Synthesis of C4-alkynylisoxazoles: Via a Pd-catalyzed Sonogashira cross-coupling reaction

Article abstract of DOI:10.1039/c9ra00577c

A Pd-catalyzed Sonogashira cross-coupling reaction for the synthesis of C4-alkynylisoxazoles from 3,5-disubsitituted-4-iodoisoxazoles and terminal alkynes was described, which could afford the corresponding products with high yield (up to 98%). The result

Full text of DOI:10.1039/c9ra00577c

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Synthesis of C4-alkynylisoxazoles via a Pd-
catalyzed Sonogashira cross-coupling reaction†
Cite this: RSC Adv., 2019, 9, 8894
*
Wen Yang, Yongqi Yao, Xin Yang, Yingying Deng, Qifu Lin and Dingqiao Yang
A Pd-catalyzed Sonogashira cross-coupling reaction for the synthesis of C4-alkynylisoxazoles from 3,5-
disubsitituted-4-iodoisoxazoles and terminal alkynes was described, which could afford the
corresponding products with high yield (up to 98%). The results indicated that the steric effect from the
group at the C3 position of the isoxazole had greater influence on the cross-coupling reaction than that
from the group at the C5 position. In addition, the group at the C3 position of the isoxazole showed
negligible electronic effects on the cross-coupling reaction. Furthermore, a gram-scale reaction of the
Sonogashira coupling reaction was also investigated. Finally, a plausible mechanism for the Sonogashira
coupling reaction was proposed.
Received 23rd January 2019
Accepted 6th March 2019
DOI: 10.1039/c9ra00577c
rsc.li/rsc-advances
Sonogashira cross-coupling reaction of 3-ethoxy-5-methyl-4-
iodoisoxazole with phenylacetylene, giving product of 3-
Introduction
ethoxy-5-methyl-4-phenylethynylisoxazole for only one example
in 58% yield.6c Larock and co-workers chose 3-(3,4,5-
Isoxazole and its derivatives are important structural units of
many molecules of biological interest.1 As a result, numerous
synthetic approaches have been made to access the isoxazole
core, including the [3 + 2] cycloaddition between alkynes/
alkenes and nitrile oxides,2 intramolecular cyclo-
isomerization of a,b-unsaturated oximes,3 condensation
between hydroxylamine and 1,3-dicarbonyl compounds or a,b-
unsaturated carbonyls.4 Many of the reported methods have
two main limitations, (i) limitation to the preparation of
disubstituted isoxazoles, and (ii) low regioselectivity.5 In order
to overcome these limitations, direct functionalization of
isoxazoles or 4-haloisoxazoles has been developed by many
research groups.6
Transition-metal-catalyzed cross-coupling reactions have
become one of the most prominent and reliable methods for the
formation of carbon–carbon bonds.7 Among them, the Pd-
catalyzed Sonogashira cross-coupling reaction between
aromatic halides and terminal alkynes is very useful in the
synthesis of carbo- and heterocycles, natural products, poly-
mers, and molecular nanostructures.8 Using this powerful
reaction, some trisubstituted isoxazoles were synthesized.
Yamanaka and co-workers rst reported that the Pd(PPh3)Cl2
catalyzed Sonogashira cross-coupling reaction of 3-substituted-
5-methyl-4-iodoisoxazoles with terminal alkynes, affording
three examples of 3-substituted-5-methyl-4-alkynylisoxazole
products in good yields (up to 86% yield).6a In 2001, Kromann
and co-workers explored that Pd(PPh3)Cl2 catalyzed
trimethoxyphenyl)isoxazole-5-methyl-4-iodoisoxazole
as
a substrate to react with seven terminal alkynes, giving the
targeted products with the yields between 30% and 83%.6e In
2005,
a
series
of
3-carboxamide-5-(2,4-dihydroxy-5-
isopropylphenyl)-4-alkynylisoxazoles were synthesized through
Pd(PPh3)Cl2 catalyzed Sonogashira cross-coupling reaction of
an alkynyl moiety and an isoxazole scaffold as novel HSP90
inhibitors by Zhang and co-works.6l Recently, Guo and co-
workers reported that Sonogashira cross-coupling reaction of
3-triuoromethyl-5-phenyl-4-iodoisoxazoles
with
phenyl-
acetylene in the presence of Pd(PPh3)2Cl2, affording the targeted
product in 80% yield.9 However, none of the above researches
studied the impact of the groups at C3 position and C5 position
of isoxazole core on the Sonogashira cross-coupling reaction.
Because of the decreased symmetry in isoxazole, when
compared to furan, pyrrole, and benzene, reaction channels
which are equivalent in furan, pyrrole, and benzene will lead to
the different results in isoxazole. For examples, Fall and co-
workers discovered that 3-carboxylate-5-methylisoxazole reac-
ted with 1-(4-bromophenyl)ethan-1-one to afford the targeted
product, but 4-carboxylate-5-methylisoxazole did not afford
desired product.6f Coffman and co-workers investigated the
effects of the groups of 3,5-, 4,5-, and 3,4-bis(2-nitrophenyl)
isoxazoles on the reaction.10 Lately, Morita and co-workers re-
ported intramolecular electrophilic aromatic substitution
reaction only occurred at the 5-position of isoxazole rather than
at the 3-position.11
Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education,
School of Chemistry and Environment, South China Normal University, Guangzhou
510006, People's Republic of China. E-mail: yangdq@scnu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra00577c
Herein, we investigated the effect of the groups at C3 and C5
positions of the isoxazole on the Sonogashira cross-coupling
reaction.
Using
3,5-disubstituted-4-iodoisoxazoles
and
8894 | RSC Adv., 2019, 9, 8894–8904
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terminal alkynes as the substrates, we synthesized a series of
3,5-disubstituted-4-alkylnylisoxazole products.
We chose 3-(tert-butyl)-4-iodo-5-phenylisoxazole (3a) with
phenylacetylene as a model substrate to identify the feasi-
bility of our process. When 3a reacted with phenylacetylene in
anhydrous DMF at 60 ꢀC in the presences of Pd(PPh3)2Cl2
(5 mol%), CuI (10 mol%), and Et2NH (2 equiv.) under nitrogen
atmosphere, the desired product 4a was obtained in 26%
yield aer 20 h and the conversion of starting material 3a was
47% (Table 1, entry 1). To improve the reaction efficiency,
three kinds of phosphine ligands, such as PPh3, PCy3 and
DPPP, were examined for this reaction under similar condi-
tion (Table 1 entries 2–4). Unfortunately, the yield of targeted
product 4a could only be up to 30% (Table 1, entry 2). Then,
different palladium catalysts were screened for the reaction
(Table 1, entries 5–9). Among them, 3a reacted with phenyl-
acetylene to afford the corresponding product 4a in 60% yield
and the conversion of 3a could be increased to 66% in the
presence of Pd(acac)2 (Table 1, entry 9). Encouraged by this
result, a series of phosphine ligands, such as PPh3, TFP, PCy3
and DPPP, were tested for this reaction under similar condi-
tion (Table 1, entries 9–12). The general trends in yields of
product 4a related to different phosphine ligands were as
followed: PPh3 > TFP > PCy3 > DPPP. The impact of the catalyst
loading on the reaction was also investigated, and the yield of
4a was strongly inuenced by the amount of catalyst loading
(Table 1, entries 13 and 14). The yield of 4a was decreased
with the amount of catalyst loading decreased to 3.5 mol%
(Table 1, entry 13). However, a further increase the amount of
catalyst loading did not improve the yield of 4a (Table 1, entry
14).
Results and discussion
During our investigation, intermediate ynones
1 were
prepared by the Sonogashira cross-coupling of an acid chlo-
ride and a terminal alkyne in the presence of Pd(PPh3)2Cl2.
The O-methyl oximes 2 were prepared by the reaction of
ynones 1 with methoxylamine hydrochloride in the presence
of pyridine and anhydrous Na2SO4. The substrates of 3,5-
disubstituted-4-iodoisoxazoles 3 were prepared through the
electrophilic cyclization of O-methyl oxime 2 in the presence of
ICl (Scheme 1).
Scheme 1 Preparation of 3,5-disubstituted-4-iodoisoxazoles 3.
Table 1 Effects of catalyst precursors, ligands and catalyst loadingsa
The effects of bases, solvents and temperatures were then
examined (Table 2). No reaction took place without bases (not
shown in Table 2). Moderate yields were obtained when Et2NH
and Et3N were used as bases (Table 2, entries 1 and 2). As we
added the base n-butylamine or DIPEA (N,N-diisopropylethyl-
amine) to this reaction system, the reaction proceeded to give
the targeted product 4a with low yields (25% and 18%, respec-
tively) (Table 2, entries 3 and 4). The selection of solvents proved
to have a dramatic inuence on the reaction (Table 2, entries 1,
5–8). When the reaction was carried out in anhydrous DMF,
a dipolar aprotic solvent, targeted product 4a could be obtained
in 60% yield (Table 2, entry 1). Other solvents, such as anhy-
drous THF, MeCN, toluene and DCE, resulted in low yields
(30%, 25%, 22% and 20%, respectively) (Table 2, entries 5–8). At
last, the effects of temperatures on the reaction were investi-
gated (Table 2, entries 1 and 9 and 10). The results showed that
Entry Catalyst (mol%) Ligand (mol%) 3a conv.b (%) 4a yieldb (%)
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2 (5)
—
47
49
48
35
43
52
24
50
66
42
56
36
48
64
26
30
28
20
26
31
18
29
60
26
46
22
35
58
Pd(PPh3)2Cl2 (5) PPh3 (10)
Pd(PPh3)2Cl2 (5) PCy3 (10)
Pd(PPh3)2Cl2 (5) DPPP (5)
Pd(PPh3)4 (5)
Pd(OAc)2 (5)
Pd(TFA)2 (5)
ꢀ
the optimum reaction temperature was 60 C in terms of yield
(Table 2, entry 1).
—
PPh3 (10)
PPh3 (10)
With the above optimized reaction condition in hand
(5 mol% Pd(acac)2, 10 mol% PPh3, 10 mol% CuI, and 2 equiv.
Et2NH in anhydrous DMF at 60 ꢀC under N2 atmosphere), the
effects of the substituent at 3 and 5 position of the isoxazole
were examined (Table 3). We used the substrate 3a to react
with three different kinds of terminal alkynes, affording the
corresponding targeted products (4a, 4b, and 4c) with the
yields of 60%, 61%, and 63%, respectively (Table 3). For these
reactions, the substrate 3a couldn't be completely transferred,
and its conversion was 66%, 68%, and 69%, respectively.
Pd(MeCN)2Cl2 (5) PPh3 (10)
9
Pd(acac)2 (5)
Pd(acac)2 (5)
Pd(acac)2 (5)
Pd(acac)2 (5)
Pd(acac)2 (3.5)
Pd(acac)2 (7.5)
PPh3 (10)
PCy3 (10)
TFP (10)
DPPP (5)
PPh3 (7)
PPh3 (15)
10
11
12
13
14
a
Reaction condition: 3a (0.3 mmol,
1
equiv.), phenylacetylene
(0.6 mmol, 2 equiv.), [Pd], ligand, CuI (10 mol%), Et2NH (2 equiv.),
DMF (3 mL), 60 ꢀC under N2 protection. b Isolated yield.
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Table 2 Effects of bases, solvents and temperaturesa
Entry
Base
Solvent
Temp. (ꢀC)
3a conv.b (%)
4a yieldb (%)
1
2
3
4
5
6
7
8
9
10
Et2NH
Et3N
DMF
DMF
DMF
DMF
THF
MeCN
Toluene
DCE
60
60
60
60
60
60
60
60
30
90
66
63
38
25
41
46
33
26
38
82
60
58
25
18
30
35
22
20
22
40
n-Butylamine
DIPEA
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
DMF
DMF
a
The reaction was carried out with 3a (0.3 mmol, 1 equiv.), phenylacetylene (0.6 mmol, 2 equiv.), CuI (10 mol%), base (2.0 equiv.) in the solvent at
b
the stated temperature in the presence of Pd(acac)2 (5 mol%) and PPh3 (10 mol%) under N2 atmosphere. Isolated yield.
When we used 3b as the substrate, with a phenyl group at the 3
Based on the above results (Table 3), 3,5-diphenyl-4-
position and a tert-butyl group at the 5 position to react with iodoisoxazole 3h was chosen as a substrate to react with
three kinds of terminal alkynes, the targeted products (4d–4f) a variety of terminal alkynes in the presence of Pd(acac)2/PPh3
were obtained in high yields (up to 97%) and almost full complex (Table 4). The results showed that both electron-
conversion of 3b was gained within 8 h. Such phenomena were donating and electron-withdrawing substituents on the
very interesting, which encouraged us to investigate the phenyl groups of the terminal alkynes were well accommo-
impact of the groups at the 3 and 5 positions of 4-iodoisox- dated, achieving the desired products (5a–5g) in high yields.
azoles on the reaction. First, we studied the impact of the The 4-ethynyl-1,10-biphenyl could also be converted into 5h in
group at the 5 position of 4-iodoisoxazoles on the reaction. 53% yield. Furthermore, R3 ¼ thiophenyl was also afforded
When we used the substrate 3c (5 position was cyclopropyl the targeted product 5i in 91% yield. Both 1-ethynylcyclo-
group) or 3d (5 position was n-pentyl group) to react with the hexene and 1-ethynylcyclohexane could be component
three kinds of terminal alkynes, all of the products (4g–4l) coupling partner for this transformation (5j–5k). And 3-
could be obtained in high yields, accompanied by almost full methoxyprop-1-yne could achieve the desired product 5l in
conversation of 3c or 3d within 8 h. Second, we examined the 80% yield as well.
effect of the group at the 3 position of 4-iodoisoxazole on the
To further demonstrate the synthetic application of the
reaction. We chose the substrate 3e, with an isopropyl group at developed protocol, a gram-scale reaction was tested using
the 3 position, to react with the three kinds of terminal substrates 3h to react with phenylacetylene, and it could
alkynes, affording the targeted products (4m, 4n, and 4o) in proceed smoothly, affording the targeted product 5a in high
high yields (90%, 91%, and 93%, respectively), and 3e was yields (Scheme 2).
almost transferred in the three reactions. As the steric
In addition, to gain insight into the mechanism of the
hindrance from the tert-butyl group is greater than that from Sonogashira coupling reaction, a control experiment had been
the isopropyl group, this implied that 4-iodoisoxazoles con- conducted (Scheme 3). The yield of targeted product 4a was
taining large steric hindrance functional groups at the 3 slightly decreased when run in the presence of radical inhibitor
position was poor for this type Sonogashira cross-coupling (2.0 equiv. TEMPO). The result excluded the possible involve-
reaction. Then, we further investigated the electronic effects ment of radical species.
of the group at the 3 position of 4-iodoisoxazoles. We chose 3f
Based on the above experiments and classical description of
containing strong electron donor group (OCH3) and 3g con- the Sonogashira coupling reaction, a plausible mechanism for
taining strong electron-withdrawing group (CF3) to test the the reaction was depicted in Scheme 4, involving two connected
electronic effects on the reaction. To our delight, all of the catalytic cycles (cycle A and cycle B).8,12 In the cycle A, the cata-
targeted products (4p–4u) could be obtained with high yields lytically active species Pd[0](PPh3)2 D was formed by reduction
and the starting materials (3f and 3g) could be completely of Pd[II](PPh3)2(acac)2 C (activation) which was produced in situ
transferred with 8 h. The results implied that the steric effect by combination two equivalents of triphenylphosphine with
rather than the electronic effect of the group at the 3 position a Pd(II)(acac)2. Oxidative addition of palladium[0] catalyst D to
affected the efficiency of the cross-coupling reactions.
4-iodoisoxazoles 3 produced intermediate E, followed by
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Table 3 Pd-catalyzed Sonogashira cross-coupling between 3,5-disubstituted-4-iodoisoxazoles 3a–3g and terminal alkynesa
a
Reaction condition: 3 (0.3 mmol, 1 equiv.), terminal alkynes (0.6 mmol, 2 equiv.), Pd(acac) (5 mol%), PPh3 (10 mol%), CuI (10 mol%), Et2NH (2
equiv.), and DMF (3 mL) under N2 protection. b Isolated yield.
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Table 4 Pd-catalyzed Sonogashira cross-coupling between 3,5-diphenyl-4-iodoisoxazole 3h and various terminal alkynesa
a
Reaction condition: 3h (0.3 mmol, 1 equiv.), terminal alkynes (0.6 mmol, 2 equiv.), Pd(acac)2 (5 mol%), PPh3 (10 mol%), CuI (10 mol%), Et2NH (2
equiv.), and anhydrous DMF (3 mL) under N2 protection. b Isolated yield.
a transmetallation reaction of intermediate E with alkynyl In the cycle B, terminal alkyne reacted with Et2NH and CuI to
copper F to give intermediate G. Reductive elimination of form alkynyl copper F, followed via transmetallation with
intermediate G to give the targeted product 4 and 5. Meanwhile, intermediate E to afford intermediate G and regenerate CuI for
the generating Pd[0](PPh3)2 D promoted the next catalytic cycle. the next catalytic cycle.
Scheme 2 A gram-scale reaction.
8898 | RSC Adv., 2019, 9, 8894–8904
Scheme 3 The control experiment.
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4,4-Dimethyl-1-phenylpent-1-yn-3-one (1a). Prepared accord-
ing to general procedure (I). Intermediate 1a was obtained as
yellow oil (753.7 mg, 81% yield). The 1H NMR spectral data are in
good agreement with the literature data.13
4,4-Dimethyl-1-phenylpent-2-yn-1-one (1b). Prepared accord-
ing to general procedure (I). Intermediate 1b was obtained as
yellow oil (770.8 mg, 77% yield). The 1H NMR spectral data are in
good agreement with the literature data.14
3-Cyclopropyl-1-phenylprop-2-yn-1-one (1c). Prepared accord-
ing to general procedure (I). Intermediate 1c was obtained as
yellow oil (646.4 mg, 76% yield). The 1H NMR spectral data are in
good agreement with the literature data.15
1-Phenyloct-2-yn-1-one (1d). Prepared according to general
procedure (I). Intermediate 1d was obtained as yellow oil
1
(900.5 mg, 90% yield). The H NMR spectral data are in good
agreement with the literature data.16
4-Methyl-1-phenylpent-1-yn-3-one (1e). Prepared according
to general procedure (I). Intermediate 1e was obtained as yellow
oil (602.3 mg, 70% yield). The 1H NMR spectral data are in good
agreement with the literature data.17
1-(4-Methoxyphenyl)-4,4-dimethylpent-2-yn-1-one (1f). Prepared
according to general procedure (I). Intermediate 1f was obtained as
a yellow oil (780.9 mg, 73% yield). The 1H NMR spectral data are in
good agreement with the literature data.18
Scheme 4 Plausible reaction mechanism.
4,4-Dimethyl-1-(4-(triuoromethyl)phenyl)pent-2-yn-1-one (1g).
Prepared according to general procedure (I). Intermediate 1g was
obtained as yellow oil (889.4 mg, 70% yield). H NMR (600 MHz,
Conclusions
1
In summary, we report herein the Pd(acac)2/PPh3 complex
catalyzed Sonogashira cross-coupling reaction of 3,5-
disubstituted-4-iodoisoxazoles with terminal alkynes, which
affords 3,5-disubstituted-4-alkynylisoxazole products in excel-
lent yields. The effects of the groups at C3 and C5 positions of
the isoxazole on the Sonogashira cross-coupling reaction were
investigated. The group at C3 position of the isoxazole has great
inuence on the reaction due to steric effect, whereas the
electric effect of the group at C3 position was negligible.
Furthermore, a gram-scale reaction demonstrated potential
synthetic application of this protocol.
CDCl3) d 8.21 (d, J ¼ 8.3 Hz, 2H), 7.73 (d, J ¼ 8.3 Hz, 2H), 1.39 (s,
9H). 13C NMR (150 MHz, CDCl3) d 177.2, 139.7, 135.5, 133.7 (q, J ¼
31.5 Hz), 129.9, 125.8 (q, J ¼ 3.0 Hz), 123.8 (q, J ¼ 271.5 Hz), 105.6,
78.1, 30.2, 28.3. 19F NMR (564 MHz, CDCl3) d ꢂ63.10. HRMS (ESI-
ion trap): m/z [M + H]+ calcd for C14H14F3O: 255.0997; found:
255.0995.
1,3-Diphenylprop-2-yn-1-one (1h). Prepared according to
general procedure (I). Intermediate 1h was obtained as yellow
oil (927.3 mg, 90% yield). The 1H NMR spectral data are in good
agreement with the literature data.16
General procedure (II) for the preparation of intermediate ynone
O-methyl oximes (2)
Experimental section
General procedure (I) for the preparation of intermediate ynones
(1)
Intermediates 2 were prepared according to a literature proced-
ure.3d To a 50 mL round-bottomed ask were added the alky-
Intermediates 1 were prepared according to a literature.3d To nones (3.5 mmol), methoxylamine hydrochloride (7.0 mmol, 579
a 50 mL round-bottomed ask were added CuI (19 mg, 0.1 mg), anhydrous Na2SO4 (7.0 mmol, 994 mg), pyridine (1.0 mL),
mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), and triethylamine (10 and anhydrous methanol (10 mL). The reaction mixture was
mL). The ask was ushed with nitrogen atmosphere, and the stirred at room temperature overnight. The mixture was diluted
terminal acetylene (5.0 mmol) was added to the stirred suspen- with water (25 mL) and extracted with ethyl acetate (3 ꢁ 25 mL).
sion, followed by immediately dropwise addition of acyl chloride The organic layers were combined, washed with brine, and dried
(6.5 mmol). The resulting mixture was allowed to stir at room over anhydrous MgSO4. The solvent was removed under
temperature overnight. Water (10 mL) was added to the reaction a vacuum, and the residue was puried by ash column chro-
mixture to work up. The resulting mixture was extracted with matography on silica gel (200–300 mesh) using ethyl acetate/
ethyl acetate (3 ꢁ 20 mL). The organic layers were combined and petroleum ether as the eluent to afford the desired products 2.
dried over anhydrous MgSO4. The solvent was removed under
(Z)-4,4-Dimethyl-1-phenylpent-1-yn-3-one O-methyl oxime (2a).
a vacuum, and the residue was puried by column chromatog- Prepared according to general procedure (II). Intermediate 2a was
raphy on silica gel (200–300 mesh) using ethyl acetate/petroleum obtained as yellow oil (617.5 mg, 82% yield). The 1H NMR spectral
ether as the eluent to afford the desired products 1.
data are in good agreement with the literature data.19
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solid (961.4 mg, 98% yield). Mp 80–82 ꢀC. The 1H NMR spectral
data are in good agreement with the literature data.19
(Z)-4,4-Dimethyl-1-phenylpent-2-yn-1-one O-methyl oxime (2b).
Prepared according to general procedure (II). Intermediate 2b was
obtained as yellow oil (492.7 mg, 70% yield). The 1H NMR spectral
data are in good agreement with the literature data.19
5-(tert-Butyl)-4-iodo-3-phenylisoxazole (3b). Following general
procedure (III), the substrate 3b was obtained as a yellow solid
1
ꢀ
(971.3 mg, 99% yield). Mp 91–93 C. The H NMR spectral data
are in good agreement with the literature data.19
(Z)-3-Cyclopropyl-1-phenylprop-2-yn-1-one O-methyl oxime (2c).
Prepared according to general procedure (II). Intermediate 2c was
obtained as a yellow oil (383.3 mg, 55% yield). The 1H NMR
spectral data are in good agreement with the literature data.20
(Z)-1-Phenyloct-2-yn-1-one O-methyl oxime (2d). Prepared
according to general procedure (II). Intermediate 2d was obtained
5-Cyclopropyl-4-iodo-3-phenylisoxazole (3c). Following general
procedure (III), the substrate 3c was obtained as a yellow solid
1
ꢀ
(914.3 mg, 98% yield). Mp 73–75 C. H NMR (400 MHz, CDCl3)
d 7.76 (dt, J ¼ 7.4, 3.2 Hz, 2H), 7.51–7.45 (m, 3H), 2.18 (dq, J ¼ 8.4,
5.1 Hz, 1H), 1.25–1.20 (m, 2H), 1.14 (ddd, J ¼ 11.5, 6.9, 4.6 Hz, 2H).
13C NMR (150 MHz, CDCl3) d 174.7, 163.1, 130.1, 128.9, 128.8,
128.7, 56.5, 9.4, 8.8. HRMS (ESI-ion trap): m/z [M + H]+ calcd for
C12H11INO: 311.9885; found: 311.9880.
1
as yellow oil (641.7 mg, 80% yield). H NMR (500 MHz, CDCl3)
d 7.88–7.82 (m, 2H), 7.40–7.35 (m, 3H), 4.09 (s, 3H), 2.55 (t, J ¼
7.2 Hz, 2H), 1.72–1.65 (m, 2H), 1.51–1.34 (m, 4H), 0.94 (t, J ¼
7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 140.4, 134.1, 129.6, 128.4,
126.6, 104.1, 71.6, 63.1, 31.2, 28.1, 22.3, 19.9, 14.1. HRMS (ESI-ion
trap): m/z [M + H]+ calcd for C15H20NO: 230.1545; found: 230.1540.
(Z)-4-Methyl-1-phenylpent-1-yn-3-one O-methyl oxime (2e).
Prepared according to general procedure (II). Intermediate 2e
4-Iodo-5-pentyl-3-phenylisoxazole (3d). Following general proce-
dure (III), the substrate 3d was obtained as yellow oil (992.4 mg,
1
97% yield). H NMR (500 MHz, CDCl3) d 7.85–7.79 (m, 2H), 7.49–
7.44 (m, 3H), 2.91–2.83 (m, 2H), 1.82–1.72 (m, 2H), 1.39 (td, J ¼ 7.2,
3.6 Hz, 4H), 0.98–0.89 (m, 3H). 13C NMR (125 MHz, CDCl3) d 174.8,
162.6, 129.9, 128.9, 128.6, 128.5, 57.3, 31.2, 27.1, 26.9, 22.3, 13.9.
HRMS (ESI-ion trap): m/z [M + H]+ calcd for C14H17INO: 342.0355;
found: 342.0341.
4-Iodo-3-isopropyl-5-phenylisoxazole (3e). Following general
procedure (III), the substrate 3e was obtained as a white solid
(901.5 mg, 96% yield). Mp 70–72 ꢀC. 1H NMR (600 MHz, CDCl3)
d 8.01 (dd, J ¼ 5.2, 2.8 Hz, 2H), 7.52–7.46 (m, 3H), 3.05 (dt, J ¼
13.9, 6.9 Hz, 1H), 1.40 (d, J ¼ 7.0 Hz, 6H). 13C NMR (150 MHz,
CDCl3) d 169.9, 167.6, 130.6, 128.8, 127.7, 127.5, 56.8, 28.1, 20.9.
HRMS (ESI-ion trap): m/z [M + H]+ calcd for C12H12INO:
314.0042; found: 314.0040.
1
was obtained as yellow oil (492.7 mg, 70% yield). The H NMR
spectral data are in good agreement with the literature data.21
(Z)-1-(4-Methoxyphenyl)-4,4-dimethylpent-2-yn-1-one O-methyl
oxime (2f). Prepared according to general procedure (II). Inter-
1
mediate 2f was obtained as yellow oil (642.1 mg, 80% yield). H
NMR (600 MHz, CDCl3) d 7.77 (d, J ¼ 8.8 Hz, 2H), 6.89 (d, J ¼
8.8 Hz, 2H), 4.05 (s, 3H), 3.82 (s, 3H), 1.38 (s, 9H). 13C NMR (150
MHz, CDCl3) d 160.8, 139.9, 128.0, 126.9, 113.8, 111.3, 70.2, 62.8,
55.4, 30.8, 28.6. HRMS (ESI-ion trap): m/z [M + H]+ calcd for
C15H20NO2: 246.1494; found: 246.1488.
(Z)-4,4-Dimethyl-1-(4-(triuoromethyl)phenyl)pent-2-yn-1-one
O-methyl oxime (2g). Prepared according to general procedure
(II). Intermediate 2g was obtained as yellow oil (792.7 mg, 80%
yield). 1H NMR (600 MHz, CDCl3) d 7.95 (d, J ¼ 8.3 Hz, 2H), 7.62
(d, J ¼ 8.4 Hz, 2H), 4.11 (s, 3H), 1.39 (s, 9H). 13C NMR (150 MHz,
CDCl3) d 139.1, 137.6, 131.3 (q, J ¼ 31.5 Hz), 126.9, 125.4 (q, J ¼
3.0 Hz), 126.9, 124.3 (q, J ¼ 270.0 Hz), 112.6, 69.8, 63.3, 30.8, 28.8.
19F NMR (564 MHz, CDCl3) d ꢂ62.70. HRMS (ESI-ion trap): m/z [M
+ H]+ calcd for C15H17F3NO: 284.1262; found: 284.1258.
5-(tert-Butyl)-4-iodo-3-(4-methoxyphenyl)isoxazole (3f). Following
general procedure (III), the substrate 3f was obtained as a yellow
1
solid (1017.6 mg, 95% yield). Mp 75–77 ꢀC. H NMR (600 MHz,
CDCl3) d 7.66–7.61 (m, 2H), 7.02–6.98 (m, 2H), 3.85 (s, 3H), 1.54 (s,
9H). 13C NMR (150 MHz, CDCl3) d 177.8, 164.5, 160.9, 130.6, 121.4,
114.1, 55.4, 34.5, 28.4. HRMS (ESI-ion trap): m/z [M + H]+ calcd for
C14H17INO: 358.0304; found: 358.0304.
5-(tert-Butyl)-4-iodo-3-(4-(triuoromethyl)phenyl)isoxazole (3g).
Following general procedure (III), the substrate 3g was obtained as
a yellow solid (1019.1 mg, 86% yield). Mp 99–101 ꢀC. 1H NMR (600
MHz, CDCl3) d 7.82 (d, J ¼ 8.1 Hz, 2H), 7.75 (d, J ¼ 8.2 Hz, 2H), 1.55
(s, 9H). 13C NMR (150 MHz, CDCl3) d 163.2, 132.9, 131.9 (q, J ¼ 31.5
Hz), 129.8, 125.6 (q, J ¼ 4.5 Hz), 126.9, 124.1 (q, J ¼ 271.5 Hz), 53.4,
34.7, 28.5. 19F NMR (564 MHz, CDCl3) d ꢂ62.80. HRMS (ESI-ion
(Z)-1,3-Diphenylprop-2-yn-1-one O-methyl oxime (2h).
Prepared according to general procedure (II). Intermediate 2h
was obtained as yellow oil (501.9 mg, 61% yield). The H NMR
spectral data are in good agreement with the literature data.19
1
General procedure (III) for iodocyclization using ICl as a catalyst (3)
To a stirred solution of the appropriate O-methyl oxime (3.0 mmol) trap): m/z [M + H]+ calcd for C14H14F3INO: 396.0072; found:
in CH2Cl2 (30 mL), ICl (1 M in CH2Cl2, 1.2 equiv.) was added by 396.0070.
dropwise, and then the solution was allowed to stir at room
4-Iodo-3,5-diphenylisoxazole (3h). Following general proce-
temperature. The reaction was monitored by TLC to establish dure (III), the substrate 3h was obtained as a colourless solid
1
completion. The excess ICl was removed by washing with a satu- (739.1 mg, 71% yield). Mp 176–178 ꢀC. The H NMR spectral
rated aqueous solution of Na2S2O3. The aqueous solution was then data are in good agreement with the literature data.22
extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic layers
were dried over anhydrous MgSO4 and concentrated under
a vacuum to yield the crude product, which was puried by ash
chromatography on silica gel (200–300 mesh) using ethyl acetate/
General procedure (IV) for the synthesis of C4-alkynyl isoxazoles
(4 or 5)
petroleum ether as the eluent to afford the desired products 3.
A 10 mL two-neck round-bottomed ask with a reux condenser
3-(tert-Butyl)-4-iodo-5-phenylisoxazole (3a). Following general was ame-dried under a stream of nitrogen and cooled to room
procedure (III), the substrate 3a was obtained as a colourless temperature. 3 (0.3 mmol, 1.0 equiv.), Pd(acac)2 (4.7 mg,
8900 | RSC Adv., 2019, 9, 8894–8904
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5 mol%), PPh3 (7.9 mg, 10 mol%), CuI (5.8 mg, 10 mol%), and (84.2 mg, 89% yield). Mp 81–83 C. H NMR (600 MHz, CDCl3)
Et2NH (43.9 mg, 2 equiv.) were added, followed by the addition d 8.09–8.04 (m, 2H), 7.49–7.47 (m, 3H), 7.36 (d, J ¼ 8.1 Hz, 2H), 7.17
of anhydrous DMF (2.5 mL). The ask was ushed with nitrogen (d, J ¼ 7.9 Hz, 2H), 2.38 (s, 3H), 1.56 (s, 9H). 13C NMR (150 MHz,
and the terminal acetylene (1.0 M in DMF, 2.0 equiv.) was added CDCl3) d 182.0, 162.3, 138.9, 132.7, 131.1, 130.1, 129.4, 129.0, 128.7,
gradually by a syringe. The resulting solution was allowed to stir 128.6, 128.0, 120.2, 96.9, 96.1, 78.9, 34.8, 28.5, 21.7. HRMS (ESI-ion
at 60 C until completion as monitored by thin layer chroma- trap): m/z [M + H]+ calcd for C22H22NO: 316.1701; found: 316.1694.
tography. Aer cooling to room temperature, the reaction was 5-Cyclopropyl-3-phenyl-4-(phenylethynyl)isoxazole (4g). Following
ꢀ
poured into 10 mL ethyl acetate and washed three times (3 ꢁ 10 general procedure (IV), the product 4g was obtained as yellow oil
mL) with water. The organic layers were combined, dried with (82.1 mg, 96% yield). 1H NMR (400 MHz, CDCl3) d 8.07 (dt, J ¼ 9.3,
anhydrous MgSO4, and then ltered. The ltrate was concen- 2.8 Hz, 2H), 7.55–7.43 (m, 4H), 7.32 (dd, J ¼ 5.0, 3.0 Hz, 1H), 7.18 (dd,
trated in vacuum, and the resulting residue was puried on J ¼ 5.0, 1.0 Hz, 1H), 2.37–2.27 (m, 1H), 1.38–1.32 (m, 2H), 1.21–1.16
silica gel column (200–300 mesh) using ethyl acetate/petroleum (m, 2H). 13C NMR (100 MHz, CDCl3) d 177.0, 161.6, 131.4, 130.2,
ether as eluent to afford the desired products 4 or 5.
128.9, 128.8, 128.7, 128.6, 127.8, 123.1, 97.5, 94.8, 78.6, 9.0, 8.9.
3-(tert-Butyl)-5-phenyl-4-(phenylethynyl)isoxazole (4a). Following HRMS (ESI-ion trap): m/z [M + H]+ calcd for C21H18NO: 300.1388;
general procedure (IV), the product 4a was obtained as yellow oil found: 300.1386.
(54.2 mg, 60% yield). 1H NMR (400 MHz, d6-DMSO) d 8.14–8.11 (m,
5-Cyclopropyl-4-((4-uorophenyl)ethynyl)-3-phenylisoxazole
2H), 7.60 (dddd, J ¼ 6.3, 5.7, 3.3, 1.7 Hz, 5H), 7.49–7.46 (m, 3H), 1.48 (4h). Following general procedure (IV), the product 4h was ob-
1
(s, 9H). 13C NMR (100 MHz, d6-DMSO) d 170.7, 169.0, 131.2, 130.9, tained as a yellow solid (82.8 mg, 91% yield). Mp 85–87 C. H
ꢀ
129.3, 129.0, 126.5, 125.9, 121.7, 96.8, 96.2, 79.4, 33.0, 27.8. HRMS NMR (500 MHz, CDCl3) d 8.11–8.03 (m, 2H), 7.48 (dd, J ¼ 7.4,
(ESI-ion trap): m/z [M + H]+ calcd for C21H20NO: 302.1545; found: 6.0 Hz, 5H), 7.06 (t, J ¼ 8.5 Hz, 2H), 2.37–2.27 (m, 1H), 1.40–1.34
302.1542.
(m, 2H), 1.22–1.15 (m, 2H). 13C NMR (125 MHz, CDCl3) d 177.0,
3-(tert-Butyl)-4-((4-uorophenyl)ethynyl)-5-phenylisoxazole (4b). 163.8, 161.8, 161.6, 133.4, 133.3, 130.2, 128.8, 128.7, 127.8,
Following general procedure (IV), the product 4b was obtained as 119.3, 119.2, 116.0, 115.8, 97.4, 93.7, 78.3, 9.0, 8.9. 19F NMR (564
1
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a white solid (58.4 mg, 61% yield). Mp 81–83 C. H NMR (500 MHz, CDCl3) d ꢂ109.90, ꢂ109.91. HRMS (ESI-ion trap): m/z [M +
MHz, CDCl3) d 8.17 (d, J ¼ 7.5 Hz, 2H), 7.50 (dt, J ¼ 15.9, 7.1 Hz, H]+ calcd for C20H15FNO: 304.1138; found: 304.1130.
5H), 7.09 (t, J ¼ 8.5 Hz, 2H), 1.54 (s, 9H). 13C NMR (125 MHz,
5-Cyclopropyl-3-phenyl-4-(p-tolylethynyl)isoxazole (4i). Following
CDCl3) d 171.5, 169.8, 163.9, 161.9, 133.3, 133.2, 130.7, 129.0, 127.7, general procedure (IV), the product 4i was obtained as yellow oil
126.5, 119.3, 119.2, 116.2, 116.1, 96.9, 96.0, 80.2, 33.6, 28.3. 19F (82.6 mg, 92% yield). H NMR (400 MHz, CDCl3) d 8.15–8.06 (m,
1
NMR (470 MHz, CDCl3) d ꢂ109.90. HRMS (ESI-ion trap): m/z [M + 2H), 7.53–7.45 (m, 3H), 7.41 (d, J ¼ 8.0 Hz, 2H), 7.18 (d, J ¼ 7.9 Hz,
H]+ calcd for C21H19FNO: 320.1451; found: 320.1443.
2H), 2.39 (s, 3H), 1.40–1.34 (m, 2H), 1.23–1.16 (m, 2H). 13C NMR
3-(tert-Butyl)-5-phenyl-4-(p-tolylethynyl)isoxazole (4c). Following (100 MHz, CDCl3) d 176.7, 161.5, 138.9, 131.3, 130.2, 129.3, 128.8,
general procedure (IV), the product 4c was obtained as a white 128.7, 127.7, 120.0, 97.6, 94.9, 77.8, 21.7, 8.9, 8.8. HRMS (ESI-ion
solid (59.6 mg, 63% yield). Mp 77–79 ꢀC. 1H NMR (500 MHz, trap): m/z [M + H]+ calcd for C21H18NO: 300.1388; found: 300.1386.
CDCl3) d 8.21 (dd, J ¼ 8.1, 0.8 Hz, 2H), 7.52–7.42 (m, 5H), 7.21 (d, J
5-Pentyl-3-phenyl-4-(phenylethynyl)isoxazole (4j). Following
¼ 7.9 Hz, 2H), 2.40 (s, 3H), 1.56 (s, 9H). 13C NMR (125 MHz, CDCl3) general procedure (IV), the product 4j was obtained as yellow oil
d 171.6, 169.5, 139.2, 131.3, 130.6, 129.5, 128.9, 127.8, 126.5, 120.1, (89.9 mg, 95% yield). 1H NMR (500 MHz, CDCl3) d 8.14–8.06 (m,
97.4, 97.3, 79.8, 33.6, 28.4, 21.8. HRMS (ESI-ion trap): m/z [M + H]+ 2H), 7.52–7.45 (m, 5H), 7.10–7.03 (m, 2H), 2.96 (t, J ¼ 7.5 Hz,
calcd for C22H22NO: 316.1701; found: 316.1694.
2H), 1.86 (p, J ¼ 7.3 Hz, 2H), 1.41 (dd, J ¼ 7.2, 3.6 Hz, 4H), 0.93 (t,
5-(tert-Butyl)-3-phenyl-4-(phenylethynyl)isoxazole (4d). Following J ¼ 6.8 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 176.9, 163.8, 161.8,
general procedure (IV), the product 4d was obtained as a white solid 161.3, 133.5, 133.4, 130.2, 128.8, 127.7, 119.1, 116.1, 115.9, 98.7,
1
(87.6 mg, 97% yield). Mp 58–60 ꢀC. H NMR (400 MHz, CDCl3) 93.9, 78.3, 31.3, 26.9, 26.7, 22.4, 14.1. HRMS (ESI-ion trap): m/z
d 8.08 (dd, J ¼ 6.5, 3.1 Hz, 2H), 7.51–7.45 (m, 5H), 7.39–7.33 (m, 3H), [M + H]+ calcd for C22H22NO: 316.1701; found: 316.1690.
1.58 (s, 9H). 13C NMR (100 MHz, CDCl3) d 182.2, 162.3, 131.1, 130.1,
4-((4-Fluorophenyl)ethynyl)-5-pentyl-3-phenylisoxazole (4k).
128.9, 128.8, 128.7, 128.6, 128.0, 123.2, 96.8, 95.9, 79.6, 34.8, 28.5. Following general procedure (IV), the product 4k was obtained
1
HRMS (ESI-ion trap): m/z [M + H]+ calcd for C21H20NO: 302.1545; as yellow oil (91.9 mg, 92% yield). H NMR (500 MHz, CDCl3)
found: 302.1539.
d 8.13 (td, J ¼ 4.2, 2.5 Hz, 2H), 7.51–7.48 (m, 4H), 7.37 (dd, J ¼
5-(tert-Butyl)-4-((4-uorophenyl)ethynyl)-3-phenylisoxazole (4e). 4.2, 2.3 Hz, 3H), 3.01–2.91 (m, 2H), 1.87 (p, J ¼ 7.3 Hz, 2H), 1.42
Following general procedure (IV), the product 4e was obtained as (dd, J ¼ 4.2, 3.1 Hz, 4H), 0.94 (dt, J ¼ 7.0, 3.4 Hz, 3H). 13C NMR
yellow oil (86.2 mg, 90% yield). 1H NMR (600 MHz, CDCl3) d 8.06– (125 MHz, CDCl3) d 176.9, 161.3, 131.5, 130.2, 128.9, 128.8,
8.01 (m, 2H), 7.48 (d, J ¼ 4.0 Hz, 3H), 7.43 (dd, J ¼ 8.1, 5.7 Hz, 2H), 128.7, 128.6, 127.8, 123.1, 98.9, 95.0, 78.6, 31.4, 27.0, 26.7, 22.4,
7.05 (t, J ¼ 8.5 Hz, 2H), 1.56 (s, 9H). 13C NMR (150 MHz, CDCl3) 14.1. 19F NMR (470 MHz, CDCl3) d ꢂ110.30. HRMS (ESI-ion
d 182.2, 163.6, 162.4, 162.0, 133.1, 133.0, 132.7, 130.2, 129.4, 128.9, trap): m/z [M + H]+ calcd for C22H21FNO: 334.1607; found:
128.7, 128.6, 128.0, 119.4, 119.3, 116.0, 115.9, 96.6, 94.8, 79.3, 34.8, 334.1599.
28.5. 19F NMR (564 MHz, CDCl3) d ꢂ110.30. HRMS (ESI-ion trap):
5-Pentyl-3-phenyl-4-(p-tolylethynyl)isoxazole (4l). Following
general procedure (IV), the product 4l was obtained as yellow oil
m/z [M + H]+ calcd for C21H19FNO: 320.1451; found: 320.1449.
5-(tert-Butyl)-3-phenyl-4-(p-tolylethynyl)isoxazole (4f). Following (91.9 mg, 98% yield). 1H NMR (500 MHz, CDCl3) d 8.18–8.11 (m,
general procedure (IV), the product 4f was obtained as a white solid 2H), 7.53–7.46 (m, 3H), 7.42 (d, J ¼ 8.0 Hz, 2H), 7.19 (d, J ¼
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7.9 Hz, 2H), 2.97 (t, J ¼ 7.5 Hz, 2H), 2.39 (s, 3H), 1.86 (dd, J ¼ 7.9 Hz, 2H), 7.01–6.98 (m, 2H), 3.86 (s, 3H), 2.38 (s, 3H), 1.55 (s,
14.7, 7.3 Hz, 2H), 1.46–1.39 (m, 4H), 0.95 (dd, J ¼ 10.0, 4.0 Hz, 9H). 13C NMR (150 MHz, CDCl3) d 181.8, 161.9, 161.1, 138.8,
3H). 13C NMR (125 MHz, CDCl3) d 176.7, 161.2, 138.9, 131.4, 131.1, 129.5, 129.4, 121.5, 120.2, 114.1, 96.6, 95.9, 79.2, 55.5, 34.7,
130.1, 129.3, 128.9, 128.7, 127.7, 120.0, 99.0, 95.2, 77.8, 31.3, 28.4, 21.7. HRMS (ESI-ion trap): m/z [M + H]+ calcd for
26.9, 26.6, 22.4, 21.6, 14.0. HRMS (ESI-ion trap): m/z [M + H]+ C23H24NO2: 346.1807; found: 346.1798.
calcd for C23H24NO: 330.1858; found: 330.1852.
5-(tert-Butyl)-4-(phenylethynyl)-3-(4-(triuoromethyl)phenyl)
3-Isopropyl-5-phenyl-4-(phenylethynyl)isoxazole (4m). Following isoxazole (4s). Following general procedure (IV), the product 4s
general procedure (IV), the product 4m was obtained as yellow oil was obtained as yellow oil (107.5 mg, 97% yield). 1H NMR (600
1
(77.6 mg, 90% yield). H NMR (600 MHz, CDCl3) d 8.23–8.18 (m, MHz, CDCl3) d 8.21 (d, J ¼ 8.2 Hz, 2H), 7.76 (d, J ¼ 8.3 Hz, 2H),
2H), 7.57–7.55 (m, 2H), 7.53–7.46 (m, 3H), 7.42–7.38 (m, 3H), 3.27 7.51–7.45 (m, 2H), 7.41–7.34 (m, 3H), 1.58 (s, 9H). 13C NMR (150
(dt, J ¼ 14.0, 7.0 Hz, 1H), 1.49 (d, J ¼ 7.0 Hz, 6H). 13C NMR (150 MHz, CDCl3) d 182.8, 161.1, 132.5, 132.1, 131.8, 131.2, 129.7,
MHz, CDCl3) d 169.9, 168.8, 131.5, 130.7, 129.0, 128.9, 128.7, 127.6, 129.0, 128.7, 128.3, 125.7 (q, J ¼ 4.5 Hz), 125.1, 123.2, 122.9,
126.4, 123.0, 97.6, 96.6, 79.2, 27.1, 20.7. HRMS (ESI-ion trap): m/z 96.9, 96.4, 78.9, 34.9, 28.5. 19F NMR (564 MHz, CDCl3) d ꢂ62.80.
[M + H]+ calcd for C20H18NO: 288.1388; found: 288.1385.
HRMS (ESI-ion trap): m/z [M + H]+ calcd for C22H19F3NO:
4-((4-Fluorophenyl)ethynyl)-3-isopropyl-5-phenylisoxazole (4n). 370.1419; found: 370.1416.
Following general procedure (IV), the product 4n was obtained as
5-(tert-Butyl)-4-((4-uorophenyl)ethynyl)-3-(4-(triuoromethyl)
yellow oil (83.3 mg, 91% yield). 1H NMR (600 MHz, CDCl3) d 8.20– phenyl)isoxazole (4t). Following general procedure (IV), the
8.14 (m, 2H), 7.54–7.47 (m, 5H), 7.12–7.06 (m, 2H), 3.25 (dt, J ¼ product 4t was obtained as a yellow solid (110.4 mg, 95% yield).
14.0, 7.0 Hz, 1H), 1.48 (d, J ¼ 7.0 Hz, 6H). 13C NMR (150 MHz, Mp 77–79 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.18 (d, J ¼ 8.2 Hz, 2H),
CDCl3) d 169.8, 168.9, 163.7, 162.1, 133.5, 133.4, 130.7, 130.6, 129.0, 7.75 (d, J ¼ 8.3 Hz, 2H), 7.44 (dd, J ¼ 8.7, 5.4 Hz, 2H), 7.07 (t, J ¼
128.8, 127.6, 127.5, 126.4, 119.2, 119.1, 116.1, 116.0, 97.5, 95.4, 8.6 Hz, 2H), 1.57 (s, 9H). 13C NMR (150 MHz, CDCl3) d 182.8, 163.8,
78.9, 27.1, 20.9, 20.6. 19F NMR (564 MHz, CDCl3) d ꢂ109.90. HRMS 162.2, 161.1, 133.2, 133.1, 132.4, 132.1, 131.9, 128.3, 127.2, 125.7 (q,
(ESI-ion trap): m/z [M + H]+ calcd for C20H17FNO: 306.1294; found: J ¼ 3 Hz), 125.1, 123.2, 119.0, 118.9, 116.2, 116.0, 96.7, 95.3, 78.7,
306.1288.
34.9, 29.0, 28.4. 19F NMR (564 MHz, CDCl3) d ꢂ62.80, ꢂ109.80.
3-Isopropyl-5-phenyl-4-(p-tolylethynyl)isoxazole (4o). Following HRMS (ESI-ion trap): m/z [M + H]+ calcd for C22H19F4NO: 388.1325;
general procedure (IV), the product 4o was obtained as yellow oil found: 388.1319.
1
(84.1 mg, 93% yield). H NMR (600 MHz, CDCl3) d 8.26–8.17 (m,
5-(tert-Butyl)-4-(p-tolylethynyl)-3-(4-(triuoromethyl)phenyl)
2H), 7.52–7.44 (m, 5H), 7.21 (d, J ¼ 7.9 Hz, 2H), 3.27 (dt, J ¼ 13.9, isoxazole (4u). Following general procedure (IV), the product 4u
7.0 Hz, 1H), 2.40 (s, 3H), 1.49 (dd, J ¼ 7.0, 1.7 Hz, 6H). 13C NMR was obtained as a yellow solid (111.4 mg, 97% yield). Mp 83–
(150 MHz, CDCl3) d 169.8, 168.6, 139.1, 131.4, 130.6, 129.4, 128.9, 85 ꢀC. 1H NMR (600 MHz, CDCl3) d 8.22 (d, J ¼ 8.2 Hz, 2H), 7.75
127.68, 126.4, 119.9, 97.8, 96.8, 78.5, 27.1, 21.7, 20.6. HRMS (ESI- (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.1 Hz, 2H), 7.19 (d, J ¼ 7.9 Hz,
ion trap): m/z [M + H]+ calcd for C21H20NO: 302.1545; found: 2H), 2.39 (s, 3H), 1.58 (s, 9H). 13C NMR (150 MHz, CDCl3)
302.1539.
d 182.5, 161.1, 139.2, 132.5, 132.2, 132.0, 131.8, 131.6, 131.1,
129.5, 128.3, 126.8, 125.7 (q, J ¼ 3 Hz), 123.2, 121.4, 119.8, 97.1,
5-(tert-Butyl)-3-(4-methoxyphenyl)-4-(phenylethynyl)isoxazole
(4p). Following general procedure (IV), the product 4p was ob- 96.6, 78.3, 34.9, 28.4, 21.7. 19F NMR (564 MHz, CDCl3) d ꢂ62.80.
tained as yellow oil (89.4 mg, 90% yield). H NMR (600 MHz, HRMS (ESI-ion trap): m/z [M + H]+ calcd for C23H21F3NO:
1
CDCl3) d 8.04 (d, J ¼ 8.8 Hz, 2H), 7.49–7.45 (m, 2H), 7.36 (dd, J ¼ 384.1575; found: 384.1571.
5.1, 1.9 Hz, 3H), 7.01 (d, J ¼ 8.8 Hz, 2H), 3.86 (s, 3H), 1.56 (s, 9H).
3,5-Diphenyl-4-(phenylethynyl)isoxazole (5a). Following general
13C NMR (150 MHz, CDCl3) d 182.1, 161.9, 161.1, 131.1, 129.4, procedure (IV), the product 5a was obtained as a yellow solid
1
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128.6, 123.3, 121.4, 114.1, 96.5, 95.8, 79.9, 55.5, 34.8, 28.4. HRMS (90.6 mg, 94% yield). Mp 90–92 C. H NMR (400 MHz, CDCl3)
(ESI-ion trap): m/z [M + H]+ calcd for C22H22NO2: 332.1651; found: d 8.30 (dd, J ¼ 8.1, 1.4 Hz, 2H), 8.21–8.14 (m, 2H), 7.61–7.51 (m,
332.1647.
8H), 7.41 (dd, J ¼ 6.4, 2.7 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 170.0, 162.6, 131.5, 130.9, 130.4, 129.1, 129.0, 128.8, 128.7, 128.6,
5-(tert-Butyl)-4-((4-uorophenyl)ethynyl)-3-(4-methoxyphenyl)
isoxazole (4q). Following general procedure (IV), the product 4q 128.0, 127.4, 126.5, 122.8, 97.5, 96.6, 79.9. HRMS (ESI-ion trap): m/z
1
was obtained as yellow oil (95.3 mg, 91% yield). H NMR (600 [M + H]+ calcd for C23H16NO: 322.1232; found: 322.1229.
MHz, CDCl3) d 8.00 (d, J ¼ 8.7 Hz, 2H), 7.47–7.41 (m, 2H), 7.06 (t, J
4-((4-Fluorophenyl)ethynyl)-3,5-diphenylisoxazole (5b). Following
¼ 8.6 Hz, 2H), 7.00 (d, J ¼ 8.7 Hz, 2H), 3.86 (s, 3H), 1.55 (s, 9H). general procedure (IV), the product 5b was obtained as a white solid
13C NMR (150 MHz, CDCl3) d 182.1, 163.6, 161.9, 161.1, 133.1, (96.6 mg, 96% yield). Mp 100–102 C. H NMR (500 MHz, CDCl3)
1
ꢀ
133.0, 129.3, 121.3, 119.4, 119.3, 116.0, 115.9, 114.1, 96.3, 94.7, d 8.26 (d, J ¼ 7.3 Hz, 2H), 8.17–8.11 (m, 2H), 7.56–7.49 (m, 8H), 7.09
79.6, 55.5, 34.8, 28.4. 19F NMR (564 MHz, CDCl3) d ꢂ110.34, (t, J ¼ 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3) d 170.1, 163.9, 162.7,
ꢂ110.35, ꢂ110.36, ꢂ110.37, ꢂ110.38, ꢂ110.39, ꢂ110.40. HRMS 162.0, 133.5, 133.4, 130.9, 130.4, 129.1, 128.8, 128.6, 128.0, 127.5,
(ESI-ion trap): m/z [M + H]+ calcd for C22H22FNO2: 350.1556; 126.6, 119.0, 118.9, 116.2, 116.0, 97.3, 95.5, 79.7. 19F NMR (470 MHz,
found: 350.1552.
CDCl3) d ꢂ109.62. HRMS (ESI-ion trap): m/z [M + H]+ calcd for
5-(tert-Butyl)-3-(4-methoxyphenyl)-4-(p-tolylethynyl)isoxazole
C23H15FNO: 340.1138; found: 340.1130.
(4r). Following general procedure (IV), the product 4r was ob-
3,5-Diphenyl-4-(p-tolylethynyl)isoxazole (5c). Following general
1
tained as yellow oil (95.3 mg, 92% yield). H NMR (600 MHz, procedure (IV), the product 5c was obtained as a white solid
CDCl3) d 8.07–8.01 (m, 2H), 7.37 (d, J ¼ 8.1 Hz, 2H), 7.17 (d, J ¼ (95.5 mg, 95% yield). Mp 106–108 ꢀC. 1H NMR (400 MHz, CDCl3)
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d 8.31 (d, J ¼ 6.9 Hz, 2H), 8.23–8.15 (m, 2H), 7.58–7.43 (m, 8H), 7.22 2H), 7.60–7.48 (m, 7H), 7.36 (dd, J ¼ 4.9, 3.0 Hz, 1H), 7.23 (dd, J ¼
(d, J ¼ 7.9 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) d 169.8, 5.0, 0.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 170.1, 162.7, 130.9,
162.6, 139.2, 131.4, 130.8, 130.3, 129.4, 129.0, 128.8, 128.7, 128.0, 130.3, 129.7, 129.3, 129.2, 129.1, 128.9, 128.6, 128.0, 127.4, 126.9,
127.5, 126.5, 119.8, 97.6, 96.8, 79.2, 21.7. HRMS (ESI-ion trap): m/z 126.5, 125.9, 121.8, 97.4, 91.9, 79.3. HRMS (ESI-ion trap): m/z [M +
[M + H]+ calcd for C24H18NO: 336.1388; found: 336.1382.
H]+ calcd for C21H14NOS: 328.0796; found: 328.0790.
3,5-Diphenyl-4-(m-tolylethynyl)isoxazole (5d). Following general
4-(Cyclohex-1-en-1-ylethynyl)-3,5-diphenylisoxazole
(5j).
procedure (IV), the product 5d was obtained as a yellow solid Following general procedure (IV), the product 5j was obtained
1
1
ꢀ
(92.5 mg, 92% yield). Mp 95–97 C. H NMR (600 MHz, CDCl3) as yellow oil (88.8 mg, 91% yield). H NMR (400 MHz, CDCl3)
d 8.29 (d, J ¼ 7.5 Hz, 2H), 8.22–8.12 (m, 2H), 7.57–7.51 (m, 6H), 7.36 d 8.27–8.20 (m, 2H), 8.12 (dd, J ¼ 6.2, 2.7 Hz, 2H), 7.56–7.44 (m,
(d, J ¼ 5.9 Hz, 2H), 7.29 (t, J ¼ 7.8 Hz, 1H), 7.21 (d, J ¼ 7.6 Hz, 1H), 6H), 6.28–6.21 (m, 1H), 2.30–2.24 (m, 2H), 2.21–2.15 (m, 2H),
2.39 (s, 3H). 13C NMR (150 MHz, CDCl3) d 170.1, 162.7, 138.5, 1.74–1.63 (m, 4H). 13C NMR (100 MHz, CDCl3) d 169.3, 162.5,
132.1, 130.9, 130.4, 129.9, 129.1, 128.8, 128.7, 128.6, 128.1, 127.5, 136.1, 130.6, 130.2, 128.9, 128.8, 128.7, 127.9, 127.6, 126.4,
126.6, 122.7, 97.6, 96.9, 79.5, 21.5. HRMS (ESI-ion trap): m/z [M + 120.7, 98.7, 97.9, 28.8, 25.9, 22.3, 21.6. HRMS (ESI-ion trap): m/z
H]+ calcd for C24H18NO: 336.1388; found: 336.1381.
[M + H]+ calcd for C23H20NO: 326.1545; found: 326.1540.
3,5-Diphenyl-4-((4-propylphenyl)ethynyl)isoxazole (5e). Following
4-(Cyclohexylethynyl)-3,5-diphenylisoxazole (5k). Following
general procedure (IV), the product 5e was obtained as a yellow solid general procedure (IV), the product 5k was obtained as a white
1
1
ꢀ
ꢀ
(102.4 mg, 94% yield). Mp 97–99 C. H NMR (400 MHz, CDCl3) solid (96.2 mg, 98% yield). Mp 97–99 C. H NMR (600 MHz,
d 8.31 (d, J ¼ 6.8 Hz, 2H), 8.19 (dd, J ¼ 6.4, 2.8 Hz, 2H), 7.53 (ddd, J ¼ CDCl3) d 8.27–8.23 (m, 2H), 8.12 (dd, J ¼ 6.6, 3.0 Hz, 2H), 7.50
25.3, 12.3, 7.4 Hz, 8H), 7.22 (d, J ¼ 8.0 Hz, 2H), 2.64 (t, J ¼ 7.6 Hz, (dd, J ¼ 8.2, 5.1 Hz, 5H), 2.83–2.63 (m, 1H), 1.97–1.90 (m, 2H),
2H), 1.68 (dd, J ¼ 15.0, 7.5 Hz, 2H), 0.98 (t, J ¼ 7.3 Hz, 3H). 13C NMR 1.78 (dt, J ¼ 12.8, 5.2 Hz, 2H), 1.65–1.57 (m, 3H), 1.45–1.37 (m,
(100 MHz, CDCl3) d 169.8, 162.6, 144.0, 131.4, 130.8, 130.3, 129.0, 3H). 13C NMR (150 MHz, CDCl3) d 169.4, 162.7, 130.6, 130.2,
128.9, 128.8, 128.7, 128.0, 127.5, 126.5, 120.1, 97.7, 96.9, 79.2, 38.1, 129.1, 128.8, 128.6, 127.9, 127.7, 126.3, 102.2, 98.0, 71.0, 32.4,
24.5, 13.9. HRMS (ESI-ion trap): m/z [M + H]+ calcd for C26H22NO: 30.2, 26.0, 24.9. HRMS (ESI-ion trap): m/z [M + H]+ calcd for
364.1701; found: 364.1690.
C
23H22NO: 328.1701; found: 328.1696.
4-((4-(tert-Butyl)phenyl)ethynyl)-3,5-diphenylisoxazole (5f).
4-(3-Methoxyprop-1-yn-1-yl)-3,5-diphenylisoxazole (5l). Following
Following general procedure (IV), the product 5f was obtained general procedure (IV), the product 5l was obtained as a white solid
1
as a yellow solid (105.3 mg, 93% yield). Mp 115–117 ꢀC. 1H NMR (69.4 mg, 80% yield). Mp 68–70 ꢀC. H NMR (600 MHz, CDCl3)
(600 MHz, CDCl3) d 8.29 (d, J ¼ 7.8 Hz, 2H), 8.17 (d, J ¼ 7.6 Hz, d 8.20 (dd, J ¼ 7.9, 1.5 Hz, 2H), 8.09–8.03 (m, 2H), 7.56–7.46 (m, 6H),
2H), 7.52 (dd, J ¼ 14.2, 7.5 Hz, 8H), 7.43 (d, J ¼ 8.2 Hz, 2H), 1.35 4.41 (s, 2H), 3.46 (s, 3H). 13C NMR (150 MHz, CDCl3) d 170.7, 162.9,
(s, 9H). 13C NMR (150 MHz, CDCl3) d 169.9, 162.7, 152.5, 131.4, 131.1, 130.4, 129.1, 128.8, 128.5, 128.1, 127.3, 126.6, 96.8, 92.8, 76.9,
130.9, 130.8, 130.4, 130.3, 129.2, 129.1, 128.9, 128.8, 128.7, 60.7, 58.1. HRMS (ESI-ion trap): m/z [M + H]+ calcd for C19H16NO2:
128.1, 127.9, 127.6, 126.6, 125.8, 119.9, 97.7, 96.9, 79.2, 35.1, 290.1181; found: 290.1180.
31.4. HRMS (ESI-ion trap): m/z [M + H]+ calcd for C27H24NO:
378.1858; found: 378.1849.
Conflicts of interest
4-((4-Methoxyphenyl)ethynyl)-3,5-diphenylisoxazole
(5g).
Following general procedure (IV), the product 5g was obtained There are no conicts to declare.
as a white solid (90.6 mg, 89% yield). Mp 114–116 ꢀC. 1H NMR
(600 MHz, CDCl3) d 8.32–8.26 (m, 2H), 8.21–8.13 (m, 2H), 7.56–
Acknowledgements
7.45 (m, 8H), 6.92 (d, J ¼ 8.7 Hz, 2H), 3.85 (s, 3H). 13C NMR (150
MHz, CDCl3) d 169.6, 162.6, 160.2, 133.1, 130.8, 130.4, 129.1, We gratefully thank the National Natural Science Foundation of
128.9, 128.8, 128.1, 127.6, 126.5, 115.1, 114.4, 97.8, 96.7, 78.6, China (21172081, 21372090), the Natural Science Foundation of
55.6. HRMS (ESI-ion trap): m/z [M + H]+ calcd for C22H19F4NO: Guangdong Province (S2013020013091) and the City of
352.1338; found: 352.1334.
Guangzhou Science and Technology Plan Projects
(5h). (201510010054) for nancial support.
4-([1,10-Biphenyl]-4-ylethynyl)-3,5-diphenylisoxazole
Following general procedure (IV), the product 5h was obtained
as a white solid (59.6 mg, 50% yield). Mp 120–122 ꢀC. 1H NMR
(600 MHz, CDCl3) d 8.33–8.29 (m, 2H), 8.18 (dd, J ¼ 7.7, 1.8 Hz,
2H), 7.65–7.60 (m, 6H), 7.55 (qdd, J ¼ 6.6, 4.2, 2.2 Hz, 6H), 7.48
(dd, J ¼ 10.5, 4.9 Hz, 2H), 7.41–7.38 (m, 1H). 13C NMR (150 MHz,
CDCl3) d 170.1, 162.7, 141.8, 140.3, 132.1, 131.0, 130.4, 129.2,
129.1, 128.9, 128.7, 128.1, 128.0, 127.5, 127.4, 127.2, 126.6,
121.7, 97.6, 96.5, 80.6. HRMS (ESI-ion trap): m/z [M + H]+ calcd
for C29H20NO: 398.1545; found: 398.1540.
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