Isomerizable (: E / Z)-alkynyl- O -methyl oximes employing TMSCl-NCS in chlorinative cyclization for the direct synthesis of 4-chloroisoxazoles

Article abstract of DOI:10.1039/c6ra09396e

For the first time, 4-chloroisoxazoles are directly synthesized in moderate to excellent yields from (E/Z)-alkynyl-O-methyl oximes via chlorinative cyclization. The synthesis employs the combination of N-chlorosuccinimide (NCS) and chlorotrimethylsilane (

Full text of DOI:10.1039/c6ra09396e

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Isomerizable (E/Z)-alkynyl-O-methyl oximes
employing TMSCl–NCS in chlorinative cyclization
for the direct synthesis of 4-chloroisoxazoles†
Cite this: RSC Adv., 2016, 6, 48666
c
ac
Jumreang Tummatornbc
*
Wilailak Kaewsri, Charnsak Thongsornkleeb,
and Somsak Ruchirawatbc
For the first time, 4-chloroisoxazoles are directly synthesized in moderate to excellent yields from (E/Z)-
alkynyl-O-methyl oximes via chlorinative cyclization. The synthesis employs the combination of
N-chlorosuccinimide (NCS) and chlorotrimethylsilane (TMSCl) in nitromethane solvent where chlorine
(Cl2) and hydrochloric acid (HCl) are generated in situ. In addition, the current protocol is applicable to
the synthesis of 4-bromo- and 4-iodoisoxazoles when N-bromosuccinimide (NBS) and
N-iodosuccinimide (NIS), respectively, are employed in place of NCS. The current method can improve
the overall efficiency of the preparation of 4-haloisoxazoles starting from the step where alkynyl-O-
methyl oximes are prepared since (E)-isomers can isomerize and cyclize under the conditions.
Received 12th April 2016
Accepted 8th May 2016
DOI: 10.1039/c6ra09396e
www.rsc.org/advances
uoro-, 4-bromo- and 4-iodoisoxazoles. As illustrated in
Scheme 1, Ryu4 recently utilized the combination of a gold
Introduction
Isoxazoles are an important structural motif1 found in many
biologically active compounds and currently marketed drugs,
catalyst and an electrophilic uorine source to synthesize
4-uoroisoxazoles from (Z)-only alkynyl-O-methyl oximes.
Previously, Larock5 also showed that reagents such as Br2 and
ICl could be employed to synthesize 4-bromo- and 4-iodoisox-
azole derivatives, respectively, via the cyclization of also (Z)-only
alkynyl-O-methyl oximes.
For the synthesis of 4-chloroisoxazole derivatives, no proce-
dure has been reported to date for the direct cyclization from
alkynyl-O-methyl oximes. The current synthesis of 4-chlor-
oisoxazole derivatives relies on the chlorination of 4-unsub-
stituted isoxazole compounds under strongly acidic (NCS and
sulfuric acid in reuxing acetic acid) or oxidative (hydrogen
chloride and hydrogen peroxide in reuxing acetic acid)
conditions.6 In this work, we aim to search for the new method
which could prepare 4-chloroisoxazoles by direct conversion of
alkynyl-O-methyl oximes, which would provide a useful and
concise synthetic access to such compounds. We recently re-
ported a halogenation procedure for aromatic compounds
such as valdecoxib and oxacillin,
a non-steroidal anti-
inammatory drug and b-lactamase-resistant antibiotic
a
drug, respectively. Pertaining to the medicinal properties of
compounds, several studies have shown that the inclusion of
halogen atoms can improve their biological activities as
compared to the non-halogenated variants.2 Due to these
important pharmacological aspects of halogenated compounds
and the roles the isoxazole nucleus plays in medicinal chem-
istry, preparative methods for halogenated isoxazoles are of
interest among organic and medicinal chemists. Furthermore,
the halogen atoms in halogenated isoxazoles can serve as
synthetic handles for a variety of C–C and C–heteroatom bond
formations via cross-coupling reactions,3 thus facilitating
further functionalization and increasing the molecular
diversity.
One of the most widely used strategies for the construction
of the 4-haloisoxazole nucleus in general is the cyclization of (Z)-
alkynyl-O-methyl oximes mediated by electrophilic halogens,
which are presently available only for the preparation of 4-
aLaboratory of Organic Synthesis, Chulabhorn Research Institute, 54 Kamphaeng Phet
6, Laksi, Bangkok 10210, Thailand. E-mail: charnsak@cri.or.th
bLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng
Phet 6, Laksi, Bangkok 10210, Thailand
cProgram on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence
on Environmental Health and Toxicology (EHT), Ministry of Education, 54
Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
Scheme
synthesis of 4-haloisoxazoles.
1 Halogenative cyclization strategy employed in the
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of compounds 1a–1u, 2a–2u and 3d. See DOI: 10.1039/c6ra09396e
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in a signicantly improved conversion (53%, entry 2). Next,
more TMSCl (1.0 equiv.) was employed but this resulted in
a slightly lower conversion (46%, entry 3), which may have been
due to the concentration effect. Therefore, the concentration of
the substrate was lowered to 0.1 M (entry 4) which led to >99%
conversion to product 2a. Aer the optimal concentration was
established, we next investigated additional solvents, including
THF and DCM, both of which were found to be less effective,
giving lower conversions than in CH3NO2 (entries 5–6). We next
attempted the reaction in CH3NO2 with lower equivalent of
TMSCl (0.5 equiv.) and found the conversion dropping to 52%
(entry 7). Additionally, we attempted the reaction with NCS only
(entry 8) and TMSCl only (entry 9) and no reaction occurred in
either case. This indicated that both reagents were required for
the successful conversion of the substrate. Moreover, this
outcome also supported the proposed mechanism of formation
of product (Scheme 2), which required chlorine, generated from
combination of NCS and TMSCl, to induce the cyclization by
activating the triple bond. Therefore, the optimal conditions
required the reaction to be conducted in CH3NO2 at room
temperature using 1.1 equiv. of NCS and 1.0 equiv. of TMSCl at
0.1 M concentration of substrate for 1 h.
Scheme 2 Proposed mechanism of the reaction.
which relies on the in situ generation of interhalogen species
(X–Cl) and hydrochloric acid (HCl) from chlorotrimethylsilane
(TMSCl) and N-halosuccinimide (NXS) in wet acetonitrile.7 For
the combination of TMSCl and N-chlorosuccinimide (NCS), we
hypothesized that chlorine (Cl2) generated under the conditions
may enable the direct formation of 4-chloroisoxazoles via elec-
trophilic Cl2-induced cyclization, thus constituting the rst
direct synthesis of 4-chloroisoxazoles via chlorinative cyclization
of alkynyl-O-methyl oximes (Scheme 2). In addition, we also
envisioned that the inherently acidic conditions may be advan-
tageous in isomerizing the normally unreactive (E)-alkynyl-O-
methyl oximes to the (Z)-isomers appropriate for the cyclization.
With the optimal conditions in hand, we began to study the
scope of alkynyl-O-methyl oximes, beginning with R1 and R2 as
aryl groups. The preparation of these substrates started from
ynones, which could be prepared by lithium acetylide addition
to aldehydes followed by oxidation of the resulting propargylic
alcohols8 or by Sonogashira coupling between acid chlorides
and terminal alkynes.9 The condensation of ynones with
methoxyamine hydrochloride salt10 then afforded the corre-
sponding alkynyl-O-methyl oximes in moderate to good overall
yields (Scheme 3). Substrates employed in Table 2 (R1 ¼ R2 ¼
aryl groups) were obtained only as (Z)-isomers aer purication
while almost all substrates employed in Table 3 (R1 ¼ alkyl
groups, R2 ¼ Ph or alkyl groups) were obtained as (E/Z)-isomeric
mixtures. The results of the cyclization of these compounds are
summarized below.
Results and discussion
We started the investigation of our proposed cyclization of
alkynyl-O-methyl oximes with compound 1a which was ob-
tained only as (Z)-isomer aer purication and can be prepared
in good overall yield from benzaldehyde and phenylacetylene.8
Compound 1a was subjected to different conditions as
summarized in Table 1.
We rst applied our original conditions7 to substrate 1a in
commercial-grade CH3CN at rt for 1 h (entry 1) which resulted in
only 17% conversion. We next studied the effects of other
solvents. Changing the solvent from CH3CN to CH3NO2 resulted
As shown in Table 2, in most cases the reactions proceeded
under mild conditions (rt, 1 h). For the substrate with R1 ¼ R2 ¼
Ph groups, the reaction afforded quantitative yield of the
desired product (2a-Cl). We then varied the electronic property
of R1 while keeping R2 as the phenyl group. With R1 being an
electronically neutral o-tolyl ring, the cyclization proceeded to
afford the corresponding 4-chloroisoxazole 2b in 83% yield. We
Table 1 Optimization for the cyclization of (Z)-alkynyl-O-methyl
oximes 1a
NCS
(equiv.)
TMSCl
(equiv.)
[1a]
(M)
Conversiona
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
—
0.1
0.1
1.0
1.0
1.0
1.0
0.5
—
0.4
0.4
0.4
0.1
0.1
0.1
0.1
0.1
0.1
CH3CN
CH3NO2
CH3NO2
CH3NO2
THF
17
53
46
>99
68
28
52
NR
NR
DCM
CH3NO2
CH3NO2
CH3NO2
1.0
a
1
Conversions were determined by H NMR.
Scheme 3 Preparation of alkynyl-O-methyl oximes 1.8–10
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Table 2 Scope of intramolecular cyclization of (Z)-alkynyl-O-methyl Table 3 Intramolecular cyclization of mixtures of (E/Z)-alkynyl-O-
oximes 1a
methyl oximes 1a
a
Isolated yields. b The reaction required heating at reux for 1 h.
next attempted the reactions with substrates containing mildly
electron-withdrawing biphenyl systems. For the substrate con-
taining the p-biphenyl group (1c), the desired product (2c) was
obtained uneventfully in 69%. For the o-biphenyl substrate (1d),
the desired product (2d) was obtained in 59% along with 25% of
by-product 3d formed via the intramolecular cyclization by the
adjacent o-phenyl ring. This result showed the tethered
o-biphenyl group to be the competing nucleophile (leading to
3d), although the reaction with the methoxy oxygen as the
nucleophile (leading to 2d) was still more prevalent. The
a
b
c
Isolated yields. Reaction time was 5 h. 1.0 equiv. of TMSCl was
employed.
reaction pathways under the conditions faster than the cycli-
zation. Next, substrates with R1 ¼ p-F-, p-Cl- and m-Cl-phenyl
groups were examined. The reactions proceeded uneventfully
to give the desired products 2f, 2g, and 2h in 88%, 75% and 96%
yields, respectively. In these cases, the halogen atom at the
meta-position of the aryl ring of R1 seemed to facilitate the
cyclization to a greater degree. For the substrate containing p-
Br-phenyl group (1i), the reaction was more sluggish and
required reux for 1 h for a complete conversion to afford
product 2i in 70% yield. We next explored substrates containing
a variety of R2 while keeping R1 ¼ Ph (1j–1l). With R2 ¼ p-OMe-
phenyl group (1j), the reaction proceeded smoothly to give the
1
structure of by-product 3d was proposed and conrmed by H
and 13C NMR spectroscopy, both 1D and 2D techniques, as well
as HRMS, however, the geometry of the vinyl chloride could not
be conclusively assigned. In case of R1 ¼ p-OMe-phenyl group,
the reaction proceeded to give no desired cyclized product (2e),
instead the formation of complex mixture was observed. We
speculated that when R1 ¼ aryl group containing electron-
donating substituent, it became competitive in reacting with
the electrophilic chlorine and underwent other undesired
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desired product 2j in 72% yield. This result was in contrast to s-Bu; (E) : (Z) ¼ 20 : 80) and 1s (R1 ¼ cyclohexyl; (E) : (Z) ¼
the result of substrate 1e, in which many side-reactions 20 : 80) underwent the reactions uneventfully to give isoxazoles
occurred and no desired product was observed due to the 2q-Cl (76%), 2r (72%) and 2s-Cl (77%) in good yields. Finally, R1
competitive reactions occurring on the electron-rich aryl ring. ¼ 3ꢀ alkyl group was investigated. Thus, the reaction of O-
The successful outcome of substrate 1j illustrated that the p- methyl oxime 1t (R1 ¼ t-Bu), obtained only as (Z)-isomer, pro-
OMe-phenyl substituent of the alkyne helped stabilizing the ceeded to provide the corresponding product 2t in 88% yield. In
chloronium ion intermediate (A, Scheme 2) which eventually this case, the reaction, which started with only the (Z)-isomer of
led to the desired product 2j. For substrates 1k and 1l con- 1t, needed only 1.0 equiv. of TMSCl for a complete conversion to
taining R2 ¼ p-F- and p-Cl-phenyl groups, the reactions afforded deliver the product in excellent yield. The result implied that no
the desired 4-chloroisoxazole products 2k and 2l in 71% and additional TMSCl was needed for the HCl generation to assist in
95% yields, respectively. Additionally, our method was appli- the (E) / (Z) isomerization process. In the reaction of 1t, TMSCl
cable for the synthesis of other 4-haloisoxazole derivatives, was consumed only for the generation of Cl2 to facilitate the
requiring appropriate N-halosuccinimides. Thus, (Z)-alkynyl-O- cyclization, which further substantiated our hypothesis
methyl oxime 1a could be conveniently transformed in good to regarding the role of TMSCl. Although the yield of 2t was high, it
excellent yields to both 4-bromoisoxazole 2a-Br (80%) and 4- was still inferior compared to 2a (R1 ¼ Ph, 99%, Table 2). These
iodoisoxazole 2a-I (85%).
results showed the general trend of the reaction regarding
We next tested our hypothesis that our protocol could yields of products as related to the effect of R1 (with R2 ¼ Ph) as
isomerize (E)-alkynyl-O-methyl oximes and then cyclize to the followed: Ph > 3ꢀ > 2ꢀ > 1ꢀ > CH3. Finally, the substrate with both
desired 4-chloroisoxazoles by preparing (E)-1m,11 which was the R1 ¼ R2 ¼ alkyl groups was studied in compound 1u (R1 ¼ n-
only easily accessible oxime as the pure (E)-isomer. In further C5H11, R2 ¼ n-C4H9, (E) : (Z) ¼ 32 : 68) which was transformed
optimizing the conditions, we found that an additional equiv- to 4-chloroisoxazole 2u-Cl in 47% yield. This latter result also
alent of TMSCl was benecial in facilitating the isomerization of showed the general trend in yields of products related to R1 and
(E/Z)-isomeric substrates. We then subjected (E)-1m to 1.1 R2 as followed: R1 ¼ R2 ¼ aryl > R1 ¼ alkyl, R2 ¼ aryl > R1 ¼ R2 ¼
equiv. of NCS and 2.0 equiv. of TMSCl in CH3NO2 at rt and alkyl.
found that the desired isoxazole 2m-Cl could be obtained in
The yields of 4-chloroisoxazoles 2n-Cl (68%) and 2q-Cl (76%)
29% yield. The reaction of (E)-1m was also attempted with NBS, in Table 3 further proved that the (E)-alkynyl-O-methyl oximes
which afforded the corresponding 2m-Br in 22% yield. In both in the mixtures of substrates 1n and 1q were isomerized and
cases, side-reactions were also observed. Surprisingly, when NIS cyclized to the desired products since the yields obtained for
was employed in the reaction at rt for 5 h, the corresponding each case were higher than the proportions of (Z)-isomer in the
2m-I was gratifyingly obtained in excellent yield (89%) with starting materials. As exemplied with alkynyl-O-methyl oxime
much less side-reactions. The results of these three reactions 1m, our method was applied to prepare 4-bromo- and 4-iodoi-
clearly supported our hypothesis that our protocol could facil- soxazoles from other alkynyl-O-methyl oximes. As shown in
itate the isomerization of the normally non-cyclizable (E)- Table 3, alkynyl-O-methyl oxime 1n ((E) : (Z) ¼ 34 : 66) was
alkynyl-O-methyl oxime to the (Z)-isomer, which could readily converted to the corresponding 4-bromoisoxazole 2n-Br in 74%
cyclize to the desired isoxazole products under the reaction yield while alkynyl-O-methyl oxime 1o ((E) : (Z) ¼ 20 : 80) was
conditions, thus enabling the preparation of 4-haloisoxazoles also converted smoothly to product 1o-Br in 81% yield. Simi-
from both (E)- and (Z)-alkynyl-O-methyl oximes. These results larly, compound 1q ((E) : (Z) ¼ 28 : 72) underwent the reaction
also suggested that the outcome of the reactions seemed to to the corresponding 4-bromoisoxazole (2q-Br) in 89% yield. In
depend on the nature of N-halosuccinimide. We next applied case of compound 1s ((E) : (Z) ¼ 25 : 75), the reaction produced
our protocol to mixture of (E/Z)-alkynyl-O-methyl oximes 1m (R1 the desired product (2s-Br) in 78% yield. Finally, for substrate
¼ CH3, (E) : (Z) ¼ 41 : 59) using NCS and NIS as shown in Table 1u ((E) : (Z) ¼ 32 : 68), the reactions with NBS and NIS produced
3. In these cases, isoxazoles 2m-Cl and 2m-I were obtained in the corresponding products 2u-Br and 2u-I in 60% and 55%
56% and 86% yields, respectively. The scope of the substrates yields, respectively. Among these cases, yields of products 2m-
was further studied with starting materials 1n to 1u, which were Cl, (from (E/Z)-1m), 2o-Cl, 2p, 2r, 2s-Cl, 2u-Br and 2u-I were
prepared (R1 ¼ alkyl group, R2 ¼ Ph or alkyl group, Table 3) and slightly lower than the proportions of the (Z)-isomers present in
obtained as mixtures of (E)- and (Z)-isomers in varying ratios, the starting materials. However, as the conversions of the (Z)-
except for 1t which was obtained only as the (Z)-isomer; the starting materials could not always be quantitative, it could be
results are summarized in Table 3.
implicated that the (E)-isomers could isomerize and cyclize,
With R1 ¼ Et, O-methyl oxime 1n ((E) : (Z) ¼ 34 : 66) was thus contributing to the overall yields of products. Moreover,
transformed to isoxazole 2n-Cl in 68% yield. For substrates with the isomerization-cyclization process of the (E)-isomers could
longer 1ꢀ alkyl groups, R1 ¼ n-C5H11 (1o; (E) : (Z) ¼ 20 : 80) and be supported by the yields of products 2n-Cl, 2q-Cl, 2n-Br, 2o-Br,
R1 ¼ n-C11H23 (1p; (E) : (Z) ¼ 34 : 66), the reactions led to the 2q-Br, 2s-Br and 2m-I (from (E/Z)-1m) as they were greater than
corresponding products 2o-Cl and 2p in 76% and 58% yields, or equal to the proportions of the (Z)-isomers present in the
respectively. These results showed that longer R1 alkyl chains starting materials. The strongest cases to support such isom-
could tolerate the reaction conditions well to provide the erization process were demonstrated in the reactions of pure
products in moderate to good yields. We then looked at R1 ¼ 2ꢀ (E)-1m which gave isoxazoles 2m-Cl, 2m-Br and 2m-I in 29%,
alkyl groups, substrates 1q (R1 ¼ i-Pr; (E) : (Z) ¼ 28 : 72), 1r (R1 ¼ 22% and 89% yields, respectively (Table 3).
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(Z)-1,3-Diphenylprop-2-yn-1-one O-methyl oxime (1a).5b Yield
Conclusions
340.3 mg (53%, white solid); mp 44.9–45.1 ꢀC; IR (neat): nmax
1
We have developed the rst method for the direct conversion of 3058, 2936, 2820, 2213, 1444, 1337, 1048 cmꢁ1; H NMR (300
alkynyl-O-methyl oximes to 4-chloroisoxazoles via chlorinative MHz, CDCl3) d 8.00–7.97 (m, 2H), 7.68–7.65 (m, 2H), 7.47–7.39
cyclization. This is also the rst method which could be (m, 6H), 4.19 (s, 3H); 13C NMR (75 MHz, CDCl3) d 139.8, 133.5,
employed for both (E)- and (Z)-alkynyl-O-methyl oximes. This is 132.1, 129.6, 129.5, 128.38, 128.36, 126.4, 121.7, 101.1, 79.4,
due to the fact that the unreactive (E)-isomers can be isomerized 63.0; HRMS (ESI) calcd for C16H14NO (M + H)+ 236.1070, found
and cyclized under the reaction conditions. The current method 236.1060.
therefore constitutes a protocol having higher efficiency than
(E)-3-Phenyl-1-(o-tolyl)prop-2-yn-1-one
O-methyl
oxime
the previous methods, and can be employed for mixtures of (1b).5b Yield 17.5 mg (14%, yellow oil); IR (neat): nmax 3749, 3058,
both (E/Z)-alkynyl-O-methyl oximes. The protocol conveniently 2934, 2818, 1689, 1046, 758 cmꢁ1; H NMR (300 MHz, CDCl3)
1
employs the combination of TMSCl and NCS in nitromethane at d 7.48–7.45 (m, 3H), 7.31–7.15 (m, 6H), 4.05 (s, 3H), 2.47 (s, 3H);
room temperature, which produces Cl2 and HCl in situ to 13C NMR (75 MHz, CDCl3) d 140.8, 136.8, 133.4, 132.1, 131.0,
promote the cyclization to furnish 4-chloroisoxazole products in 129.5, 129.4, 129.1, 128.4, 125.9, 121.8, 101.2, 80.7, 63.0, 20.8;
moderate to excellent yields. This method is effectively appli- HRMS (ESI) calcd for C17H16NO (M + H)+ 250.1226, found
cable to a broad range of substrates and is also appropriate for 250.1235.
the preparation of 4-bromo- and 4-iodoisoxazole derivatives
simply by using NBS and NIS instead of NCS.
(Z)-1-([1,10-Biphenyl]-4-yl)-3-phenylprop-2-yn-1-one O-methyl
oxime (1c). Yield 105.5 mg (40%, white solid); mp 111.7–112.1
ꢀC; IR (neat): nmax 3364, 2923, 2852, 2349, 2216, 1047 cmꢁ1; 1H
NMR (300 MHz, CDCl3) d 8.00–7.97 (m, 2H), 7.66–7.62 (m, 6H),
7.48–7.37 (m, 6H), 4.16 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 142.4, 140.4, 139.6, 132.5, 132.1, 129.5, 128.8, 128.4, 127.6,
127.1, 127.0, 126.9, 121.7, 101.2, 79.4, 63.1; HRMS (ESI) calcd for
Experimental
General procedure
C
22H18NO (M + H)+ 312.1383, found 312.1374.
Commercial grade chemicals were used without further puri-
cation, unless otherwise specied. All solvents were used as
received. Oven-dried glassware (110 ꢀC at least for 2 h) was used
for all reactions. Crude reaction mixtures were concentrated
under reduced pressure on a rotary evaporator. Column chro-
matography was performed using silica gel 60 (particle size
0.06–0.2 mm; 70–230 mesh ASTM). Analytical thin-layer chro-
matography (TLC) was performed with silica gel 60 F254
aluminum sheets. Nuclear magnetic resonance (NMR) spectra
were recorded in deuterochloroform (CDCl3) or dimethyl sulf-
oxide-d6 (DMSO-d6) with 300 and 600 MHz spectrometers.
Chemical shis for 1H NMR and 13C NMR spectra are reported
in parts per million (ppm, d), relative to tetramethylsilane (TMS)
as the internal reference. Coupling constants (J) are reported in
hertz (Hz). Infrared spectra were measured using an FT-IR
spectrometer and are reported in cmꢁ1. High-resolution mass
spectra (HRMS) were obtained using a time-of-ight (TOF)
instrument.
(E)-1-([1,10-Biphenyl]-2-yl)-3-phenylprop-2-yn-1-one O-methyl
oxime (1d). Yield 100.2 mg (28%, colorless oil); IR (neat): nmax
3059, 2935, 2210, 1951, 1443, 1044, 748 cmꢁ1 1H NMR (300
;
MHz, CDCl3) d 7.58–7.55 (m, 1H), 7.42–7.28 (m, 7H), 7.24–7.10
(m, 4H), 7.06–7.03 (m, 2H), 3.97 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 141.5, 141.3, 140.9, 133.0, 131.9, 130.6, 129.7, 129.5,
129.4, 129.1, 128.2, 128.0, 127.4, 127.1, 121.6, 101.5, 80.5, 62.9;
HRMS (ESI) calcd for C22H18NO (M + H)+ 312.1383, found
312.1384.
(Z)-1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-one O-methyl
oxime (1e).12 Yield 279.1 mg (63%, white solid); mp 63.2–63.4
ꢀC; IR (neat): nmax 2935, 2899, 2838, 2213, 1944, 1606, 1047
cmꢁ1; 1H NMR (300 MHz, CDCl3) d 7.90–7.85 (m, 2H), 7.64–7.61
(m, 2H), 7.42–7.35 (m, 3H), 6.96–6.91 (m, 2H), 4.13 (s, 3H), 3.84
(s, 3H); 13C NMR (75 MHz, CDCl3) d 160.9, 139.5, 132.1, 129.4,
128.4, 127.9, 126.2, 121.8, 113.8, 100.8, 79.5, 62.9, 55.3; HRMS
(ESI) calcd for C17H16NO2 (M + H)+ 266.1176, found 266.1179.
(Z)-1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-one
O-methyl
oxime (1f).4a Yield 72.8 mg (26%, yellow oil); IR (neat): nmax 2937,
2901, 2214, 1602, 1046 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 7.92–
7.87 (m, 2H), 7.62–7.59 (m, 2H), 7.39–7.33 (m, 3H), 7.10–7.05
General procedure for the preparation of (Z)-alkynyl-O-methyl
oximes 1a–u
(m, 2H), 4.12 (s, 3H); 13C NMR (75 MHz, CDCl3) d 163.7 (d, JC–F
¼
The solution of 1,3-diphenylprop-2-yn-1-one (561.2 mg, 2.72
mmol, 1.0 equiv.) in MeOH (12.0 mL, 4.5 mL mmolꢁ1) was
added sequentially with MeONH2$HCl (469.6 mg, 5.44 mmol,
2.0 equiv.), Na2SO4 (864.3 mg, 5.44 mmol, 2.0 equiv.), and
pyridine (1.2 mL, 14.9 mmol, 5.5 equiv.). The resulting reaction
mixture was stirred overnight and quenched by addition of
water. The mixture was then extracted with EtOAc, and the
combined organic layers were washed with brine, dried over
anhydrous MgSO4 and concentrated on a rotary evaporator. The
crude product was puried by SiO2 column chromatography
(2% EtOAc–hexane) to afford (Z)-1,3-diphenylprop-2-yn-1-one O-
methyl oxime (1a) (340.3 mg, 53%).
248 Hz), 138.8, 132.1, 129.7 (d, JC–F ¼ 3 Hz), 129.6, 128.4 (d, JC–F
¼ 5 Hz), 128.3, 121.6, 115.4 (d, JC–F ¼ 22 Hz), 101.3, 79.2, 63.1;
HRMS (ESI) calcd for C16H13FNO (M + H)+ 254.0976, found
254.0973.
(Z)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-one
O-methyl
oxime (1g).5b Yield 80.1 mg (30%, colorless oil); IR (neat): nmax
2935, 2891, 2213, 1489, 1050 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.85 (d, J ¼ 8.7 Hz, 2H), 7.62–7.59 (m, 2H), 7.42–7.35 (m, 5H),
4.13 (s, 3H); 13C NMR (75 MHz, CDCl3) d 138.9, 135.7, 132.2,
132.1, 129.7, 128.6, 128.5, 127.7, 121.6, 101.5, 79.0, 63.2; HRMS
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(ESI) calcd for C16H13ClNO (M + H)+ (Cl-35) 270.0680, found 62.4, 16.6; HRMS (ESI) calcd for C11H12NO (M + H)+ 174.0913,
270.0668.
(Z)-1-(3-Chlorophenyl)-3-phenylprop-2-yn-1-one
found 174.0917.
O-methyl
1-Phenylpent-1-yn-3-one O-methyl oxime (1n). Yield 126.2
oxime (1h). Yield 59.1 mg (28%, colorless oil); IR (neat): nmax mg (73%, (E) : (Z) ¼ 34 : 66, colorless oil); IR (neat): nmax 3559,
1
3063, 2937, 2818, 2217, 1594, 1328, 1043, 821, 756 cmꢁ1 1H 3058, 2927, 2851, 2370, 1947, 1725, 1265, 1095 cmꢁ1; H NMR
;
NMR (300 MHz, CDCl3) d 7.93 (s, 1H), 7.81 (dd, J ¼ 7.2, 1.8 Hz, (600 MHz, CDCl3) d 7.54–7.51 (m, 2H), 7.39–7.32 (m, 3H), 3.98
1H), 7.65–7.62 (m, 2H), 7.44–7.31 (m, 5H), 4.16 (s, 3H); 13C NMR (s, 3H), 2.52 (q, J ¼ 7.8 Hz, 1.02H, minor), 2.44 (q, J ¼ 7.8 Hz,
1
(75 MHz, CDCl3) d 138.6, 135.3, 134.4, 132.1, 129.7, 129.60, 2H), 1.25–1.20 (m, 3H); H NMR (300 MHz, CDCl3) d 7.57–7.52
129.58, 128.4, 126.3, 124.7, 121.5, 101.6, 78.9, 63.3; HRMS (ESI) (m, 2H), 7.43–7.33 (m, 3H), 3.99 (s, 3H), 2.53 (q, J ¼ 7.5 Hz,
calcd for C16H13ClNO (M + H)+ (Cl-35) 270.0680, found 1.02H, minor), 2.45 (q, J ¼ 7.8 Hz, 2H), 1.28–1.20 (m, 3H); 13C
270.0683.
NMR (75 MHz, CDCl3) d 148.0, 142.7, 131.9, 131.8, 129.2, 128.8,
(Z)-1-(4-Bromophenyl)-3-phenylprop-2-yn-1-one
O-methyl 128.2, 121.9, 121.6, 99.5, 91.3, 84.0, 80.0, 62.3, 62.1, 27.8, 22.5,
oxime (1i). Yield 97.0 mg (24%, colorless oil); IR (neat): nmax 11.6, 10.3; HRMS (ESI) calcd for C12H13NNaO (M + Na)+
2925, 2853, 2370, 2213, 1053 cmꢁ1; 1H NMR (300 MHz, CDCl3) 210.0889, found 210.0879.
d 7.83–7.79 (m, 2H), 7.64–7.52 (m, 4H), 7.45–7.36 (m, 3H), 4.15
(Z)-1-Phenyloct-1-yn-3-one O-methyl oxime (1o). Yield 145.4
(s, 3H); 13C NMR (75 MHz, CDCl3) d 138.9, 132.5, 132.1, 131.5, mg (97%, (E) : (Z) ¼ 20 : 80, yellow oil); IR (neat): nmax 3902,
129.6, 128.4, 127.9, 123.9, 121.5, 101.5, 78.9, 63.2; HRMS (ESI) 3750, 2957, 2930, 2858, 1048 cmꢁ1; 1H NMR (300 MHz, CDCl3)
calcd for C16H13BrNO (M + H)+ (Br-79) 314.0175, found d 7.55–7.48 (m, 2H), 7.38–7.31 (m, 3H), 3.972 (s, 3H), 3.965 (s,
314.0170.
0.74H, minor), 2.49 (t, J ¼ 7.5 Hz, 0.49H, minor), 2.40 (t, J ¼ 7.5
(Z)-3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one O-methyl Hz, 2H), 1.73–1.63 (m, 2H), 1.39–1.33 (m, 4H), 0.93–0.89 (m,
oxime (1j).5b Yield 82.0 mg (52%, colorless oil); IR (neat): nmax 3H); 13C NMR (75 MHz, CDCl3) d 147.1, 141.9, 132.0, 131.8,
3058, 2962, 2935, 2837, 2208, 1604, 1249, 1042 cmꢁ1; H NMR 129.2, 128.9, 128.3, 122.0, 121.7, 99.4, 90.9, 84.5, 80.3, 62.3, 62.1,
1
(300 MHz, CDCl3) d 7.94–7.91 (m, 2H), 7.60–7.55 (m, 2H), 7.43– 34.2, 31.4, 31.0, 29.1, 26.7, 25.5, 22.3, 13.9; HRMS (ESI) calcd for
7.38 (m, 3H), 6.93–6.88 (m, 2H), 4.15 (s, 3H), 3.84 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 160.6, 140.1, 133.8, 133.7, 129.6, 128.3,
C
15H20NO (M + H)+ 230.1539, found 230.1549.
1-Phenyltetradec-1-yn-3-one O-methyl oxime (1p). Yield
126.5, 114.1, 113.7, 101.6, 78.6, 63.0, 55.3; HRMS (ESI) calcd for 206.1 mg (65%, (E) : (Z) ¼ 34 : 66, dark brown oil); IR (neat): nmax
C
17H15NNaO2 (M + Na)+ 288.0995, found 288.0996.
2925, 2854, 2208, 1464, 1047, 755 cmꢁ1
;
1H NMR (300 MHz,
(Z)-3-(4-Fluorophenyl)-1-phenylprop-2-yn-1-one
O-methyl CDCl3) d 7.54–7.48 (m, 2H), 7.38–7.30 (m, 3H), 3.96 (s, 3H), 2.49
oxime (1k). Yield 133.4 mg (54%, colorless oil); IR (neat): nmax (t, J ¼ 7.5 Hz, 1.04H, minor), 2.39 (t, J ¼ 7.5 Hz, 2H), 1.72–1.60
3449, 2938, 2213, 1506, 1234, 1048, 836, 692 cmꢁ1; 1H NMR (300 (m, 2H), 1.33–1.26 (m, 16H), 0.88 (t, J ¼ 6.3 Hz, 3H); 13C NMR (75
MHz, CDCl3) d 7.96–7.93 (m, 2H), 7.66–7.59 (m, 2H), 7.45–7.40 MHz, CDCl3) d 147.2, 142.0, 132.1, 131.9, 129.3, 128.9, 128.3,
(m, 3H), 7.13–7.05 (m, 2H), 4.17 (s, 3H); 13C NMR (75 MHz, 122.1, 121.8, 99.5, 91.0, 84.5, 80.3, 62.3, 62.2, 34.3, 31.9, 29.6,
CDCl3) d 163.2 (d, JC–F ¼ 250 Hz), 139.7, 134.1 (d, JC–F ¼ 9 Hz), 29.5, 29.30, 29.27, 28.9, 27.0, 25.9, 22.6, 14.1; HRMS (ESI) calcd
133.4, 129.7, 128.4, 126.4, 117.8 (d, JC–F ¼ 4 Hz), 115.8 (d, JC–F
¼
for C21H32NO (M + H)+ 314.2478, found 314.2487.
4-Methyl-1-phenylpent-1-yn-3-one O-methyl oxime (1q).
Yield 502.0 mg (92%, (E) : (Z) ¼ 28 : 72, light yellow oil); IR
22 Hz), 100.0, 79.2, 63.0; HRMS (ESI) calcd for C16H13NOF (M +
H)+ 254.0976, found 254.0975.
1
(Z)-3-(4-Chlorophenyl)-1-phenylprop-2-yn-1-one
O-methyl (neat): nmax 2968, 2936, 2213, 1444, 1034, 755 cmꢁ1; H NMR
oxime (1l).13 Yield 63.2 mg (34%, colorless oil); IR (neat): nmax (300 MHz, CDCl3) d 7.55–7.50 (m, 2H), 7.40–7.30 (m, 3H), 3.96
1
3455, 2071, 1638, 1335, 828 cmꢁ1; H NMR (300 MHz, CDCl3) (s, 3H), 3.40 (sept, J ¼ 6.9 Hz, 0.38H, minor), 2.73 (sept, J ¼ 6.9
d 7.93–7.91 (m, 2H), 7.57–7.54 (m, 2H), 7.43–7.36 (m, 5H), 4.16 Hz, 1H), 1.23 (d, J ¼ 6.9 Hz, 6H), 1.16 (d, J ¼ 6.9 Hz, 2.28H,
(s, 3H); 13C NMR (75 MHz, CDCl3) d 139.6, 135.7, 133.3, 129.7, minor); 13C NMR (75 MHz, CDCl3) d 152.4, 146.8, 132.0, 131.8,
128.8, 128.4, 126.4, 120.2, 99.8, 80.3, 63.1; HRMS (ESI) calcd for 129.2, 128.8, 128.2, 122.0, 121.8, 100.1, 92.0, 82.4, 78.8, 62.2,
C
16H13ClNO (M + H)+ (Cl-35) 270.0680, found 270.0686.
62.0, 33.3, 26.8, 20.4, 19.4; HRMS (ESI) calcd for C13H16NO (M +
4-Phenylbut-3-yn-2-one O-methyl oxime (1m).5b Yield 157.4 H)+ 202.1226, found 202.1229.
mg (69%, (E) : (Z) ¼ 41 : 59, colorless oil); IR (neat): nmax 3580,
4-Methyl-1-phenylhex-1-yn-3-one O-methyl oxime (1r). Yield
1
2925, 2855, 2309, 1731, 1462, 1262 cmꢁ1; H NMR (300 MHz, 194.5 mg (89%, (E) : (Z) ¼ 20 : 80, yellow oil); IR (neat): nmax
CDCl3) d 7.54–7.49 (m, 2H), 7.40–7.29 (m, 3H), 3.98 (s, 2.11H, 3525, 2965, 2934, 2876, 2210, 1457, 1041, 755, 689 cmꢁ1 1H
;
minor), 3.97 (s, 3H), 2.13 (s, 3H), 2.09 (s, 2.11H, minor); 13C NMR (300 MHz, CDCl3) d 7.55–7.49 (m, 2H), 7.40–7.31 (m, 3H),
NMR (75 MHz, CDCl3) d 142.1 (minor), 137.2, 131.9, 131.7 3.97 (s, 3H), 3.95 (s, 0.75H, minor), 3.24 (sex, J ¼ 6.6 Hz, 0.25H,
(minor), 129.2, 128.8 (minor), 128.2, 121.8 (minor), 121.5, 98.9, minor), 2.48 (sex, J ¼ 6.9 Hz, 1H), 1.77–1.41 (m, 2H), 1.21 (d, J ¼
90.0 (minor), 85.4 (minor), 80.9, 62.2 (minor), 62.0, 20.4, 16.4 6.6 Hz, 3H), 1.14 (d, J ¼ 6.9 Hz, 0.75H, minor), 0.94 (t, J ¼ 7.5 Hz,
(minor); HRMS (ESI) calcd for C11H12NO (M + H)+ 174.0913, 3H); 13C NMR (75 MHz, CDCl3) d 151.8, 146.2, 132.1, 131.9,
found 174.0917.
129.2, 128.8, 128.3, 122.1, 121.8, 100.0, 91.6, 82.6, 78.8, 62.2,
(E)-4-Phenylbut-3-yn-2-one O-methyl oxime (1m).5b Yield 81.9 62.1, 40.2, 33.7, 27.6, 27.2, 18.4, 17.4, 11.8, 11.7; HRMS (ESI)
mg (22%, colorless oil); H NMR (300 MHz, CDCl3) d 7.52–7.49 calcd for C14H18NO (M + H)+ 216.1383, found 216.1390.
1
(m, 2H), 7.34–7.29 (m, 3H), 3.98 (s, 3H), 2.08 (s, 3H); 13C NMR
1-Cyclohexyl-3-phenylprop-2-yn-1-one O-methyl oxime (1s).
(75 MHz, CDCl3) d 142.3, 131.9, 129.0, 128.3, 121.9, 90.1, 85.4, Yield 427.2 mg (87%, (E) : (Z) ¼ 20 : 80, yellow oil); IR (neat):
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nmax 2929, 2854, 2817, 2217, 1574, 1444, 1044, 754, 689 cmꢁ1; 1H 2853, 1492, 1459, 1448, 1397, 1127, 767, 706, 690 cmꢁ1; 1H NMR
NMR (300 MHz, CDCl3) d 7.55–7.50 (m, 2H), 7.38–7.31 (m, 3H), (300 MHz, DMSO-d6) d 8.02–7.99 (m, 2H), 7.86–7.80 (m, 2H),
3.964 (s, 3H), 3.956 (s, 0.73H), 3.10 (tt, J ¼ 11.7, 3.0 Hz, 0.24H, 7.65–7.57 (m, 6H); 13C NMR (75 MHz, DMSO-d6) d 163.8, 160.4,
minor), 2.41 (tt, J ¼ 11.7, 3.3 Hz, 1H), 1.90–1.15 (m, 10H); 13C 131.2, 130.7, 129.4, 129.1, 128.1, 126.6, 126.4, 125.5, 104.2;
NMR (75 MHz, CDCl3) d 151.5, 146.2, 132.0, 131.8, 129.2, 128.8, HRMS (ESI) calcd for C15H11ClNO (M + H)+ (Cl-35) 256.0524,
128.2, 122.1, 121.8, 100.0, 91.7, 83.2, 79.4, 62.3, 62.1, 42.9, 36.8, found 256.0517.
30.6, 29.4, 25.8, 25.7, 25.6; HRMS (ESI) calcd for C16H20NO (M +
H)+ 242.1539, found 242.1543.
4-Bromo-3,5-diphenylisoxazole (2a-Br).5b Yield 88.9 mg (80%,
yellow solid); mp 126.1–126.5 ꢀC; IR (neat): nmax 3449, 3053,
(Z)-4,4-Dimethyl-1-phenylpent-1-yn-3-one O-methyl oxime 1613, 1447, 1115, 692 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 8.12–
(1t).5a Yield 379.2 mg (90%, dark brown oil); IR (neat): nmax 2968, 8.08 (m, 2H), 7.89–7.86 (m, 2H), 7.54–7.52 (m, 6H); 13C NMR (75
2931, 2818, 2215, 1363, 1051, 755, 690 cmꢁ1; 1H NMR (300 MHz, MHz, CDCl3) d 165.8, 162.1, 130.7, 130.2, 128.8, 128.63, 128.58,
CDCl3) d 7.55–7.52 (m, 2H), 7.40–7.31 (m, 3H), 3.97 (s, 3H), 1.26 127.8, 127.0, 126.8, 89.5; HRMS (ESI) calcd for C15H11NOBr (M +
(s, 9H); 13C NMR (75 MHz, CDCl3) d 149.1, 132.0, 129.1, 128.3, H)+ (Br-79) 300.0019, found 300.0010.
122.0, 100.3, 79.3, 62.2, 36.9, 28.2; HRMS (ESI) calcd for
14H18NO (M + H)+ 216.1383, found 216.1389.
4-Iodo-3,5-diphenylisoxazole (2a-I).5b Yield 103.8 mg (85%,
white solid); mp 161.4–161.6 ꢀC; IR (neat): nmax 3457, 2069,
C
Dodec-7-yn-6-one O-methyl oxime (1u). Yield 281.9 mg (80%, 1638, 1446, 765 cmꢁ1; 1H NMR (300 MHz, DMSO-d6) d 8.04–8.00
(E) : (Z) ¼ 32 : 68, colorless oil); IR (neat): nmax 2957, 2928, 2856, (m, 2H), 7.76–7.72 (m, 2H), 7.66–7.57 (m, 6H); 13C NMR (75
2349, 1821, 1739, 1457, 1053, 799 cmꢁ1 1H NMR (600 MHz, MHz, DMSO-d6) d 168.6, 164.8, 131.0, 130.3, 129.2, 128.84,
;
CDCl3) d 3.91 (s, 3H), 3.89 (s, 1.42H, minor), 2.43 (t, J ¼ 7.2 Hz, 128.80, 128.5, 127.6, 126.9, 59.5; HRMS (ESI) calcd for
2H), 2.38–2.34 (m, 1.95H, minor), 2.27 (t, J ¼ 7.2 Hz, 2H), 1.62–
1.52 (m, 4H), 1.48–1.42 (m, 2H), 1.36–1.28 (m, 4H), 0.94–0.89
C
15H11INO (M + H)+ (I-127) 347.9880, found 347.9877.
4-Chloro-5-phenyl-3-(o-tolyl)isoxazole (2b). Yield 64.9 mg
(m, 6H); 1H NMR (300 MHz, CDCl3) d 3.91 (s, 3H), 3.89 (s, 1.42H, (83%, colorless oil); IR (neat): nmax 3611, 3063, 2925, 2854, 1448,
minor), 2.44 (t, J ¼ 6.9 Hz, 2H), 2.39–2.33 (m, 1.95H, minor), 1389, 767, 689 cmꢁ1; 1H NMR (300 MHz, DMSO-d6) d 8.04–8.01
2.24 (t, J ¼ 7.8 Hz, 2H), 1.62–1.26 (m, 10H), 0.95–0.87 (m, 6H); (m, 2H), 7.65–7.57 (m, 3H), 7.50–7.34 (m, 4H), 2.28 (s, 3H); 13C
13C NMR (75 MHz, CDCl3) d 147.2, 142.2, 102.0, 92.6, 75.9, 72.3, NMR (75 MHz, DMSO-d6) d 162.9, 162.0, 137.1, 131.2, 130.6,
61.8, 34.3, 31.3, 30.9, 30.2, 29.0, 26.5, 25.4, 22.2, 21.81, 21.77, 130.4, 129.9, 129.4, 126.2, 126.1, 125.9, 125.6, 105.4, 19.4; HRMS
19.1, 18.8, 13.7, 13.3; HRMS (ESI) calcd for C13H24NO (M + H)+ (ESI) calcd for C16H13ClNO (M + H)+ (Cl-35) 270.0680, found
210.1852, found 210.1857.
270.0690.
3-([1,10-Biphenyl]-4-yl)-4-chloro-5-phenylisoxazole (2c). Yield
ꢀ
47.8 mg (69%, white solid); mp 136.3–136.7 C; IR (neat): nmax
General procedure for the synthesis of 4-haloisoxazoles 2a–l
3453, 3058, 2921, 2851, 2126, 1420, 768, 730 cmꢁ1; 1H NMR (300
MHz, CDCl3) d 8.01–7.98 (m, 2H), 7.93–7.90 (m, 2H), 7.69–7.64
(m, 2H), 7.59–7.55 (m, 2H), 7.49–7.37 (m, 5H), 7.31 (tt, J ¼ 7.2,
1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 164.2, 160.4, 143.1,
140.2, 130.6, 128.9, 128.6, 127.8, 127.4, 127.2, 126.6, 126.5,
126.3, 104.6; HRMS (ESI) calcd for C21H15ClNO (M + H)+ (Cl-35)
332.0837, found 332.0842.
(Table 2) and 2t (Table 3)
To the solution of (Z)-alkynyl-O-methyl oxime 1a (71.1 mg, 0.30
mmol, 1.0 equiv.) in nitromethane (3.0 mL, 10.0 mL mmolꢁ1
)
was added with NCS (45.8 mg, 0.33 mmol, 1.1 equiv.), followed
by TMSCl (38.4 mL, 0.30 mmol, 1.0 equiv.). The reaction was
monitored by TLC until completion. It was then diluted with
water and extracted with EtOAc, dried over anhydrous MgSO4
and concentrated on a rotary evaporator. The crude product was
puried by SiO2 column chromatography (10% EtOAc–hexane)
to afford 4-chloro-3,5-diphenylisoxazole (2a-Cl) (76.5 mg,
$99%).
3-([1,10-Biphenyl]-2-yl)-4-chloro-5-phenylisoxazole (2d). Yield
63.0 mg (59% as a colorless oil). IR (neat): nmax 3060, 3027, 1591,
1447, 1391, 1129, 766, 742 cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d 7.95–7.92 (m, 2H), 7.63–7.43 (m, 7H), 7.34–7.24 (m, 5H); 13C
NMR (75 MHz, CDCl3) d 163.2, 162.8, 142.2, 140.1, 130.9, 130.42,
130.36, 129.2, 128.8, 128.1, 127.3, 126.4, 126.2, 125.5, 106.2;
HRMS (ESI) calcd for C21H15ClNO (M + H)+ (Cl-35) 332.0837,
found 332.0833.
General procedure for the synthesis of 4-haloisoxazoles 2m–u
(Table 3, except 2t)
To the solution of alkynyl-O-methyl oxime 1m ((E) : (Z) ¼
(9Z)-10-(Chloro(phenyl)methylene)phenanthren-9(10H)-one
41 : 59) (62.3 mg, 0.36 mmol, 1.0 equiv.) in nitromethane (3.6 O-methyl oxime (3d). Yield 27.6 mg (25%, yellow solid); mp
mL, 10.0 mL mmolꢁ1) was added with NCS (52.8 mg, 0.40 159.7–161.2 ꢀC; IR (neat): nmax 3059, 2935, 2819, 1935, 1599,
mmol, 1.1 equiv.), followed by TMSCl (91.0 mL, 0.72 mmol, 2.0 1442, 1051, 767, 736, 700 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
equiv.). The reaction was monitored by TLC until completion. It d 7.68 (d, J ¼ 7.5 Hz, 1H), 7.59–7.40 (m, 4H), 7.33–7.11 (m, 7H),
was then diluted with water and extracted with EtOAc, dried 6.96 (d, J ¼ 8.1 Hz, 1H), 3.96 (s, 3H); 13C NMR (75 MHz, CDCl3)
over anhydrous MgSO4 and concentrated on a rotary evaporator. d 152.0, 139.5, 139.1, 137.9, 137.8, 137.6, 136.3, 131.3, 130.7,
The crude product was puried by SiO2 column chromatog- 130.3, 130.1, 129.5, 129.2, 128.2, 128.1, 127.9, 127.7, 127.0,
raphy (2% EtOAc–hexane) to afford 4-chloro-3-methyl-5- 126.9, 121.0, 62.9; HRMS (ESI) calcd for C22H17ClNO (M + H)+
phenylisoxazole (2m) (39.1 mg, 56%).
(Cl-35) 346.0993, found 346.0986.
4-Chloro-3,5-diphenylisoxazole (2a-Cl).6a Yield 76.5 mg
4-Chloro-3-(4-uorophenyl)-5-phenylisoxazole (2f). Yield
($99%, white solid); mp 65.7–65.9 ꢀC; IR (neat): nmax 3055, 2923, 69.3 mg (88%, white solid); mp 89.9–90.4 ꢀC; IR (neat): nmax
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1
3053, 1902, 1607, 1127, 840 cmꢁ1; H NMR (300 MHz, CDCl3) 3610, 2930, 2152, 1699, 1409, 767, 688 cmꢁ1; 1H NMR (300 MHz,
d 8.07–8.04 (m, 2H), 7.93–7.88 (m, 2H), 7.56–7.51 (m, 3H), 7.26– CDCl3) d 8.00–7.96 (m, 2H), 7.51–7.45 (m, 3H), 2.33 (s, 3H); 13
C
7.18 (m, 2H); 13C NMR (75 MHz, CDCl3) d 164.0 (d, JC–F ¼ 249 NMR (75 MHz, CDCl3) d 162.4, 159.4, 130.3, 128.8, 126.5, 126.1,
Hz), 164.3, 159.9, 130.7, 130.3 (d, JC–F ¼ 8 Hz), 128.9, 126.6, 105.8, 9.8; HRMS (ESI) calcd for C10H9ClNO (M + H)+ (Cl-35)
126.4, 123.6 (d, JC–F ¼ 3 Hz), 115.9 (d, JC–F ¼ 22 Hz), 104.4; ESI- 194.0367, found 194.0363.
HRMS calcd for C15H10ClFNO (M + H)+ (Cl-35) 274.0430, found
274.0419.
4-Bromo-3-methyl-5-phenylisoxazole (2m-Br).15 Yield 12.0
mg (22%, yellow oil); 1H NMR (300 MHz, CDCl3) d 8.05–8.01 (m,
4-Chloro-3-(4-chlorophenyl)-5-phenylisoxazole (2g). Yield 2H), 7.52–7.47 (m, 3H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3)
103.2 mg (75%, white solid); mp 92.3–93.5 ꢀC; IR (neat): nmax d 164.2, 160.6, 130.4, 128.8, 127.9, 126.8, 126.6, 91.1, 10.8.
1
3357, 3063, 2924, 2854, 2349, 1603, 1419 cmꢁ1; H NMR (300
4-Iodo-3-methyl-5-phenylisoxazole (2m-I).5b Yield 50.7 mg
MHz, CDCl3) d 8.06–8.02 (m, 2H), 7.85 (d, J ¼ 8.4 Hz, 2H), 7.56– (89%, yellow oil); IR (neat): nmax 3058, 2936, 2820, 2213, 1444,
7.47 (m, 5H); 13C NMR (75 MHz, CDCl3) d 164.4, 159.7, 136.5, 1337, 1048 cmꢁ1; 1H NMR (300 MHz, DMSO-d6) d 7.99–7.96 (m,
130.7, 129.5, 129.0, 128.9, 126.5, 126.3, 125.8, 104.4; HRMS (ESI) 2H), 7.61–7.56 (m, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, DMSO-
calcd for C15H10Cl2NO (M + H)+ (Cl-35) 290.0134, found d6) d 166.7, 163.2, 130.8, 129.2, 127.0, 126.9, 60.9, 12.3; HRMS
290.0138.
(ESI) calcd for C10H9INO (M + H)+ (I-131) 285.9723, found
4-Chloro-3-(3-chlorophenyl)-5-phenylisoxazole (2h). Yield 285.9723.
83.4 mg (96%, white solid); mp 86.6–86.8 ꢀC; IR (neat): nmax
4-Chloro-3-ethyl-5-phenylisoxazole (2n-Cl). Yield 70.7 mg
3059, 2936, 2326, 1439, 1378, 775 cmꢁ1
;
1H NMR (300 MHz, (68%, colorless oil); IR (neat): nmax 3062, 2979, 2939, 1713, 1594,
CDCl3) d 8.07–8.04 (m, 2H), 7.92–7.91 (m, 1H), 7.82–7.79 (m, 1448, 1072, 940, 767 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.01–
1H), 7.57–7.42 (m, 5H); 13C NMR (75 MHz, CDCl3) d 164.4, 159.5, 7.98 (m, 2H), 7.54–7.47 (m, 3H), 2.76 (q, J ¼ 7.8 Hz, 2H), 1.36 (t, J
134.7, 130.7, 130.3, 130.0, 129.0, 128.9, 128.2, 126.5, 126.3, ¼ 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 163.8, 162.6, 130.3,
126.2, 104.4; HRMS (ESI) calcd for C15H10Cl2NO (M + H)+ (Cl-35) 128.8, 126.6, 126.3, 105.2, 18.4, 11.4; HRMS (ESI) calcd for
1
290.0134, found 290.0126.
C
11H11ClNO (M + H)+ (Cl-35) 208.0524, found 208.0515.
3-(4-Bromophenyl)-4-chloro-5-phenylisoxazole (2i). Yield
4-Bromo-3-ethyl-5-phenylisoxazole (2n-Br). Yield 74.1 mg
ꢀ
23.4 mg (70%, white solid); mp 109.0–109.3 C; IR (neat): nmax (74%, colorless oil); IR (neat): nmax 3063, 2978, 2939, 1573, 1412,
3504, 2127, 1985, 1924, 1640, 830 cmꢁ1 1H NMR (300 MHz, 1063, 689 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 8.04–8.01 (m, 2H),
;
CDCl3) d 8.07–8.04 (m, 2H), 7.81–7.78 (m, 2H), 7.66 (d, J ¼ 8.4 7.54–7.48 (m, 3H), 2.75 (q, J ¼ 7.5 Hz, 2H), 1.36 (t, J ¼ 7.5 Hz,
Hz, 2H), 7.57–7.50 (m, 3H); 13C NMR (75 MHz, CDCl3) d 164.4, 3H); 13C NMR (75 MHz, CDCl3) d 164.8, 164.3, 130.4, 128.8,
159.8, 132.0, 130.7, 129.7, 128.9, 126.5, 126.30, 126.27, 124.9, 126.8, 126.7, 90.4, 19.2, 11.5; HRMS (ESI) calcd for C11H11BrNO
104.3; HRMS (ESI) calcd for C15H10BrClNO (M + H)+ (Cl-35) (Br- (M + H)+ (Br-79) 252.0019, found 252.0029.
79) 333.9629, found 333.9637.
4-Chloro-3-pentyl-5-phenylisoxazole (2o-Cl). Yield 64.1 mg
4-Chloro-5-(4-methoxyphenyl)-3-phenylisoxazole (2j). Yield (76%, yellow oil); IR (neat): nmax 2957, 2927, 2855, 2149, 1449
51.2 mg (72%, white solid); mp 97.5–97.8 ꢀC; IR (neat): nmax cmꢁ1; 1H NMR (300 MHz, CDCl3) d 8.01–7.97 (m, 2H), 7.52–7.42
3160, 3068, 2952, 2846, 1773, 1694, 1189, 833, 687 cmꢁ1
;
1H (m, 3H), 2.71 (t, J ¼ 7.5 Hz, 2H), 1.82–1.71 (m, 2H), 1.46–1.31 (m,
NMR (300 MHz, CDCl3) d 8.04–8.00 (m, 2H), 7.90–7.87 (m, 2H), 4H), 0.94–0.91 (m, 3H); 13C NMR (75 MHz, CDCl3) d 162.8, 162.5,
7.52–7.50 (m, 3H), 7.06–7.02 (m, 2H), 3.88 (s, 3H); 13C NMR (75 130.3, 128.8, 126.6, 126.2, 105.3, 31.3, 26.6, 24.6, 22.3, 13.9;
MHz, CDCl3) d 164.1, 161.3, 160.6, 130.2, 128.7, 128.21, 128.16, HRMS (ESI) calcd for C14H17ClNO (M + H)+ (Cl-35) 250.0993,
127.5, 119.2, 114.3, 103.1, 55.4; HRMS (ESI) calcd for found 250.1005.
C
16H13ClNO2 (M + H)+ (Cl-35) 286.0629, found 286.0627.
4-Chloro-5-(4-uorophenyl)-3-phenylisoxazole (2k). Yield (81%, colorless oil); IR (neat): nmax 3065, 2930, 2860, 1445, 1410,
4-Bromo-3-pentyl-5-phenylisoxazole (2o-Br). Yield 47.9 mg
50.3 mg (71%, white solid); mp 94.8–95.0 ꢀC; IR (neat): nmax 1060, 689 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 8.05–8.01 (m, 2H),
3451, 2134, 2030, 1638, 1239, 837 cmꢁ1
;
1H NMR (300 MHz, 7.53–7.48 (m, 3H), 2.71 (t, J ¼ 7.5 Hz, 2H), 1.82–1.72 (m, 2H),
CDCl3) d 8.09–8.04 (m, 2H), 7.90–7.87 (m, 2H), 7.53–7.51 (m, 1.46–1.33 (m, 4H), 0.95–0.90 (m, 3H); 13C NMR (75 MHz, CDCl3)
3H), 7.26–7.18 (m, 2H); 13C NMR (75 MHz, CDCl3) d 163.9 (d, JC– d 164.2, 163.8, 130.4, 128.8, 126.9, 126.7, 90.6, 31.4, 26.8, 25.4,
¼ 251 Hz), 163.3, 160.8, 130.4, 128.80, 128.78 (d, JC–F ¼ 9 Hz), 22.3, 13.9; HRMS (ESI) calcd for C14H17BrNO (M + H)+ (Br-79)
F
128.3, 127.3, 122.8 (d, JC–F ¼ 3 Hz), 116.2 (d, JC–F ¼ 22 Hz), 104.4; 294.0488, found 294.0499.
HRMS (ESI) calcd for C15H10ClFNO (M + H)+ (Cl-35) 274.0430,
found 274.0439.
4-Chloro-5-phenyl-3-undecylisoxazole (2p). Yield 48.6 mg
(58%, colorless oil); IR (neat): nmax 2924, 2854, 1594, 1449, 1072,
4-Chloro-5-(4-chlorophenyl)-3-phenylisoxazole (2l). Yield 766, 689 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 8.01–7.97 (m, 2H),
ꢀ
52.1 mg (95%, white solid); mp 105.9–106.1 C; IR (neat): nmax 7.52–7.45 (m, 3H), 2.71 (t, J ¼ 7.5 Hz, 2H), 1.81–1.71 (m, 2H),
3463, 3068, 2344, 2127, 1131, 834, 696 cmꢁ1; 1H NMR (300 MHz, 1.44–1.26 (m, 16H), 0.88 (t, J ¼ 6.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 7.94–7.90 (m, 2H), 7.82–7.77 (m, 2H), 7.46–7.39 (m, CDCl3) d 162.8, 162.5, 130.3, 128.8, 126.6, 126.3, 105.3, 31.9,
5H); 13C NMR (75 MHz, CDCl3) d 163.0, 160.8, 136.7, 130.3, 29.6, 29.5, 29.3, 29.21, 29.20, 27.0, 24.6, 22.7, 14.1; HRMS (ESI)
129.2, 128.8, 128.2, 127.7, 127.2, 124.9, 104.9; HRMS (ESI) calcd calcd for C20H29ClNO (M + H)+ (Cl-35) 334.1932, found
for C15H10Cl2NO (M + H)+ (Cl-35) 290.0134, found 290.0130.
334.1938.
4-Chloro-3-isopropyl-5-phenylisoxazole (2q-Cl). Yield 62.1
4-Chloro-3-methyl-5-phenylisoxazole (2m-Cl).14 Yield 39.1
mg (56%, white solid); mp 35.7–36.2 ꢀC; IR (neat): nmax 3749, mg (76%, colorless oil); IR (neat): nmax 3063, 2973, 2934, 1448,
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1131, 768, 690 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 7.99 (dd, J ¼ (m, 6H), 0.96–0.88 (m, 6H); 13C NMR (75 MHz, CDCl3) d 169.9,
7.8, 2.1 Hz, 2H), 7.53–7.44 (m, 3H), 3.13 (sept, J ¼ 7.2 Hz, 1H), 162.4, 91.5, 31.4, 28.9, 26.7, 25.5, 25.3, 22.3, 22.1, 13.9, 13.6;
1.40 (d, J ¼ 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 166.9, 162.8, HRMS (ESI) calcd for C12H21BrNO (M + H)+ (Br-79) 274.0801,
130.3, 128.8, 126.6, 126.4, 104.7, 26.0, 20.2; HRMS (ESI) calcd for found 274.0808.
C
12H13ClNO (M + H)+ (Cl-35) 222.0680, found 222.0685.
4-Bromo-3-isopropyl-5-phenylisoxazole (2q-Br). Yield 78.4 yellow oil); IR (neat): nmax 2957, 2931, 2862, 1587, 1465, 1047,
5-Butyl-4-iodo-3-pentylisoxazole (2u-I). Yield 49.3 mg (55%,
mg (89%, colorless oil); IR (neat): nmax 3062, 2972, 2931, 2878, 894, 763 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 2.77 (t, J ¼ 7.5 Hz,
1948, 1447, 1036, 767 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 8.04– 2H), 2.59 (t, J ¼ 7.5 Hz, 2H), 1.75–1.63 (m, 4H), 1.43–1.31 (m,
8.00 (m, 2H), 7.52–7.48 (m, 3H), 3.11 (sept, J ¼ 6.9 Hz, 1H), 1.41 6H), 0.96–0.89 (m, 6H); 13C NMR (75 MHz, CDCl3) d 173.3, 164.3,
(d, J ¼ 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 167.8, 164.4, 58.9, 31.3, 29.2, 27.0, 26.6, 26.5, 22.3, 22.1, 13.9, 13.6; HRMS
130.4, 128.7, 126.9, 126.8, 89.9, 26.6, 20.4; HRMS (ESI) calcd for (ESI) calcd for C12H21INO (M + H)+ (I-131) 322.0662, found
C
12H13BrNO (M + H)+ (Br-79) 266.0175, found 266.0179.
322.0655.
3-(sec-Butyl)-4-chloro-5-phenylisoxazole (2r). Yield 42.7 mg
(72%, colorless oil); IR (neat): nmax 3526, 2968, 2934, 2877, 2152,
Acknowledgements
1
1449, 1131, 768, 689 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.00
(dd, J ¼ 7.8, 2.1 Hz, 2H), 7.53–7.44 (m, 3H), 2.95 (sex, J ¼ 7.2 Hz, This research work was supported in part by grants from the
1H), 1.91 (sept, J ¼ 7.5 Hz, 1H), 1.71 (sept, J ¼ 7.2 Hz, 1H), 1.38 Chulabhorn Research Institute, Mahidol University, and the
(d, J ¼ 7.2 Hz, 3H), 0.97 (t, J ¼ 7.5 Hz, 3H); 13C NMR (75 MHz, Center of Excellence on Environmental Health and Toxicology,
CDCl3) d 166.0, 162.7, 130.3, 128.8, 126.7, 126.3, 104.9, 32.6, Science & Technology Postgraduate Education and Research
27.5, 17.9, 11.7; HRMS (ESI) calcd for C13H15ClNO (M + H)+ (Cl- Development Office (PERDO), Ministry of Education.
35) 236.0837, found 236.0845.
4-Chloro-3-cyclohexyl-5-phenylisoxazole (2s-Cl).14 Yield 50.6
mg (77%, white solid); mp 63.9–64.5 ꢀC; IR (neat): nmax 3065,
Notes and references
2930, 2854, 1960, 1448, 1129, 768, 689 cmꢁ1; 1H NMR (300 MHz,
CDCl3) d 7.98 (dd, J ¼ 7.8, 1.8 Hz, 2H), 7.51–7.42 (m, 3H), 2.80
(tt, J ¼ 11.7, 3.3 Hz, 1H), 2.06–2.02 (m, 2H), 1.90–1.85 (m, 2H),
1.78–1.58 (m, 3H), 1.48–1.25 (m, 3H); 13C NMR (75 MHz, CDCl3)
d 166.0, 162.5, 130.2, 128.7, 126.6, 126.3, 104.7, 35.3, 30.4, 26.1,
25.8; HRMS (ESI) calcd for C15H17ClNO (M + H)+ (Cl-35)
262.0993, found 262.0991.
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49, part 1, pp. 1–116; (c) P. Grınanger and P. Vita-Finzi, in
4-Bromo-3-cyclohexyl-5-phenylisoxazole (2s-Br). Yield 91.1
mg (78%, yellow oil); IR (neat): nmax 3064, 2929, 2853, 1447,
Chemistry of Heterocyclic Compounds, ed. E. C. Taylor and P.
Wipf, John Wiley & Sons, New York, 1999, vol. 49, part 2,
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1414, 1070, 768 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.03–7.99
(m, 2H), 7.51–7.46 (m, 3H), 2.77 (tt, J ¼ 11.7, 3.6 Hz, 1H), 2.07–
2.03 (m, 2H), 1.90–1.85 (m, 2H), 1.78–1.57 (m, 3H), 1.48–1.25
(m, 3H); 13C NMR (75 MHz, CDCl3) d 167.0, 164.1, 130.3, 128.7,
126.8, 126.7, 89.9, 35.9, 30.6, 26.1, 25.8; HRMS (ESI) calcd for
C
15H17BrNO (M + H)+ (Br-79) 306.0488, found 306.0498.
3-(tert-Butyl)-4-chloro-5-phenylisoxazole (2t). Yield 138.6 mg
2 (a) M. Z. Hernandes, S. M. T. Cavalcanti, D. R. M. Moreira,
W. Filgueira de Azevedo Jr and A. C. L. Leite, Curr. Drug
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(88%, colorless oil); IR (neat): nmax 3063, 2973, 2935, 2873, 1574,
1050, 768, 689 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 7.99–7.96 (m,
2H), 7.52–7.43 (m, 3H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 167.8, 163.7, 130.3, 128.7, 126.7, 126.5, 104.4, 33.2, 27.7;
HRMS (ESI) calcd for C13H15ClNO (M + H)+ (Cl-35) 236.0837,
found 236.0841.
5-Butyl-4-chloro-3-pentylisoxazole (2u-Cl). Yield 43.4 mg
(47%, colorless oil); IR (neat): nmax 2958, 2932, 2863, 2152, 1610,
1
1122, 1053, 891 cmꢁ1; H NMR (300 MHz, CDCl3) d 2.74 (t, J ¼
7.5 Hz, 2H), 2.63 (t, J ¼ 7.5 Hz, 2H), 1.73–1.66 (m, 4H), 1.43–1.30
(m, 6H), 0.96–0.88 (m, 6H); 13C NMR (75 MHz, CDCl3) d 168.0,
161.4, 105.9, 31.4, 28.8, 26.6, 24.9, 24.6, 22.3, 22.1, 13.9, 13.6;
HRMS (ESI) calcd for C12H21ClNO (M + H)+ (Cl-35) 230.1306,
found 230.1297.
¨
de Meijere, S. Brase and M. Oestreich, Wiley-VCH,
Weinheim, Germany, 2014; (d) New Trend in Cross-
Coupling: Theory and Applications, ed. T. J. Colacot, RSC
Catalysis Series 21, Royal Society of Chemistry, Cambridge,
UK, 2015.
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4-Bromo-5-butyl-3-pentylisoxazole (2u-Br). Yield 49.3 mg
(60%, colorless oil); IR (neat): nmax 2958, 2932, 2863, 1602, 1466,
1
1416, 1057, 890 cmꢁ1; H NMR (300 MHz, CDCl3) d 2.74 (t, J ¼
7.5 Hz, 2H), 2.62 (t, J ¼ 7.5 Hz, 2H), 1.75–1.63 (m, 4H), 1.43–1.31
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