Monofluorinated 5-membered ringsviafluoromethylene transfer: synthesis of monofluorinated isoxazolineN-oxides

Article abstract of DOI:10.1039/d1ob00270h

The synthesis of five-membered rings using fluoromethylene transfer chemistry is an attractive method for building fluorinated products of high value. This work demonstrates for the first time that one-fluorine-one-carbon modification of a substrate could

Full text of DOI:10.1039/d1ob00270h

Organic &
Biomolecular Chemistry
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Monofluorinated 5-membered rings via
fluoromethylene transfer: synthesis of
monofluorinated isoxazoline N-oxides†
Cite this: Org. Biomol. Chem., 2021,
19, 2688
Arturs Sperga, Armands Kazia and Janis Veliks
*
The synthesis of five-membered rings using fluoromethylene transfer chemistry is an attractive method
for building fluorinated products of high value. This work demonstrates for the first time that one-
fluorine-one-carbon modification of a substrate could be a viable strategy to access monofluorinated
five-membered rings. The synthetic methodology was developed to access monofluorinated isoxazoline-
N-oxides in one step starting from substituted 2-nitroacrylates using fluoromethylsulfonium reagents.
Received 12th February 2021,
Accepted 26th February 2021
DOI: 10.1039/d1ob00270h
rsc.li/obc
Fluorine atoms are of increasing prevalence in drug mole- salts via an ylide to access 3-membered cycles-fluorocyclopro-
cules;1 thus, the development of new strategies for obtaining panes and fluoroepoxides,8 could be adapted to access deriva-
fluorinated organic compounds is of critical importance tives of monofluorinated isoxazolines to showcase formal [1 +
in medicinal chemistry,2 agrochemistry,3 and materials.4 4] cyclization, yielding 5-membered heterocycles.
Strategies for synthesizing fluorinated 5-membered rings5 can
As a prominent class of isoxazoline derivatives, isoxazoline-
be classified into two major categories (Fig. 1A): (1) synthetic N-oxides have gained broad interest from the perspective of
routes that involve a direct fluorination step (formation of C–F their synthesis and application.16
bonds) and6 (2) the utilization of fluorinated building blocks.7
Both of these approaches are used to access high-value fluo-
rine-containing products.5c Recently, we have developed reac-
tions involving fluoromethylene transfer8 (mimicking fluoro-
carbene chemistry) where the simplest C–F-containing build-
ing block (CHF:) is incorporated into a substrate— the one-
fluorine-one-carbon modification of a target structure which
could be considered as a middle ground of the aforemen-
tioned classical approaches. To date, fluoromethylene transfer
has been successfully demonstrated only for the synthesis of
vinyl fluorides9 and monofluorinated 3-membered rings.10 To
the best of our knowledge, 5-membered ring formation by
such a strategy has not been demonstrated thus far. The isoxa-
zole scaffold11 can be found among the list12 of the most com-
monly used heterocycles in pharmaceuticals, and its partially
saturated analog isoxazoline13 derivatives also have relevant
biological activity, as illustrated in Fig. 1B.14 Despite the fact
that perfluoro- and trifluoromethyl isoxazolines are widely
studied, their monofluorinated analogs are extremely rare.15
We envisioned that our recently developed technology invol-
ving fluoromethylene transfer from fluoromethyl sulfonium
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
E-mail: janis.veliks@osi.lv
Fig. 1 (A) Strategies used to access monofluorinated five-membered
heterocycles. (B) Biologically relevant compounds containing isoxazo-
line moieties. (C) Synthesis of 5-fluoro-isoxazoline-N-oxides by using a
fluoromethylene transfer strategy.
†Electronic supplementary information (ESI) available. CCDC 2057602 and
2057603. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00270h
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As a platform for the demonstration of 5-membered cycle
formation by monofluoromethylene transfer, 2-nitroacrylates17
were selected to afford previously unreported monofluorinated
isoxazoline-N-oxides at the C5 position. Optimization studies
were performed by using ethyl 2-nitro-3-phenylacrylate (1a)
as a model substrate to form 3-(ethoxycarbonyl)-5-fluoro-4-
phenyl-4,5-dihydroisoxazole N-oxide (3a) as the reaction
product. Solvent screening (Table 1, entries 1–5) indicated that
tetrahydrofuran is a superior reaction solvent. Sodium hydride
turned out to be the most efficient base for the in situ gene-
ration of sulfur fluoromethylide that is to be trapped with
nitroacrylate 1a (entries 5, 7 and 8). 2,3,4,5-Tetramethylphenyl
substituted sulfonium reagent 2a18 gave a slightly better yield;
however, the simpler and affordable reagent 2b 19 performance
was comparable (entries 5 and 6). The optimal reaction con-
ditions therefore consist of treating 1a with 2a (2 equiv) and
sodium hydride (3 equiv) in anhydrous tetrahydrofuran at 0 °C
giving the desired product 3a in a good yield as a mixture of
diastereomers (entry 5).
Under the optimized conditions (Table 1, entry 5), the sub-
strate scope obtained by fluoromethylene transfer to nitroacry-
lates 1 was investigated (Scheme 1). The reaction conditions
tolerate a large variety of arylidene nitro esters 1 bearing
unsubstituted phenyl group 1a, halogen substituents 1b–e,
electron donating groups 1f–i, electron withdrawing groups
1j–m, or substrates bearing conjugated vinyl-substituent 1n,
five-membered heterocycles 1o–q, and alicyclic substrate 1r.
The corresponding isoxazoline-N-oxides 3 were obtained in
moderate to very good yields. To our surprise, most of the pro-
ducts were chromatographically purifiable compounds with
good to moderate stability. For all but 3l and 3q, the diastereo-
Scheme 1 Substrate scope of the formal [4 + 1] cyclization reaction.
The reactions were performed under optimized reaction conditions on
0.1 to 0.2 mmol scale of 1, see ESI† for more details. Isolated yields,
unless otherwise stated. 1H NMR yields in parentheses determined for
crude product 3 before isolation. 1H NMR yields determined by using
EtOAc as the internal standard. dr determined from 1H NMR of crude.
Table 1 Optimization of fluoromethylene transfer to 2-nitro-3-pheny-
lacrylate (1a)
mers could be easily separated. This is the first example of iso-
lable16n monofluoro isoxazoline-N-oxides. The fluoromethyl-
ene transfer process is highly efficient; however, for less stable
products (3m, q, t, and s) the lowered yield was determined by
their partial decomposition upon isolation. In contrast to
other nitroalkenes,19 in the fluoromethylene transfer reaction
of 2-nitroacrylates 1 using reagent 2a the formation of fluorocy-
clopropanation products was not observed. The stereo-
chemistry of both diastereomers was determined by compari-
Entrya Base
2
Solvent
Yield of 3a, % b dr trans : cis
1
2
NaH
NaH
a
a
a
a
a
b
a
a
MeCN
DMF
44
Traces
1.2 : 1
n.d.
3
NaH
NaH
NaH
NaH
1,4-Dioxaned 52
1.4 : 1
1.4 : 1
1.6 : 1
1.4 : 1
—
4
DCM
THF
THF
THF
THFf
72
82 (78)
79
0
5c
6c
7
3
son of the corresponding JH(4)–H(5) coupling constants in 1H
DBU
8
LiHMDSe
8
1 : 1
NMR spectra with estimated dihedral angles H–C(4)–C(5)–H
for trans-3a (0 Hz and ∼104° angle) and cis-3a (5.5 Hz and
∼25° angle). This was further unambiguously supported by the
X-ray structures of cis-3i and trans-3j isomers.
To test the scalability of the reaction, we performed an
upscaled reaction for the [4 + 1] cyclization of nitroacrylate
1a. For the upscaled reaction (Scheme 2), more affordable 2,4-
a Reaction conditions:
A
base was added to
a
mixture of 1a
(0.0452 mmol) and 2 in a solvent (1.8 ml) under an Ar atmosphere at
0 °C. The reaction mixture was stirred at 0 °C, and the reaction pro-
gress was monitored by TLC. The crude reaction mixture was analyzed
by 1H NMR. b 1H NMR yield determined using EtOAc as an internal
reference. Isolated yield in parenthesis. c 0.109 mmol scale of 1a. d RT.
e −78 to 0 °C. f 1 M THF.
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methylene transfer technology using fluoromethylide precur-
sors 2a and 2b in combination with [3 + 2] dipolar cyclo-
addition can be used to reach high complexity monofluori-
nated products in just two steps.
In conclusion, we have demonstrated for the first time that
fluoromethylene transfer from sulfonium reagents is a viable
strategy that can be used for the construction of monofluori-
nated five-membered rings. Consequently, the synthetic meth-
odology was developed to access monofluorinated isoxazoline-
N-oxides as new monofluorinated scaffolds, which can be used
for further modifications.
Scheme 2 Upscale of 3a synthesis. Isolated yield dr determined from
1H NMR spectra.
dimethyl-substituted fluoromethyl sulfonium salt 2b19 was
used instead of tetramethyl reagent 2a, giving access to the
desired isoxazoline-N-oxides 3a on the 0.2 g and 0.8 g scales
with comparable yields to those reported in Scheme 1.
Conflicts of interest
The corresponding N-oxide 3a was reduced by using
trimethyl phosphite16h,k to give isoxazole 4a, albeit as a
mixture of completely saturated isoxazoline 5. Notably, per-
forming the reaction with pure cis-3a we observed the for-
mation of 6% trans-4a in addition to the major cis-4a product.
This could be rationalized by the partial reversibility of HF
elimination/addition for products 4 and 5. Both reaction pro-
ducts 4 and 5 were separated by silica gel column chromato-
graphy (Scheme 3).
Furthermore, we investigated the possibility of performing
the [3 + 2] dipolar cycloaddition of alkenes with N-oxide 3a16n
as a 1,3-dipole. The reaction proceeds well with terminal
alkenes activated with electron-withdrawing groups, as exem-
plified on dipolarophiles such as phenyl acrylate (6) and
phenyl vinylsulfone (8). The cycloaddition reaction proceeded
smoothly in DMSO used as a reaction solvent at ambient temp-
erature; however, full conversion was achieved in 3 to 4 days.
The reaction proceeded with excellent regioselectivity and
notable diastereoselectivity – out of 8 possible diastereomers,
only two were detected. This demonstrates that our fluoro-
There are no conflicts to declare.
Acknowledgements
Financial support was provided by the Latvian Council of
Science project LZP-2019/1-0258. We acknowledge Prof.
Dr Aigars Jirgensons for scientific advice and LIOS analytical
service for NMR (Juris Popelis, Marina Petrova), MS (Solveiga
Grinberga, Dace Hartmane, Valerija Krizanovska, Baiba
Gukalova), X-ray crystallography (Sergey Belyakov) and elemen-
tal analysis (Emma Sarule).
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