformation. The examination of
with two electron-withdrawing groups attached to one
terminal of the ethylene, the olefin of 1-Br-ESF
2 will be an
even stronger Michael acceptor than that of ethenesulfonyl
fluoride (ESF), a described “the most perfect Michael acceptor
ever found". 1, 7 In this paper, we describe an application of 1-
bromoethene-1-sulfonyl fluoride (1-Br-ESF)
2 for regioselective
construction of 5-sulfonylfluoro isoxazoles via a 1,3-dipolar
cycloaddition process (Figure 1, 4b).
Isoxazoles, a family of important five-membered aromatic
heterocycles, have emerged as significantly valuable
heterocyclic moieties presented in pharmaceuticals and
materials, and also been widely used as versatile building
the effect of the amount of 1-Br-ESF
2 to this annulative
process revealed that the use of 4.0 equivalents afforded the
highest yield of the cyclization product (entry 13-15). Our
experiments indicated that 1-Br-ESF 2 was sensitive to base
conditions to decompose to very reactive species or undergo
further polymerization. Therefore, the use of excess amount of
1-Br-ESF 2 is necessary to complete the consumption of the
blocks in natural product synthesis, material science, medicinal
8
chemistry.
sulfamethoxazole, an antibiotic; oxacillin,
Parecoxib,
a
COX-2 selective inhibitor;
penicillinase-
a
resistant β-lactam; isocarboxazid, a non-selective, irreversible
monoamine oxidase inhibitor (MAOI) are all life-saving drugs
containing isoxazole structure (Figure 2). Recent advances in
the synthesis of isoxazole are mainly divided into following five
aspects: [3+2] cycloaddition of alkenes / alkynes with nitrile
other starting materials, the N-hydroxybenzimidoyl chlorides
3
.
However, it is interesting to observe, that the use of more than
4.0 equivalents of 1-Br-ESF decreased the yield of the [3+2]
cycloaddition. The yield was increased to 80% when starting
9
10
oxides;
reactions;
cycloisomerization reactions;
condensation
and other
11
12
functionalization of isoxazoles
material
2 was dissolved in t-BuOH and added to the reaction
methods. 13 However, most of these procedures suffer from
some drawbacks more or less, such as transition-metal
catalysts, harsh reaction conditions or tedious multistep
process. The sulfonyl fluorides are also a class of potential
covalent pharmacophores to provide permanent inhibition of
target proteins, which will be valuable starting points for the
discovery of covalent drugs, in addition, there are already 152
approved SVI-containing drugs in the market. 3b, 14 In addition,
sulfonyl fluorides biological probes (Figure 2) have also
captured widely attention worldwidely. 15 The typical approach
for the introducing of sulfonyl fluoride group is by Cl-F
exchange from their corresponding sulfonyl chloride using
mixture dropwise instead of in one single portion (entry 17),
which was identified as the optimized condition.
Table 1. Selected optimization results.a
Entry Base
2
:
3b
Solvent
Toluene
MeOH
Yield b (%)
1
2
3
Et3N
Et3N
Et3N
Et3N
DIPEA
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
16
0
20
2
14
39
20
12
<1
9
t-BuOH
DMF
16
KF/18-crown-6 in water. Recently, several protocols were
successfully developed by employing the DABSO as a “SO2”
source followed by electrophilic fluorination with fluorinated
4
5
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
6
Tripropylamine 1 : 1.5
17, 18
reagent for the sulfonyl fluoride compounds.
of such strategies include harsh acidic treatment of arenes to
Limitations
7
TMEDA
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
3 : 1
8
DBU
access sulfonyl chloride precursors by electrophilic aromatic
sulfonation,
9
NaHCO3
20
expensive starting material, and the
10
11
12
13c
14d
15e
16f
NaOAc
requirement of metal catalysts. Viewing on the significance of
both isoxazoles and sulfonyl fluoride as structurally ubiquitous
motif in many important areas, we envision the development
of a straightforward approach for simultaneously introducing
isoxazole and sulfonyl fluoride groups will be particularly
useful in medicinal chemistry and pharmaceutical industry.
K3PO4
5
LiOAc
6
Tripropylamine
Tripropylamine
Tripropylamine
37
47
32
57
80
4 : 1
5 : 1
Tripropylamine 4 : 1
17f, g Tripropylamine 4 : 1
Conditions: a A mixture of 3b (1.5 equiv., 0.15 mmol, 39 mg),
2
(1.0 equiv., 0.1 mmol, 18.9 mg), base (5 equiv., 0.5 mmol), and
solvent (2 mL) was reacted at room temperature for 2 h.; b The
yield was determined by HPLC using 4b as the external
standard. [t4b = 9.416 min, λmax = 240.5 nm, methanol / water =
80 : 20 (v / v)]; c the ratio of
3b was 4 : 1; e the ratio of
2
to 3b was 3 : 1; d the ratio of
2
2
to
to
f
2
to 3b was 5 : 1; the ratio of
g
Figure 2 Representative isoxazoles and sulfonyl fluorides.
We initially began our exploration by using 4-(benzyloxy)-N-
hydroxybenzimidoyl chloride 3b, a general nitrile oxide
3b was 4 : 1, tripropylamine (2.5 equiv., 0.25 mmol);
2 was
2 | J. Name., 2012, 00, 1-3
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dissolved in another 2 mL t-BuOH and added to the reaction smoothly provided 2.05 g of the desired 5-sulfonylfluoro
mixture dropwise.
isoxazole 4b in one hour (Scheme 1).
With the optimized reaction condition in hand, we then
investigated the scope of N-hydroxybenzimidoyl chlorides for
this cycloaddition reaction (Table 2). A series of different
Scheme 1. Multigram scale synthesis of 4b
.
substituted N-hydroxybenzimidoyl chlorides
2
acceptable to excellent yield within 1-2 h. The substrates with
an electron-donating group (benzyloxy, 4b; phenyl, 4c; methyl,
4h; methoxy, 4m) on the phenyl ring were transformed into
their corresponding isoxazoles in better yields than those with
3
with 1-Br-ESF , affording the desired products
were reacted
in an
4
A plausible mechanism for the 1,3-dipolar cycloaddition
reaction was proposed (Scheme 2). Firstly, the nitrile oxides
was generated from with the assistance of base, which,
subsequently, annulated with 1-Br-ESF to generate
intermediate isoxazoline II (path a), due to the steric hindrance,
another possible cycloaddition intermediate II’ (path b) was
I
3
2
electron-withdrawing groups (4d
functional groups of nitro (4d), mesyl (4e), halogen (4f
,
4e and 4g). Substrates with
4l
,
)
excluded
disubstituted isoxazole
.
Finally, the exclusively regioselective product 3,5 -
was obtained through releasing of
were all compatible using this developed protocol.
Interestingly, the sterically hindered N-hydroxybenzimidoyl
chloride also proceeded efficiently, providing the
4
HBr under the effect of another equivalent of base.
corresponding products in satisfactory yields (4j
Polycyclic substrates (3p 3q) were also able to form their
corresponding isoxazoles (4p 4q) in acceptable yields of 70%
and 78% respectively. The product containing a vinyl group (4r
, 4k and 4m).
,
,
)
was also successfully obtained from its parent starting material
cinnamyl aldehyde in a moderate yield of 40%. Alkyl and
heteroaromatic starting materials could also transform into
their corresponding products (4t, 4s and 4u) with acceptable
yields.
Scheme 2. A plausible mechanism for the formation of
isoxazole 4.
Table 2. Scope of N-hydroxybenzimidoyl chlorides for the
cycloaddition reaction.a
It is interesting to find that the performance of 1-
bromoethene-1-sulfonyl fluoride (1-Br-ESF) and ethenesulfonyl
fluoride (ESF) vary significantly when react with aniline as
Michael acceptors. The reaction of aniline
eq) of 1-Br-ESF gave only mono-adducted product
quantitative yield without the formation of any bis-adducted
product while in the reaction of aniline and ethenesulfonyl
6
with excess (2.05
2
7
in
8
6
fluoride (ESF) the opposite result was obtained under identical
conditions (Scheme 3). 5a, 5b
Scheme 3. A reactivity comparison between (1-Br-ESF) and ESF
in Michael addition.
a
Conditions:
A mixture of 1 (1.0 equiv., 1.0 mmol),
Another significant property of 1-Br-ESF appeared in the
coupling reaction. It is interesting to find that the oxidative
Heck coupling between 1-Br-ESF and arylbronoic acid didn’t
occur by employing the conditions used for coupling of ESF
with arylbronoic acid (Scheme 4, a, b). It is worthy noting that
the Suzuki coupling product 13 can be generated under a
specific reaction condition using Pd catalyst to provide the first
example of 1-aryl ethenesulfonyl fluoride of its kind with
proceeding the competitive Heck type of oxidative coupling to
form compound 12. This new class of 1-aryl ethenesulfonyl
fluorides 13 have great potentiality to be applied in polymer
synthesis and chemical biology. 21 Interestingly, the oxidative
heck-coupling product 12 was accessible through a cascade
tripropylamine (2.5 equiv., 2.5 mmol, 358 mg), and t-BuOH (5
mL) was stirred in a tube, (4 equiv., 4 mmol, 756 mg) was
dissolved in another 5 mL t-BuOH and added to the reaction
2
mixture dropwise.
To evaluate the practicality of this regioselective 1,3-dipolar
cycloaddition, a gram-scale reaction was carried out. We were
pleased to find that the efficiency of [3+2] cycloaddition was
not decreased, the reaction of 2.09 grams of N-
hydroxybenzimidoyl chloride 3b (8 mmol) and 6.05 grams of 1-
Br-ESF
2 (32 mmol) under the previous optimal conditions,
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1083. b) H. Wang, F. Zhou, G. Ren, Q. Zheng, H. Chen, B. Gao,
L. Klivansky, Y. Liu, B. Wu, Q. Xu, J. Lu, K. B. Sharpless, P. Wu,
Angew. Chem. Int. Ed. 2017, 56, 11203. c) A. J. Brouwer, N.
Herrero Álvarez, A. Ciaffoni, H. van de Langemheen, R. M. J.
Liskamp, Bioorg. Med. Chem. 2016, 24, 3429.
process of the addition of Br2 to (E)-2-phenylethene-1-sulfonyl
fluoride 14 and the subsequent elimination with the
promotion of base (Scheme 4, c), however, the treatment of 2-
phenyl-1-bromoethene-1-sulfonyl fluoride 12 with N-
hydroxybenzimidoyl chlorides
3 did not generate the desired
6
a) A. Champseix, J. Chanet, A. Etienne, A. Leberre, J. C.
Masson, C. Napierala, R. Vessiere, Bull. Soc. Chim. Fr. 1985,
463. b) J. Chanet-Ray, R. Vessière, A. Zéroual, Heterocycles,
1987, 26, 101.
trisubstituted isoxazole 15 due to steric hindrance effect of the
phenyl substitution.
7
8
Q. Chen, P. Mayer, H. Mayr, Angew. Chem. Int. Ed. 2016, 55,
12664.
a) J. B. Carr, H. G. Durham, D. K. Hass, J. Med. Chem. 1977,
20, 934. b) R. Nesi, S. Chimichi, P. Sarti-Fantoni, P. Tedeschi,
D. Giomi, J. Chem. Soc. Perkin Trans, 1985, 1871. c) F. Himo,
T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B.
Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210. d)
M. A. F. A. Manan, D. B. Cordes, A. M. Z. Slawin, M. Bühl, V.
W. Y. Liao, H. C. Chua, M. Chebib, D. O’Hagan, Chem. Eur. J.
2017, 23, 10848. e) A. Rietz, H. Li, K. M. Quist, J. J. Cherry, C.
L. Lorson, B. G. Burnett, N. L. Kern, A. N. Calder, M. Fritsche,
H. Lusic, P. J. Boaler, S. Choi, X. Xing, M. A. Glicksman, G. D.
Cuny, E. J. Androphy, K, J. Hodgetts, J. Med. Chem. 2017, 60
4594. (f) F. Hu, M. Szostak, Adv. Synth. Catal. 2015, 357
2583.
a) A. Quilico, G. Stagno d’Alcontres, P. Grünanger, Nature
1950, 166, 226. b) V. V. Rostovtsev, L. G. Green, V. V. Fokin,
K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596. c) C.
Spiteri, S. K., J. E. Moses, Org. Lett. 2010, 12, 3368.
,
,
Scheme 4. Further derivatization of 1-Br-ESF.
9
In conclusion, we have developed a new fluorosulfonylation
reagent 1-bromoethene-1-sulfonyl fluoride (1-Br-ESF), which
possess enormous potential in the field of SuFEx click
10 a) J. P. Waldo, R. C. Larock, Org. Lett. 2005, 7, 5203. b) T.
Okitsu, K. Sato, T. M. Potewar, A. Wada, J. Org. Chem. 2011,
76, 3438. c) C. Y. Wu, T. Horibe, C. B. Jacobsen, F. D. Toste,
Nature 2015, 517, 449. d) W. J. Wolf, M. S. Winston, F. D.
chemistry. Meanwhile,
cycloaddition between
a
method for the 1,3-dipolar
diverse N-hydroxybenzimidoyl
chlorides and 1-Br-ESF was developed for the synthesis of a
series of 5-sulfonyl fluoride substituted isoxazoles. Further
applications of 1-Br-ESF in SuFEx click chemistry and their
utilizations for discovery of new drug candidates and
functional materials are ongoing in our laboratory.
Toste, Nat. Chem. 2014,
11 a) R. Harigae, K. Moriyama, H. Togo, J. Org. Chem. 2014, 79
6, 159.
,
2049. b) H. Kawai, Y. Sugita, E. Tokunaga, N. Shibata, Eur. J.
Org. Chem. 2012, 1295. c) A. Salomone, A. Scilimati, P. Vitale,
Synthesis 2015, 47, 807.
12 a) X. C. Wang, Y. Hu, S. Bonacorsi, Y. Hong, R. Burrell, J. Q.
Yu, J. Am. Chem. Soc. 2013, 135, 10326. b) K. M. Engle, T. S.
Mei, M. Wasa, J. Q. Yu, Acc. Chem. Res. 2012, 45, 788.
13 J. A. Burkhard, B. H. Tchitchanov, E. M. Carreira, Angew.
Chem. Int. Ed. 2011, 50, 5379.
We are grateful to the National Natural Science Foundation
of China (Grant No. 21772150) and Wuhan University of
Technology for their continuous encouragement towards the
research and financial support.
14 A. J. Brouwer, N. H. Álvarez, A. Ciaffoni, H. Langemheen, R.
M. J. Liskamp, Bioorg. Med. Chem. 2016, 24, 3429.
15 a) N. P. Grimster, S. Connelly, A. Baranczak, J. Dong, L. B.
Krasnova, K. B. Sharpless, E. T. Powers, I. A. Wilson, J. W.
Kelly, J. Am. Chem. Soc. 2013, 135, 5656. b) Q. Zhao, X.
Ouyang, X. Wan, K. S. Gajiwala, J. C. Kath, L. H. Jones, A. L.
Burlingame, J. Taunton, J. Am. Chem. Soc. 2017, 139, 680.
16 T. A. Bianchi, L. A. Cate, J. Org. Chem., 1977, 42, 2031.
17 A. T. Davies, J. M. Curto, S. W. Bagley, M. C. Willis, Chem.
Conflicts of interest
There are no conflicts to declare.
Notes and references
Sci., 2017, 8, 1233.
18 A. L. Tribby, I. Rodríguez, S. Shariffudin, N. D. Ball, J. Org.
Chem. 2017, 82, 2294.
19 A. S. Deeming, C. J. Russell, M. C. Willis, Angew. Chem. Int.
Ed. 2016, 55, 747.
20 E. E. Gilbert, Synthesis 1969, 1969, 3.
1
2
3
J. Dong, L. Krasnova, M. G. Finn, K. B. Sharpless, Angew.
Chem. Int. Ed. 2014, 53, 9430.
J. S. Oakdale, L. Kwisnek, V. V. Fokin, Macromolecules 2016,
49, 4473.
a) H.-L. Qin, Q. Zheng, G. A. L. Bare, P. Wu, K. B. Sharpless,
Angew. Chem. Int. Ed. 2016, 55, 14155. b) G.-F. Zha, Q.
Zheng, J. Leng, P. Wu, H.-L. Qin, K. B. Sharpless, Angew.
Chem. Int. Ed. 2017, 56, 4849. c) P. K. Chinthakindi, K. B.
Govender, A. S. Kumar, H. G. Kruger, T. Govender, T Naicker,
P. I. Arvidsson, Org. Lett. 2017, 19, 480. d) G.-F. Zha, G. A. L.
Bare, J. Leng, Z.-P. Shang, Z. Luo, H.-L. Qin, Adv. Synth. Catal.
2017, 359, 3237. e) Q. Zheng, J. Dong, K. B. Sharpless, J. Org.
Chem. 2016, 81, 11360.
21 S. Pan, S.-Y. Jang, S. S. Liew, J. Fu, D. Wang, J.-S. Lee, S. Q.
Yao, Angew. Chem. Int. Ed. 2018, 57, 579.
4
5
S. Li, P. Wu, J. E. Moses, K. B. Sharpless, Angew. Chem. Int.
Ed. 2017, 56, 2903.
a) B. Gao, L. Zhang, Q. Zheng, F. Zhou, L. M. Klivansky, J. Lu,
Y. Liu, J. Dong, P. Wu, K. B. Sharpless, Nat. Chem. 2017, 9,
4 | J. Name., 2012, 00, 1-3
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A unique SuFEx clickable tris-electrophile, 1-Br-ESF, was developed and applied for
the synthesis of 5-sulfonylfluoro isoxazoles with exclusive regioselectivity