Hydroximoyl fluorides as the precursors of nitrile oxides: Synthesis, stability and [3 + 2]-cycloaddition with alkynes

Article abstract of DOI:10.1039/c8ob02721h

The transformation of hydroximoyl fluorides to nitrile oxides for [3 + 2]-cycloaddition with alkynes has been achieved for the first time. The hydroximoyl fluorides used in this work appeared to be not stable, which was proved by a series of experiments. A DFT calculation was performed to better understand the properties of hydroximoyl fluorides. Although not stable, the hydroximoyl fluorides could be successfully converted to the corresponding nitrile oxides for in situ [3 + 2]-cycloaddition with alkynes to yield the isoxazoles. Furthermore, it was feasible to conduct [3 + 2]-cycloaddition reaction without purification after the synthesis of hydroximoyl fluorides from gem-difluoroalkenes. By investigating a class of interesting yet previously rarely explored fluorinated compounds, this work sheds new light on the stability and reactivity of a C-F bond on a CN double bond.

Full text of DOI:10.1039/c8ob02721h

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PAPER
Hydroximoyl fluorides as the precursors of nitrile
oxides: synthesis, stability and [3 + 2]-cycloaddition
with alkynes†
Cite this: Org. Biomol. Chem., 2018,
16, 9211
a,b
Feng-Teng Gao,‡a Zheng Fang,‡a Rui-Rui Su,a Pei-Xin Ruia and Xiang-Guo Hu
*
The transformation of hydroximoyl fluorides to nitrile oxides for [3 + 2]-cycloaddition with alkynes has
been achieved for the first time. The hydroximoyl fluorides used in this work appeared to be not stable,
which was proved by a series of experiments. A DFT calculation was performed to better understand the
properties of hydroximoyl fluorides. Although not stable, the hydroximoyl fluorides could be successfully
converted to the corresponding nitrile oxides for in situ [3 + 2]-cycloaddition with alkynes to yield the iso-
xazoles. Furthermore, it was feasible to conduct [3 + 2]-cycloaddition reaction without purification after
the synthesis of hydroximoyl fluorides from gem-difluoroalkenes. By investigating a class of interesting yet
previously rarely explored fluorinated compounds, this work sheds new light on the stability and reactivity
of a C–F bond on a CvN double bond.
Received 2nd November 2018,
Accepted 14th November 2018
DOI: 10.1039/c8ob02721h
rsc.li/obc
The C–F bond attached to an aromatic ring or a CvC bond is counterparts (e.g., acyl chloride vs. acyl fluoride), it would be
ubiquitous and its physical and chemical properties are well expected that the hydroximoyl fluorides are stable and easy-to
understood (Scheme 1). This kind of C–F bond is generally handle. However, although their O-alkylated products are
regarded as stable under most circumstances.1 As a result, known in a handful of reports,7 the research on the synthesis
monofluoroalkenes have been utilized as the peptide bond and properties of hydroximoyl fluorides is scarce.8
bioisosteres in medicinal chemistry.2 The C–F bond on a CvO Furthermore, their transformation to nitrile oxides for [3 + 2]-
bond has also been extensively studied (Scheme 1). Generally, cycloaddition has not been achieved.
amino acid fluorides are more stable and less prone to racemi-
Herein, we report our research on the synthesis, stability
zation than their corresponding acyl chlorides, rendering and reactivity study of hydroximoyl fluorides which are gener-
them as valuable coupling reagents in peptide chemistry.3 ated from gem-difluoroalkenes.9 More importantly, we disclose
However, there has been much less research on the stability in this work for the first time the successful transformation of
and chemistry of the C–F bond on a CvN bond (Scheme 1).4
Among various compounds that contain a C–F bond on a
CvN double bond, hydroximoyl fluorides are of particular
interest as potential precursors of nitrile oxides because they
are a class of important intermediates that have been fre-
quently used in [3 + 2]-cycloaddition,5a which is one prototype
reaction of click chemistry.5b One straightforward way for the
generation of nitrile oxides is the elimination of hydroximoyl
halides, including hydroximoyl chlorides, bromides and even
iodides (Scheme 1).6 Based on the knowledge of their CvO
aNational Engineering Research Center for Carbohydrate Synthesis,
Jiangxi Normal University, Nanchang 330022, P. R. China.
E-mail: huxiangg@iccas.ac.cn
bKey Laboratory of Small Functional Organic Molecule, Ministry of Education,
Jiangxi Normal University, Nanchang, Jiangxi 330022, P. R. China
†Electronic supplementary information (ESI) available. CCDC 1838903. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02721h
‡These authors contributed equally.
Scheme 1 Compounds bearing F–CvX bonds and this work.
Org. Biomol. Chem., 2018, 16, 9211–9217 | 9211
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hydroximoyl fluorides to the corresponding nitrile oxides for
[3 + 2]-cycloaddition with alkynes.
In 2017, we explored the chemistry of C–F on a hydrazone
group (CvNNH2) and developed a green method for the syn-
thesis of tetrazines.10 Based on this work, we envisioned that
hydroximoyl fluorides could be prepared by the reaction of
gem-difluoroolefins11 with hydroxylamine, through a sequence
of addition and elimination.12 Thus, we chose 1 as the model
substrate to react with hydroxylamine under similar conditions
reported for fluorohydrazones10 (for other conditions, see
Table S5†). As expected, two products, possibly the E,Z-isomers
of hydroximoyl fluoride 2a, were observed on thin layer chrom-
atography (TLC) after a reaction time of 3 hours. However, the
isolation of hydroximoyl fluoride 2a proved to be very difficult
at first and normal work-up yielded no desired products. After
much investigation, we found that quick extraction, removal of
the solvent at a temperature lower than 25 °C and purification
with flash column chromatography (FCC) could yield the
Scheme 3 The stability study of hydroximoyl fluoride 2a.
at room temperature for 24 hours (Scheme 3a). Second,
stirring of 2a with either neutral alumina or silica gel
(common stationary phase for column chromatography) in dry
ethyl acetate resulted in partial decomposition of 2a to the
corresponding nitrile 3a (Scheme 3b). This α-elimination is
significantly different from that of the corresponding hydroxi-
moyl chlorides, for which similar reactions usually require
forcing conditions or metal-catalysts.13 Furthermore, hydroxi-
moyl fluoride 2a is very sensitive to acids, even making deute-
rated chloroform as an unsuitable NMR solvent. Indeed, 2a
quickly decomposed to ester 4a in methanol in the presence of
a catalytic amount of hydrochloric acid (Scheme 3c).14
Mechanistically, the formation of both imine-type and
enamine-type products, 2 and 5, is possible (Fig. 1). However,
during the synthesis and stability study of hydroximoyl fluo-
ride 2 (Schemes 2 and 3), we didn’t observe the formation of 5.
To explain this experimental observation, we have conducted a
preliminary DFT calculation of 2a at the B3LYP/6-31+G(d, p)
level of theory, using the SMD solvation model15 accounting
for the solvation effects of DMF (ESI†). As shown in Fig. 1, the
imine-type product 2a is thermodynamically much more
favored than the enamine-type product 5a, with Z-2a being
40 kJ mol−1 lower than Z-5a in energy (Fig. 1). Based on this
calculation, it is reasonable to expect that the enamine-type
product 5 may be kinetically formed during the reaction, but it
either quickly transformed to 2 or decomposed to other side
products.
desired product 2a [1H-NMR: 3.94 (d, J = 17.9 Hz, PhC
̲H2̲
); 19F
NMR −89.4 (td, J = 18.0, 9.2 Hz, F–CvNOH)] in 26% yield,
̲
along with an unexpected side product, nitrile 3a, in 40%
yield.
Because the pure sample of 2a appeared to be a white solid
and the reaction medium was N,N-dimethyl formamide
(DMF), we then tried to purify 2a via precipitation. To our
delight, slow addition of the reaction mixture to cold water led
to the isolation of 2a with a greatly increased yield (90%).
Encouraged by this result, we next attempted to apply the
same procedure for the access of other hydroximoyl fluorides
(Scheme 2). Indeed, 2b could be obtained in the same manner
in 77% yield. 2c was relatively stable and was isolated by FCC
as an E,Z-mixture in 79% yield. However, 2d–2f could not be
isolated either via precipitation or FCC purification, reflecting
again the intrinsic instability of hydroximoyl fluorides. It
should be pointed out that TLC did show that 2d–2f (products
have similar retention factors to those of 2a–c) were formed
during the reaction. The formation of 2d–2f was also proved by
using them for [3 + 2]-cycloaddition later in this work with
alkynes without purification.
The instability of the hydroximoyl fluorides is worthy of
further comments (2a was taken for example). First, the colour
of 2a turned from white to black upon standing on the bench
Scheme 2 Synthesis of hydroximoyl fluoride 2 from difluoroalkenes 1.
9212 | Org. Biomol. Chem., 2018, 16, 9211–9217
Fig. 1 The mechanism and relative Gibbs free energy of 2a and 5a.
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Having established a synthetic method and having a good
understanding of the properties of hydroximoyl fluorides 2, we
next proceeded to test the possibility of converting them into
nitrile oxides, for [3 + 2]-cycloaddition with alkynes. As is
reported that hydroximoyl chlorides and bromides could gene-
rate the corresponding nitrile oxides under basic conditions,
we firstly screened a series of bases using 2a as the model com-
pound, and found that triethylamine afforded the best yield
(entries 1–5, Table 1).5a We next examined different metal salts
as additives and identified that silver carbonate (0.2 equiv.)
was a very effective promoter (entries 6–13, Table 1).16 We also
explored a number of different silver salts such as AgNO3,
AcOAg, AgSbF6, and AgOTf, and found that AgSbF6 was equally
efficient as that of Ag2CO3 (entries 14–17). However, AgSbF6
was not used for further study due to its hygroscopic nature
and high cost. Finally, back screening of the base showed that
sodium ethoxide as a base gave the desired product in 90%
yield (entry 18). Comparison experiments proved the impor-
tance of using dichloromethane as the solvent and sodium
ethoxide as the base, respectively (entries 19–23).
Scheme 4 Reaction of hydroximoyl fluoride 2a with different alkynes.
the phenyl-ring, and 6c and 6d were obtained in similar yields.
Alkynes with a heterocycle are also viable substrates, and 6e
was formed in 80% yield. Alkyl substituted alkynes also under-
went the reaction successfully to afford the desired products in
moderate yields (6h–f). The structure of 6d was proved unam-
biguously by X-ray crystallographic analysis (Fig. 2).17
We next explored the substrate scope with respect to the
hydroximoyl fluoride. As mentioned previously, hydroximoyl
fluorides 2d–2f could not be isolated, we thus determined to
use 2 directly after a quick workup. As shown in Scheme 5,
different hydroximoyl fluorides 2, generated from the corres-
ponding gem-difluoroalkenes 1, could be trapped by phenyl
acetylene to give the desired products 7a–f. The yields for
7d–7f were relatively moderate, which may be due to the
instability of the hydroximoyl fluorides 2d–f. However,
considering that it involved a three-step reaction, the average
With the optimal conditions in hand (entry 18, Table 1), we
next proceeded to explore the substrate scope with respect to
alkynes (Scheme 4). For phenyl acetylenes, the reaction toler-
ated a range of functional groups, including halo (6b), trifluor-
omethyl (6c), ether (6d), and alkyl (6e–f) groups. The reaction
is not sensitive to the electron-properties of substituents on
Table 1 Reaction optimization
Entry
Base
Additive (equiv.)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
EtONa
tBuOK
DBU
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
—
—
—
—
DMF
DMF
DMF
DMF
10
—
—
20
21
26
23
20
—
20
35
58
55
36
42
58
23
90
68
76
87
23
0
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
CuSO4·5H2O
FeCl3 (0.1)
CuBr2 (0.1)
RhCl3 (0.1)
CuCl2 (0.1)
Ag2CO3 (0.1)
Ag2CO3 (0.2)
Ag2CO3 (0.4)
AgNO3 (0.2)
AgOAc (0.2)
AgSbF6 (0.2)
AgOTf (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Fig. 2 X-Ray structure of 6d.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
EtONa
EtONa
EtONa
EtONa
EtONa
—
Cl(CH2)2Cl
CHCl3
THF
CH2Cl2
Reaction conditions: 2a (0.1 mmol), alkyne (0.35 mmol), base
(0.5 mmol), solvent (2 mL) at 40 °C under a nitrogen atmosphere for
12 h. a Isolated yields.
Scheme 5 Reaction of hydroximoyl fluorides 2a–f with phenylacetylene.
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yield per step is still impressive (e.g., >74% per step even for Melting points were determined using a WRX-4 visual melting
7d). In order to further increase the synthetic efficiency, we point apparatus. NMR spectra were recorded in CDCl3 (with
also tried to conduct the reaction of 1a in a one-pot fashion TMS as an internal standard) or D2O or MeOD on a Bruker
(without the work up of 2a and the switching of the solvent AV400 (1H at 400 MHz, 13C at 100 MHz, 19F at 376 MHz) mag-
from DMF to dichloromethane), but this yielded a complex of netic resonance spectrometer. Chemical shifts (δ) are reported
mixtures.
in ppm, and coupling constants (J) are in Hz. The following
abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet. The
HRMS were measured using an ESI model (specified in the
section of characterization data).
Conclusions
In the present paper, we report the research on the synthesis,
stability and reactivity study of hydroximoyl fluorides. We have
Stability study
achieved for the first time the transformation of hydroximoyl To a solution of (E,Z)-2-([1,1′-biphenyl]-4-yl)-N-hydroxyacetimi-
fluorides to nitrile oxides for [3 + 2]-cycloaddition with doyl fluoride 2a (45.8 mg, 0.2 mmol) in dry ethyl acetate
alkynes. The hydroximoyl fluorides appeared to: (i) be not (10 mL), was added neutral alumina or silica gel (200 mg), and
stable on the bench at room temperature; (ii) decompose par- the reaction mixture was stirred under a nitrogen atmosphere
tially in deuterated chloroform and on both silica gel and at room temperature for 3 hours. Then, the reaction mixture
neutral alumina absorbent; (iii) turn quickly to the corres- was concentrated under reduced pressure. The resultant
ponding ester in acidic methanol. The unstable nature posed residue was purified by silica gel chromatography (petroleum
significant challenge during the isolation and gave an expla- ether/EtOAc = 20/1) to afford 3a. 2-([1,1′-Biphenyl]-4-yl)aceto-
nation why there is a lack of research. A DFT calculation was nitrile (3a); 1H NMR (400 MHz, CDCl3) δ 7.54–7.49 (m, 4H),
performed to better understand the properties of hydroximoyl 7.38 (t, J = 7.6 Hz, 2H), 7.35–7.27 (m, 3H), 3.73 (s, 2H);
fluorides, which suggests they are much more stable than their 13C NMR (100 MHz, CDCl3) δ 140.1, 139.2, 127.8, 127.7, 127.3,
enamine-type isomers 5. Although not stable, in the presence 126.8, 126.6, 126.0, 116.8, 22.3. {lit. 1H-NMR (400 MHz, CDCl3)
of a base and a silver additive, the hydroximoyl fluorides could δ 7.57–7.54 (m, 4H), 7.42 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 7.6 Hz,
be successfully converted to the corresponding nitrile oxides 3H), 3.71 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 140.9, 140.0,
for the in situ [3 + 2]-cycloaddition with alkynes to yield the iso- 128.8, 128.7, 128.2, 127.6, 127.5, 126.9, 117.8, 23.1}.18
xazoles. Furthermore, it was feasible to conduct [3 + 2]-cyclo-
To a solution of (E,Z)-2-([1,1′-biphenyl]-4-yl)-N-hydroxyaceti-
addition reaction without purification after the synthesis of midoyl fluoride (2a, 23 mg, 0.1 mmol) in methanol (MeOH,
hydroximoyl fluorides from gem-difluoroalkenes, thus provid- 3 mL) was added 2 M HCl (0.01 mmol, 5 μL). After 2 hours,
ing a possible solution to utilizing the unstable yet useful TLC indicated that all the starting material disappeared, and
intermediates. Overall, from a synthetic perspective, we admit then the solution was removed under reduced pressure and
that hydroximoyl fluorides are not as good as other hydroxi- the crude product was purified by flash column chromato-
moyl halides in terms of the preparation of nitrile oxides due graphy [silica gel (#100–200), petroleum/EtOAc = 10 : 1] to give
to the unstable nature and limited substrate scope. However, (4a). Methyl 2-([1,1′-biphenyl]-4-yl)acetate (4a); yellow oil.
through investigating a class of interesting but previously 1H NMR (400 MHz, CDCl3) δ 7.62–7.51 (m, 4H), 7.43 (t, J =
rarely explored fluorinated compounds, this work sheds new 7.5 Hz, 2H), 7.35 (dd, J = 8.5, 2.5 Hz, 3H), 3.71 (s, 3H), 3.67 (s,
light on the stability and reactivity of a C–F bond on a CvN 2H); 13C NMR (101 MHz, CDCl3) δ 172.0, 140.8, 140.1, 133.0,
double bond, which should promote more research in this 129.7, 128.76, 128.8, 127.4, 127.3, 127.1, 52.1, 40.8.
area.
{lit. 1H-NMR (400 MHz, CDCl3): 1H NMR (270 MHz, CDCl3)
δ 7.52–7.27 (m, 9H), 3.64 (s, 3H), 3.60 (s, 2H)}.19
General procedure for the synthesis of hydroximoyl fluorides
from the corresponding difluoroalkenes
Experimental
General information
To a solution of gem-difluoroolefins (1 mmol) in N,N-dimethyl-
All reagents were used as received from commercial sources formamide (DMF, 10 mL) were added hydroxylamine hydro-
without further purification. All solvents were dried over 4 Å chloride (350 mg, 5 mmol), triethylamine (505 mg, 0.5 mmol)
molecular sieves before use unless otherwise stated. Reaction and powdery 4 Å molecular sieves. After stirring at room tem-
mixtures were stirred using Teflon-coated magnetic stirring perature for 6 hours, the desired products were isolated via
bars. Analytical TLC was performed with 0.20 mm silica gel either precipitation or flash column chromatography (FCC)
60F plates with a 254 nm fluorescent indicator. TLC plates purification. For precipitation: the reaction mixture was added
were visualized by ultraviolet light or by treatment with a spray dropwise to cold water and the solid product was collected by
of the Pancaldi reagent {(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O} filtration, and dried under high vacuum at room temperature
or
a
solution of 0.5% ninhydrin in n-butanol. for 1 hour. For FCC: the organic phase was diluted with ethyl
Chromatographic purification of products was carried out by acetate and petroleum ether (v : v = 1 : 5, 30 mL), and then
flash column chromatography on silica gel (230–400 mesh). washed with distilled water (10 mL × 5) to remove DMF. The
9214 | Org. Biomol. Chem., 2018, 16, 9211–9217
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organic layer was combined and dried with anhydrous sodium 133.1, 132.3, 128.9, 128.2, 128.1, 127.4, 126.9, 126.6, 35.4 (d,
sulfate. The solvent was removed under vacuum at low tem- J = 29.3 Hz); HRMS (ESI): calcd for C12H10FNO [M + H]+,
perature (< room temperature) and purified by FCC quickly. 204.0819, found 204.0814.
Please note that the E,Z-isomers could not be assigned.
General procedure for the reaction of hydroximoyl fluoride 2a
with different alkynes
2-([1,1′-Biphenyl]-4-yl)-N-hydroxyacetimidoyl fluoride (2a).
90% yield of E,Z-isomers obtained by precipitation; analytically
pure samples were obtained by iterative FCC for characteriz- To a solution of (E,Z)-2-([1,1′-biphenyl]-4-yl)-N-hydroxyacetimi-
ation purpose; ratio of isomer 1 : isomer 2 = 2.59 : 1; isomer 1: doyl fluoride (2a, 23 mg, 0.1 mmol) in dichloromethane
white solid; mp: 102–103 °C; 1H NMR (400 MHz, d3-MeCN) (DCM,
2 mL) were added phenylacetylene (0.35 mmol,
δ 8.14 (d, J = 7.0 Hz, 1H), 7.67–7.35 (m, 9H), 3.94 (d, J = 38.5 μL), sodium ethoxide (34 mg, 0.5 mmol) and silver car-
17.9 Hz, 2H); 19F NMR (376 MHz, d3-MeCN) δ −89.38 (td, J = bonate (5.6 mg, 0.02 mmol) successively. The reaction flask
18.0, 9.2 Hz); 19F {1H}NMR (376 MHz, d3-MeCN) δ −89.39 (s); was wrapped with a piece of tin foil to protect the reaction mix
13C NMR (100 MHz, d3-MeCN) δ 164.0 (d, J = 242.1 Hz), 141.0, from light. After stirring at 40 °C for 12 hours, the organic
140.5, 130.0, 129.5, 128.1, 127.9, 127.8 (d, J = 2.3 Hz), 127.5, phase was filtered to remove the solid residue and the solid was
31.3 (d, J = 30.8 Hz); HRMS (ESI): calcd for C14H12FNO rinsed with dichloromethane (2 mL × 3). The combined organic
[M + H]+, 230.0975, found 230.0977. Isomer 2: white solid; mp: layer was washed with distilled water (2 mL × 3) and dried with
107–109 °C; 1H NMR (400 MHz, d3-MeCN) δ 8.33 (d, J = 3.8 Hz, anhydrous sodium sulfate. The crude product was purified by
1H), 7.68–7.64 (m, 4H), 7.50–7.47 (m, 2H), 7.41–7.38 (m, 3H), flash column chromatography [silica gel (#100–200), PE : EA =
3.69 (d, J = 14.2 Hz, 2H); 19F NMR (376 MHz, d3-MeCN) δ 50 : 1] to afford the pure isoxazoles (6a–6i).
−68.63 (td, J = 14.2, 3.7 Hz); 19F {1H}NMR (376 MHz, d3-MeCN)
3-([1,1′-Biphenyl]-4-ylmethyl)-5-phenylisoxazole (6a). 90%
1
δ −68.63 (s); 13C NMR (100 MHz, d3-MeCN) δ 152.8 (d, J = yield; white solid; mp: 129–131 °C; H NMR (400 MHz, CDCl3)
330.2 Hz), 145.7, 145.3, 138.6, 134.7, 134.2, 132.8, 132.6, δ 7.75–7.34 (m, 14H), 6.32 (s, 1H), 4.10 (s, 2H); 13C NMR
132.2, 39.6 (d, J = 29.3 Hz); HRMS (ESI): calcd for C14H12FNO (100 MHz, CDCl3) δ 170.0, 163.6, 140.7, 139.9, 136.3, 130.1,
[M + H]+, 230.0975, found 230.0977.
129.3, 129.2, 128.9, 128.8, 127.5, 127.3, 127.0, 125.8, 99.5, 32.2;
N-Hydroxy-2-(naphthalen-1-yl)acetimidoyl fluoride (2b). 77% HRMS (ESI): calcd for C22H17NO [M + H]+, 312.1382, found
yield of E,Z-isomers obtained by precipitation; analytically 312.1382.
pure samples were obtained by iterative FCC for characteriz-
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(4-chlorophenyl)isoxazole (6b).
ation purpose; ratio of isomer 1 : isomer 2 = 1 : 5.27; isomer 1: 88% yield; white solid; mp: 135–138 °C; 1H NMR (400 MHz,
white solid; mp: 96–97 °C; 1H NMR (400 MHz, d3-MeCN) CDCl3) δ 7.68–7.55 (m, 6H), 7.45–7.34 (m, 7H), 6.31 (s, 1H),
δ 8.28 (d, J = 6.9 Hz, 1H), 7.97–7.95 (m, 1H), 7.80 (dd, J = 7.8, 4.09 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 168.9, 163.7, 140.7,
1.7 Hz, 1H), 7.75–7.72 (m, 1H), 7.48–7.40 (m, 2H), 7.35–7.34 140.0, 136.2, 136.1, 129.3, 129.2, 128.8, 127.5, 127.3, 127.1,
(m, 2H), 4.23 (d, J = 16.0 Hz, 2H); 19F NMR (376 MHz, 127.0, 126.0, 99.8, 32.2. HRMS (ESI): calcd for C22H16ClNO
d3-MeCN) δ −89.46 (td, J = 16.2, 8.0 Hz); 19F {1H}NMR [M + H]+, 346.0993, found 346.0994.
(376 MHz, d3-MeCN) δ −89.49 (s); 13C NMR (100 MHz,
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(4(trifluoromethyl)phenyl)iso-
1
d3-MeCN) δ 163.6 (d, J = 242.2 Hz), 134.4, 132.3, 130.2 (d, J = xazole (6c). 70% yield; white solid; mp: 134–135 °C; H NMR
2.0 Hz), 129.3, 128.7, 128.5, 127.2, 126.7, 126.2, 123.9, 29.2 (d, (400 MHz, CDCl3) δ 7.86–7.84 (m, 2H), 7.69 (d, J = 8.2 Hz, 2H),
J = 31.3 Hz); HRMS (ESI): calcd for C12H10FNO [M + H]+, 7.59–7.56 (m, 4H), 7.46–7.34 (m, 5H), 6.42 (s, 1H), 4.12 (s, 2H);
204.0819, found 204.0815. Isomer 2. White solid; mp: 19F NMR (376 MHz, CDCl3) δ −62.95 (s); 19F {1H}NMR
102–103 °C; 1H NMR (400 MHz, d3-MeCN) δ 8.10 (d, J = 3.8 Hz, (376 MHz, CDCl3) δ −63.10 (s); 13C NMR (100 MHz, CDCl3)
1H), 8.00–7.94 (m, 1H), 7.81 (dd, J = 7.8, 1.6 Hz, 1H), 7.74 (dd, δ 168.4, 163.8, 140.6, 140.1, 136.0, 131.8 (q, J = 32.7 Hz), 130.6,
J = 7.1, 2.4 Hz, 1H), 7.48–7.40 (m, 2H), 7.37–7.32 (m, 2H), 3.98 129.3, 128.8, 127.6, 127.4, 127.0, 126.1, 126.0 (q, J = 3.6 Hz),
(d, J = 12.1 Hz, 2H); 19F NMR (376 MHz, d3-MeCN) δ −67.37 123.8 (q, J = 271.8 Hz), 101.0, 32.2; HRMS (ESI): calcd for
(td, J = 12.2, 3.9 Hz); 19F {1H}NMR (376 MHz, d3-MeCN) C23H16F3NO [M + H]+, 380.1257, found 380.1255.
δ −67.37 (s); 13C NMR (100 MHz, d3-MeCN) δ 153.4 (d, J =
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(2-methoxyphenyl)isoxazole
331.3 Hz), 134.5, 132.4, 130.5, 129.3, 128.8, 128.3, 127.0, 126.4, (6d). 74% yield; white solid; mp: 155–158 °C; 1H NMR
126.2, 124.1, 32.9 (d, J = 29.3 Hz); HRMS (ESI): calcd for (400 MHz, CDCl3) δ 7.97 (dd, J = 7.8, 1.8 Hz, 1H), 7.59–7.54 (m,
C12H10FNO [M + H]+, 204.0819, found 204.0815.
4H), 7.45–7.31 (m, 6H), 7.08–7.04 (m, 1H), 6.97 (dd, J = 8.4,
N-Hydroxy-2-(naphthalen-2-yl)acetimidoyl fluoride (2c). 79% 1.0 Hz, 1H), 6.61 (s, 1H), 4.11 (s, 2H), 3.90 (s, 3H); 13C NMR
yield by FCC; due to the instability of hydroxyiminonyl fluoride (100 MHz, CDCl3) δ 166.0, 163.3, 156.2, 140.8, 139.7, 136.6,
2c, only one isomer could be isolated and fully characterized. 131.1, 129.2, 128.8, 127.8, 127.4, 127.2, 127.0, 120.9,
White solid; mp: 115–117 °C; 1H NMR (400 MHz, d3-MeCN) 116.6, 111.1, 103.5, 55.5, 32.3; HRMS (ESI): calcd for
δ 8.30 (d, J = 3.9 Hz, 1H), 7.94–7.85 (m, 3H), 7.80 (s, 1H), C23H19NO2 [M + H]+, 342.1488, found 342.1488.
7.58–7.50 (m, 2H), 7.44 (dd, J = 8.5, 1.7 Hz, 1H), 3.81 (d, J =
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(p-tolyl)isoxazole (6e). 93%
1
14.1 Hz, 2H); 19F NMR (376 MHz, d3-MeCN) δ −68.42 (td, J = yield; white solid; mp: 149–150 °C; H NMR (400 MHz, CDCl3)
14.1, 3.9 Hz); 19F {1H}NMR (376 MHz, d3-MeCN) δ −68.42 (s); δ 7.55 (d, J = 8.0 Hz, 2H), 7.49 (dd, J = 8.0, 6.5 Hz, 4H), 7.35
13C NMR (100 MHz, d3-MeCN) δ 153.5 (d, J = 329.1 Hz), 134.0, (dd, J = 8.2, 6.9 Hz, 2H), 7.31–7.23 (m, 3H), 7.18–7.12 (m, 2H),
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6.19 (s, 1H), 4.01 (s, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, organic phase was filtered to remove the solid residue and the
CDCl3) δ 169.2, 162.4, 139.7, 139.3, 138.8, 135.4, 128.5, 128.2, solid was rinsed with dichloromethane (2 mL × 3). The com-
127.7, 126.4, 126.2, 126.0, 124.7, 123.8, 97.8, 31.1, 20.4; HRMS bined organic layer was washed with distilled water (2 mL × 3)
(ESI): calcd for C23H19NO [M + H]+, 326.1539, found 326.1535.
and dried with anhydrous sodium sulfate. The crude product
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(4-pentylphenyl)isoxazole (6f). was purified by flash column chromatography [silica gel
88% yield; white solid; mp: 112–114 °C; 1H NMR (400 MHz, (#100–200), PE : EA = 50 : 1] to afford the pure isoxazoles (7a–7f).
CDCl3) δ 7.58–7.10 (m, 13H), 6.17 (s, 1H), 3.99 (s, 2H),
3-(Naphthalen-1-ylmethyl)-5-phenylisoxazole (7b). 59% yield;
2.60–2.41 (m, 2H), 1.53 (m, 2H), 1.22 (m, 4H), 0.80 (t, J = brown oil; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.3 Hz, 1H),
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 162.4, 144.3, 7.89–7.80 (m, 2H), 7.68–7.66 (m, 2H), 7.53–7.45 (m, 4H),
139.7, 138.8, 135.4, 128.2, 127.9, 127.7, 126.4, 126.2, 125.9, 7.39–7.37 (m, 3H), 6.17 (s, 1H), 4.50 (s, 2H); 13C NMR
124.7, 123.9, 97.8, 34.8, 31.2, 30.4, 29.8, 21.5, 12.9; HRMS (100 MHz, CDCl3) δ 169.9, 163.7, 134.0, 133.2, 131.9, 130.0,
(ESI): calcd for C27H27NO [M + H]+, 382.2165, found 382.2162.
128.8, 128.8, 128.0, 127.5, 127.2, 126.4, 125.9, 125.7, 125.5,
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(thiophen-2-yl)isoxazole (6g). 123.8, 99.5, 30.2; HRMS (ESI): calcd for C20H15NO [M + H]+,
80% yield; gray solid; mp: 126–127 °C; 1H NMR (400 MHz, 286.1226, found 286.1224.
CDCl3) δ 7.62–7.53 (m, 4H), 7.50–7.33 (m, 7H), 7.08 (dd, J =
3-(Naphthalen-2-ylmethyl)-5-phenylisoxazole (7c). 71% yield;
5.0, 3.7 Hz, 1H), 6.18 (s, 1H), 4.07 (s, 2H); 13C NMR (100 MHz, white solid; mp: 96–97 °C; 1H NMR (400 MHz, CDCl3)
CDCl3) δ 165.0, 163.5, 140.7, 140.0, 136.2, 129.4, 129.3, 128.8, δ 7.87–7.63 (m, 6H), 7.52–7.35 (m, 6H), 6.28 (s, 1H), 4.22
128.0, 127.9, 127.5, 127.3, 127.1, 126.9, 99.3, 32.1; HRMS (ESI): (s, 2H); 13C NMR (100 MHz, CDCl3) δ 170.0, 163.6, 134.8,
calcd for C20H15NOS [M + H]+, 318.0947, found 318.0948.
133.6, 132.4, 130.1, 128.9, 128.5, 128.5, 99.5, 32.7; HRMS (ESI):
3-([1,1′-Biphenyl]-4-ylmethyl)-5-butylisoxazole (6h). 66% calcd for C20H15NO [M + H]+, 286.1226, found 286.1225.
yield; white solid; mp: 69–70 °C; 1H NMR (400 MHz, CDCl3)
3-(4-Bromobenzyl)-5-phenylisoxazole (7d). 43% yield; white
1
δ 7.59–7.53 (m, 4H), 7.45–7.41 (m, 2H), 7.35–7.31 (m, 3H), 5.77 solid; mp: 96–98 °C; H NMR (400 MHz, CDCl3) δ 7.72 (dd, J =
(s, 1H), 4.01 (s, 2H), 2.68 (t, J = 7.7 Hz, 2H), 1.66–1.62 (m, 2H), 7.8, 1.9 Hz, 2H), 7.52–7.33 (m, 5H), 7.17 (d, J = 8.4 Hz, 2H),
1.40–1.34 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, 6.26 (s, 1H), 4.01 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 170.2,
CDCl3) δ 173.9, 162.8, 140.8, 139.8, 136.6, 129.2, 128.8, 127.4, 163.0, 136.3, 131.9, 130.6, 130.2, 128.9, 127.4, 125.8, 120.9,
127.4, 127.2, 127.2, 127.0, 100.6, 32.2, 29.5, 26.5, 22.2, 22.2, 99.3, 32.0; HRMS (ESI): calcd for C16H12BrNO [M + H]+,
13.7; HRMS (ESI): calcd for C20H21NO [M + H]+, 292.1696, 314.0175, found 314.0173.
found 292.1692.
3-(2,6-Dimethoxybenzyl)-5-phenylisoxazole (7e). 50% yield;
3-([1,1′-Biphenyl]-4-ylmethyl)-5-(3-chloropropyl)isoxazole (6i). brown oil; 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 7.8,
68% yield; white solid; mp: 77–78 °C; 1H NMR (400 MHz, 1.8 Hz, 2H), 7.41–7.36 (m, 3H), 6.86–6.71 (m, 3H), 6.30 (s, 1H),
CDCl3) δ 7.56 (m, 4H), 7.46–7.40 (m, 2H), 7.38–7.28 (m, 3H), 4.03 (s, 2H), 3.81 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz,
5.84 (s, 1H), 4.01 (s, 2H), 3.56 (t, J = 6.3 Hz, 2H), 2.89 (t, J = CDCl3) δ 169.6, 163.6, 153.7, 151.6, 129.9, 128.9, 127.8, 127.0,
7.4 Hz, 2H), 2.21–2.05 (m, 2H); 13C NMR (100 MHz, CDCl3) 125.8, 116.6, 112.6, 111.7, 99.7, 56.1, 55.7, 26.9; HRMS (ESI):
δ 171.8, 163.0, 140.7, 139.9, 136.3, 129.2, 128.8, 127.4, 127.3, calcd for C18H17NO3 [M + H]+, 296.1281, found 296.1279.
127.2, 101.4, 43.7, 32.1 30.1, 24.0; HRMS (ESI): calcd for
C19H18ClNO [M + H]+, 312.1150, found 312.1150.
3-(4-(Benzyloxy)benzyl)-5-phenylisoxazole (7f). 48% yield;
white solid; mp: 101–102 °C; 1H NMR (400 MHz, CDCl3)
δ 7.62–7.59 (m, 2H), 7.35–7.20 (m, 8H), 7.10 (d, J = 8.3 Hz, 2H),
6.84 (d, J = 8.51 Hz, 2H), 6.15 (s, 1H), 4.93 (s, 2H), 3.88 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 169.9, 164.0, 157.8, 137.0, 130.1,
General procedure for the reaction of hydroximoyl fluorides
2a–f with phenylacetylene
To a solution of gem-difluoroolefin (1 mmol) in N,N-dimethyl- 129.9, 129.7, 128.9, 128.6, 128.0, 127.6, 127.5, 125.8, 115.2,
formamide (DMF, 10 mL) were added hydroxylamine hydro- 99.5 (2), 70.1, 31.7; HRMS (ESI): calcd for C23H19NO2 [M + H]+,
chloride (350 mg, 5 mmol), triethylamine (505 mg, 0.5 mmol) 342.1489, found 342.1483.
and powdery 4 Å molecular sieves. After stirring at room tem-
perature for 6 hours, the organic phase was diluted with ethyl
acetate and petroleum ether (v : v = 1 : 5, 30 mL), and then
washed with distilled water (10 mL × 5) to remove DMF. The
Conflicts of interest
organic layer was combined and dried with anhydrous sodium There are no conflicts to declare.
sulfate. The crude product was used directly for the next step
without any purification. To a solution of (E,Z)-2-([1,1′-biphe-
nyl]-4-yl)-N-hydroxyacetimidoyl fluoride (ca. 0.1 mmol, 10% of
the crude product obtained in the last step) in dichloro-
Acknowledgements
methane (DCM,
2
mL) were added phenylacetylene We thank the National Natural Science Foundation of China
(0.35 mmol, 38.5 μL), sodium ethoxide (34 mg, 0.5 mmol) and (21502076), the Natural Science Foundation of Jiangxi province
silver carbonate (5.6 mg, 0.02 mmol) successively. The reaction (20161BAB213068), and the Outstanding Young Talents
flask was wrapped with a piece of tin foil to protect the reac- Scheme of Jiangxi Province (20171BCB23039) for funding this
tion mix from light. After stirring at 40 °C for 12 hours, the research.
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Paper
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