Preparation of 3,5-disubstituted pyrazoles and isoxazoles from terminal alkynes, aldehydes, hydrazines, and hydroxylamine

Article abstract of DOI:10.1021/jo4027116

The reaction of terminal alkynes with n-BuLi, and then with aldehydes, followed by the treatment with molecular iodine, and subsequently hydrazines or hydroxylamine provided the corresponding 3,5-disubstituted pyrazoles or isoxazoles in good yields with high regioselectivity, through the formations of propargyl secondary alkoxides and α-alkynyl ketones. The present reactions are one-pot preparation of 3,5-disubstituted pyrazoles from terminal alkynes, aldehydes, molecular iodine, and hydrazines, and 3,5-disubstituted isoxazoles from terminal alkynes, aldehydes, molecular iodine, and hydroxylamine.

Full text of DOI:10.1021/jo4027116

Article
pubs.acs.org/joc
Preparation of 3,5-Disubstituted Pyrazoles and Isoxazoles from
Terminal Alkynes, Aldehydes, Hydrazines, and Hydroxylamine
Ryo Harigae, Katsuhiko Moriyama, and Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: The reaction of terminal alkynes with n-BuLi,
and then with aldehydes, followed by the treatment with
molecular iodine, and subsequently hydrazines or hydroxyl-
amine provided the corresponding 3,5-disubstituted pyrazoles
or isoxazoles in good yields with high regioselectivity, through
the formations of propargyl secondary alkoxides and α-alkynyl
ketones. The present reactions are one-pot preparation of 3,5-
disubstituted pyrazoles from terminal alkynes, aldehydes, molecular iodine, and hydrazines, and 3,5-disubstituted isoxazoles from
terminal alkynes, aldehydes, molecular iodine, and hydroxylamine.
ciceptive40 activities. Although the major route to isoxazoles is
INTRODUCTION
■
the 1,3-dipolar cycloaddition of nitrile oxides to alkynes,23 other
Pyrazoles and isoxazoles are extensively used as heterocyclic
methods were also reported recently.41−44 On the other hand,
units of medicines and agrochemicals.1 Pyrazoles, in particular,
terminal alkynes and aldehydes are easily available, and
have been studied for more than a century as an important class
therefore, the preparation of pyrazoles and isoxazoles with
of heterocyclic compounds2 and have continued to attract
those compomds is a very attractive option. However, to the
considerable attention due to the broad range of biological
best of our knowledge, the one-pot preparation of pyrazoles
activities, including analgesic,3 antibacterial,4 antidepressant,5
and isoxazoles using terminal alkynes and aldehydes with
anti-inflammatory,6,7 antimicrobial,6,8 antiobesity,9 antiviral,10
hydrazine and hydroxylamine is little studied. Here, as part of
appetite suppressant,11 cholesterol-lowering,12 hypoglycemic,13
our investigation of the synthetic use of molecular iodine in
antihypertensive,14 and anticancer15 activities. Pyrazoles serve
organic synthesis,45 we would like to report the one-pot
as building blocks for pharmaceutical and agricultural research,
preparation of pyrazoles by reacting a terminal alkyne with n-
and Celebrex,7 Viagra,16 Zometapine,17 Cyenopyrafen,18
BuLi and then aldehydes, followed by the treatment with
Fenpyroximate,19 and Tebufenpyrad20 are well-known com-
molecular iodine and K2CO3 and the subsequent reaction with
pounds bearing a pyrazole unit. Pyrazoles are generally
hydrazines, and the preparation of isoxazoles by reacting a
synthesized by (i) the reaction of 1,3-dicarbonyl compounds
terminal alkyne with n-BuLi and then aldehydes, followed by
the treatment with molecular iodine and K2CO3 and the
subsequent reaction with hydroxylamine.
with hydrazines,21 (ii) the reaction of α,β-unsaturated or doubly
unsaturated aldehydes or ketones with hydrazines,22 and (iii)
the 1,3-dipolar cycloaddition reaction of diazoalkanes or
nitrilimines with alkenes or alkynes23 and are occasionally
prepared by (iv) the functionalization of unsubstituted or less
RESULTS AND DISCUSSION
■
substituted pyrazoles.24 Although the major route to pyrazoles
involves the 1,3-dipolar cycloaddition of diazomethanes to
alkynes,23 other methods with metals, Lewis acids, or bases
were also recently reported.25−35 More recently, the TsOH-
catalyzed Mannich-type-cyclization-oxidation of arylhydrazines,
aromatic aldehydes, and terminal arylalkynes to form 1,3,5-
triarylpyrazoles was reported.36 However, that report should be
questioned, as we performed the same reaction carefully but
were unable to obtain pyrazoles at all using the described
procedures and conditions.36 Namely, treatment of benzalde-
hyde (1.0 equiv), phenylhydrazine (1.0 equiv), phenylacetylene
(1.2 equiv), and p-toluenesulfonic acid in dichloroethane (0.5
M) at room temperature for 24 h did not give the
corresponding pyrazole at all.
Treatment of phenylacetylene 1a with n-BuLi in THF at 0 °C,
followed by the addition of 4-methoxybenzaldehyde 2a at 0 °C
generated the adduct, propargyl secondary alkoxide (I). Further
treatment of the propargyl secondary alkoxide solution with
molecular iodine in the presence of K2CO3 under refluxing
conditions, followed by the treatment with hydrazine provided
3-(4′-methoxyphenyl)-5-phenylpyrazole 3a in 20−30% yields.
The reason for the low yield of 3-(4′-methoxyphenyl)-5-
phenylpyrazole 3a was that the oxidation of propargyl
secondary alkoxide (I) with molecular iodine did not proceed
efficiently in THF solution. Therefore, after the formation of
the propargyl secondary alkoxide (I), THF was removed by
evaporation, and t-BuOH was added to promote the oxidation
Isoxazoles possess important biological activities, such as
Received: December 12, 2013
Published: February 10, 2014
anti-inflammatory,37 antimicrobial,38 anticancer,39 and antino-
© 2014 American Chemical Society
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to the α-alkynyl ketone (II). Once the α-alkynyl ketone (II)
was formed, the reaction with hydrazine occurred smoothly to
give 3-(4′-methoxyphenyl)-5-phenylpyrazole 3a in 86% yield in
one pot, as shown in Table 1. The fourth step for the formation
molecular iodine and K2CO3 in t-BuOH and then hydrazine
under refluxing conditions (Method A) generated the
corresponding 3-aryl-5-phenylpyrazoles 3a−3k in good yields
under the same procedure and conditions, as shown in Table 1.
When t-BuOH was added to the THF solution without removal
of THF at the third step, the yields of pyrazoles were decreased
to 70−79%. Moreover, in the third step involving the oxidation
of propargyl secondary alkoxide (I) derived from furfural 2k, a
TEMPO-catalyzed (diacetoxyiodo)benzene (DIB) oxidation
system46 (Method B) instead of a molecular iodine with K2CO3
oxidation system was used to promote the clean oxidation to α-
alkynyl ketone (II).
Table 1. Preparation of 3,5-Disubstituted 1H-Pyrazoles 3
The same treatment of 4-methoxyphenylacetylene 1b, 4-
methylphenylacetylene 1c, 4-chlorophenylacetylene 1d, 2-
pyridylacetylene 1e, and 1-octyne 1f with n-BuLi in THF at 0
°C, followed by the addition of 4-methylbenzaldehyde 2b, and
the subsequent treatment with molecular iodine and K2CO3 in
t-BuOH (Method A) and then hydrazine under refluxing
conditions generated the corresponding 5-aryl-3-(4′-
methylphenyl)pyrazoles 3o−3r and 5-hexyl-3-(4′-
methylphenyl)pyrazole 3s in good yields. In the third step for
the oxidation of propargyl secondary alkoxide (I) derived from
2-pyridylacetylene, a TEMPO-catalyzed DIB oxidation system
(Method B) instead of a molecular iodine with K2CO3
oxidation system was used to promote the clean oxidation to
α-alkynyl ketone (II). The same treatment of phenylacetylene
1a with n-BuLi in THF at 0 °C, followed by the addition of
aliphatic aldehydes, such as propionaldehyde 2l and cyclo-
hexanecarboxaldehyde 2m, and the subsequent treatment with
molecular iodine and K2CO3 in t-BuOH (Method A), or
TEMPO with DIB in 1,2-dichloroethane (Method B), did not
generate α-alkynyl ketones (II), because the oxidation of
adducts (I) did not occur at all. However, it was found that the
oxidation of adducts (I) with Fe(NO3)3 in the presence of
TEMPO47 in toluene (Method C) proceeded smoothly to
generate α-alkynyl ketones (II), and further treatment of
isolated α-alkynyl ketones (II) bearing ethyl and cyclohexyl
groups with hydrazine generated 3-ethyl-5-phenylpyrazole 3l
and 3-cyclohexyl-5-phenylpyrazole 3m in 62 and 65% yields,
respectively. In contrast, the same treatment of phenylacetylene
1a with n-BuLi in THF at 0 °C, followed by the addition of
pivalaldehyde 2n, and the subsequent treatment with molecular
iodine and K2CO3 in t-BuOH (Method A) generated α-alkynyl
ketone (II) smoothly, and the further treatment with hydrazine
provided 3-t-butyl-5-phenylpyrazole 3n in 71% yield in one pot.
This may be due to the higher electron density of the oxygen
atom of adduct alkoxide (I) than those of adducts (I) formed
from the reaction of lithium phenylacetylide with propionalde-
hyde and cyclohexanecarboxaldehyde (electron-donating ability
increases as follows: Et < c-C6H11 < t-Bu). Here, when the
direct in situ oxidation of adducts (I) derived from the reaction
of lithium phenylacetylide with propionaldehyde 2l and
cyclohexanecarboxaldehyde 2m was carried out with Fe(NO3)3
in the presence of TEMPO, the yields of 3-ethyl-5-phenyl-
pyrazole 3l and 3-cyclohexyl-5-phenylpyrazole 3m were low.
The low yields obtained when the reaction was carried out in
one pot using Fe(NO3)3 in the presence of TEMPO, might
have been due to the oxidation of hydrazine with oxidizing
species, i.e., Fe(NO3)3, which was used in the third step.
Therefore, after the isolation of the α-propargyl alcohols from
adducts (I) derived from propionaldehyde 2l and cyclo-
hexanecarboxaldehyde 2m, and the oxidation of α-propargyl
alcohols with Fe(NO3)3 in the presence of TEMPO in toluene
a
b
t-BuOH (3 mL) was added without removal of THF. Reaction time
c
was 4 h at third step. Overall yield from isolated ketone (II), and the
mixture was treated with NH2NH2·H2O (1.1 equiv) in t-BuOH (3
mL) at refluxing temperature for 1 h. Reaction time was 18 h at third
d
step.
of pyrazole proceeded at room temperature. However, refluxing
conditions gave pyrazole 3a in a much higher yield than that
achieved at room temperature. Thus, treatment of phenyl-
acetylene 1a with n-BuLi in THF at 0 °C, followed by the
addition of aromatic aldehydes, such as 4-methoxybenzalde-
hyde 2a, 4-methylbenzaldehyde 2b, 2-methylbenzaldehyde 2c,
3-methylbenzaldehyde 2d, benzaldehyde 2e, 4-chlorobenzalde-
hyde 2f, 4-(trifluoromethyl)benzaldehyde 2g, 3,4-(dimethoxy)-
benzaldehyde 2h, 1-naphthaldehyde 2i, 2-thiophenecarboxalde-
hyde 2j, and furfural 2k, and the subsequent treatment with
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(Method C) gave α-alkynyl ketones (II) in higher than 80%
yield. When isolated α-alkynyl ketones (II) were treated with
hydrazine, 3-ethyl-5-phenylpyrazole 3l and 3-cyclohexyl-5-
phenylpyrazole 3m were obtained in good yields. When
methylhydrazine instead of hydrazine was used, after the
reaction of phenylacetylene 1a with n-BuLi and then 4-
methylbenzaldehyde 2b, followed by the oxidation with
molecular iodine and K2CO3 in t-BuOH (Method A) under
the same procedure and conditions, 1-methyl-3-(4′-methyl-
phenyl)-5-phenylpyrazole 5 was obtained in 90% yield as a
single isomer, as shown in Scheme 1 (eq 1). On the other hand,
supported by X-ray analysis. When acylhydrazine instead of
hydrazine was used, after the reaction of phenylacetylene 1a
with n-BuLi and then 4-methylbenzaldehyde 2b, followed by
the oxidation with molecular iodine and K2CO3 in t-BuOH
(Method A) under the same procedure and conditions, 5-
hydroxypyrazoline intermediate 7, which was not dehydrated,
was obtained in 71% yield (eq 3). In this case, the
aromatization to 1-acetylpyrazole through the dehydration of
intermediate 7 is precluded by the N-acetyl group, an electron-
withdrawing group.
Then, the one-pot preparation of isoxazoles using hydroxyl-
amine instead of hydrazine was conducted under the same
procedure and conditions. Treatment of phenylacetylene 1a
with n-BuLi in THF at 0 °C, followed by the addition of 4-
methoxybenzaldehyde 2a, and the subsequent treatment with
molecular iodine and K2CO3 in t-BuOH (Method A) and then
hydroxylamine·HCl under refluxing conditions generated a
mixture of 5-(4′-methoxyphenyl)-3-phenylisoxazole 4a and 3-
(4′-methoxyphenyl)-5-phenylisoxazole 4a′ in 91% yield (8:1),
as shown in Table 2 (entry 1). To improve the regioselective
Scheme 1. Preparation of 1,3,5-Trisubstituted 1H-Pyrazoles
5−7
Table 2. Optimal Conditions for Regioselective Preparation
of 3,5-Disubstituted Isoxazole 4a
entry
additive
4a/4a′
yield (%)
1
2
3
4
5
6
7
none
8:1
91
82
80
88
86
79
92
85
88
81
78
76
TsOH·H2O (1.0 equiv)
TfOH (1.0 equiv)
2:1
1:1.2
20:1
30:1
49:1
8:1
Et3N (1.0 equiv)
i-Pr2NEt (1.0 equiv)
DBU (1.0 equiv)
TBAI (0.1 equiv)
a
8
H2O (3 mL)
>99:1
>99:1
>99:1
>99:1
>99:1
a
9
TBAI (0.1 equiv), H2O (3 mL)
Et3N (1.0 equiv), H2O (3 mL)
i-Pr2NEt (1.0 equiv), H2O (3 mL)
DBU (1.0 equiv), H2O (3 mL)
a
10
a
11
a
12
a
After fourth step reaction, TsOH·H2O (2.5 equiv) was added, and
the mixture was stirred for 1 h at rt.
formation of 5-(4′-methoxyphenyl)-3-phenylisoxazole 4a, var-
ious acids and bases as an additive were used at the fourth step,
and it was found that the addition of water (3 mL), water (3
mL) with tetrabutylammonium iodide (TBAI), or water (3
mL) with tertiary amines, such as Et3N, i-Pr2NEt, and DBU,
gave 5-(4′-methoxyphenyl)-3-phenylisoxazole 4a in high yields
with high regioselectivity (>99:1) (entries 8−12). Especially,
addition of water (3 mL) with TBAI gave 5-(4′-methox-
yphenyl)-3-phenylisoxazole 4a in the best yield with high
regioselectivity (entry 9).
On the basis of these optimum conditions, treatment of
phenylacetylene 1a with n-BuLi in THF at 0 °C, followed by
the addition of aromatic aldehydes, such as 4-methoxybenzal-
dehyde 2a, 4-methylbenzaldehyde 2b, 2-methylbenzaldehyde
2c, 3-methylbenzaldehyde 2d, benzaldehyde 2e, 4-chloroben-
zaldehyde 2f, 4-(trifluoromethyl)benzaldehyde 2g, 3,4-
when phenylhydrazine instead of hydrazine was used under the
same procedure and conditions, dehydration to the pyrazole
skeleton did not proceed smoothly, and therefore, p-TsOH was
added for the dehydration at the fifth step at room temperature
to give 1-phenyl-5-(4′-methylphenyl)-3-phenylpyrazole 6 in
89% yield with high regioselectivity, including a trace amount of
1-phenyl-3-(4′-methylphenyl)-5-phenylpyrazole (eq 2). These
results indicate that the methylamino group of methylhydrazine
reacts at the β-position of alkynyl ketone (II), whereas the
amino group of phenylhydrazine reacts at the β-position of
alkynyl ketone (II). The structures of pyrazoles 5 and 6 were
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(dimethoxy)benzaldehyde 2h, 1-naphthaldehyde 2i, 2-thiophe-
necarboxaldehyde 2j, and furfural 2k, and the subsequent
treatment with molecular iodine and K2CO3 in t-BuOH
(Method A) and then hydroxylamine·HCl generated the
corresponding 3-phenyl-5-arylisoxazoles 4a−4k in good yields
with high regioselectivity, as shown in Table 3. It was found
ing 5-t-butyl-3-phenylisoxazole 4n in 90% yield in one pot. On
the other hand, the same treatment of phenylacetylene 1a with
n-BuLi in THF at 0 °C, followed by the addition of
propionaldehyde 2l and cyclohexanecarboxaldehyde 2m, and
the subsequent treatment with Fe(NO3)3 in the presence of
TEMPO in toluene (Method C) gave α-alkynyl ketones (II)
bearing ethyl and cyclohexyl groups in good yields. Treatment
of the isolated alkynyl ketones (II) bearing ethyl and cyclohexyl
groups with hydroxylamine·HCl under refluxing conditions,
followed by treatment with p-TsOH at room temperature
provided 5-ethyl-3-phenylisoxazole 4l and 5-cyclohexy-3-
phenylisoxazole 4m in 68 and 62% yields, respectively. In
contrast, the one-pot preparation of 5-ethyl-3-phenylisoxazole
4l and 5-cyclohexy-3-phenylisoxazole 4m through the oxidation
of alkoxide (I) to alkynyl ketone (II) by Fe(NO3)3 in the
presence of TEMPO (Method C), and the subsequent
treatment with hydroxylamine·HCl under refluxing conditions
was not effective again, and the yields were 26 and 30%,
respectively. The same treatment of 4-methoxyphenylacetylene
1b, 4-methylphenylacetylene 1c, 4-chlorophenylacetylene 1d,
2-pyridylacetylene 1e, and 1-octyne 1f with n-BuLi in THF at 0
°C, followed by the addition of 4-methylbenzaldehyde 2b, and
the subsequent treatment with molecular iodine and K2CO3 in
t-BuOH (Method A) and then hydroxylamine·HCl under
refluxing conditions generated the corresponding 3-aryl-5-(4′-
methylphenyl)isoxazoles 4o−4q and 3-hexyl-5-(4′-
methylphenyl)isoxazole 4s in good yields with high regiose-
lectivity. However, 5-(4′-methylphenyl)-3-(2′-pyridyl)isoxazole
4r was not obtained, and precursor IIIr containing a hydroxy
group at 5-position, using Method B for oxidation, was
obtained in 56% yield. It is known that the aromatic resonance
energy of isoxazoles is lower than that of pyrazoles,48 and
therefore, we believe that the formation of isoxazoles through
the dehydration of intermediates (III) is not efficient.
Therefore, the addition of p-TsOH to cyclization intermediates
(III) promoted the dehydration to give isoxazoles smoothly, as
shown in Table 3. The structure of 5-(4′-chlorophenyl)-3-
phenylisoxazole 4f was supported by X-ray analysis.
Table 3. Preparation of 3,5-Disubstituted Isoxazoles 4
A plausible reaction mechanism for the formation of
pyrazoles and isoxazoles is shown in Scheme 2. The formed
lithium acetylide reacts with aldehyde to form propargyl
secondary alkoxide (I), which is further oxidized to α-alkynyl
ketone (II) by molecular iodine in the presence of K2CO3
(Method A) mainly, and in some cases, DIB in the presence of
TEMPO (Method B) or Fe(NO3)3 in the presence of TEMPO
(Method C). Once α-alkynyl ketone (II) is formed, it smoothly
reacts with hydrazine to provide pyrazole, mainly through the
Michael-type addition of hydrazine to α-alkynyl ketone (II), the
5-exo-trig cyclization onto the ketone group, and the
subsequent dehydration. As a related reaction, treatment of 4-
methylphenyl phenylethynyl ketone, α-alkynyl ketone, with
benzylamine (1.2 equiv) as amine nucleophile, in 1,2-
dichloroethane for 11 h at 80 °C gave 2-benzylamino-2-
phenylethenyl 4′-methylphenyl ketone, β-aminovinyl ketone, in
93% yield. For isoxazoles, α-alkynyl ketone (II) smoothly reacts
with hydroxylamine through the Michael-type addition by
hydroxylamine to form β-(N-hydroxyamino)vinyl ketone (IV).
Then, the 5-exo-trig cyclization onto the ketone group and
subsequent dehydration occur. The addition of p-TsOH at the
fifth step promotes the dehydration to form 3,5-disubstituted
isoxazoles.
a
b
Reaction time was 4 h at third step. TBAI, H2O, and TsOH·H2O
c
were not added. Overall yield is from isolated ketone (II), and the
mixture was treated with NH2OH·HCl (1.1 equiv), K2CO3 (0.6
equiv), and TBAI (0.1 equiv) in t-BuOH (3 mL) at refluxing
conditions for 5 h. Then, TsOH·H2O (1.0 equiv) was added, and the
mixture was stirred at rt for 1 h. THF was not removed. TsOH·H2O
was not added. Reaction time was 18 h at third step.
d
e
f
that intermediates (III) were not efficiently dehydrated
smoothly and the addition of p-TsOH to the reaction mixture
at the fifth step at room temperature increased the yields of 3,5-
disubstituted isoxazoles. The same treatment of phenyl-
acetylene 1a with n-BuLi in THF at 0 °C, followed by the
addition of pivalaldehyde 2n, and the subsequent treatment I2
and K2CO3 in t-BuOH (Method A), and then with hydroxyl-
amine·HCl under refluxing conditions, and finally the treatment
with p-TsOH at room temperature generated the correspond-
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organic layer was washed with brine and dried over Na2SO4.
Purification by short column chromatography on silica gel (hexane/
AcOEt = 2:1) yielded 3-(4′-methoxyphenyl)-5-phenyl-1H-pyrazole 3a
(434 mg, 86%).
Scheme 2. Plausible Reaction Mechanism
General Procedure for the Preparation of 3,5-Disubstituted
1H-Pyrazoles 3k, 3r (with Method B). A solution of n-BuLi (1.58
M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (205 mg 2.0 mmol) in THF (3 mL) at 0 °C,
and then the mixture was stirred at room temperature for 1.5 h. A
solution of furfural 2k (202 mg, 2.1 mmol) in THF (2 mL) was added
to the mixture at 0 °C, and the obtained mixture was stirred at room
temperature for 2 h. Then, the solvent was removed, and 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO, 31 mg, 0.2 mmol),
(diacetoxyiodo)benzene (2.4 mmol, 773 mg), and 1,2-dichloroethane
(3 mL) were added, and the obtained mixture was stirred for 2 h under
refluxing conditions. Then, hydrazine monohydrate (194 μL, 4.0
mmol) was added, and the obtained mixture was stirred for 1 h under
refluxing conditions. The reaction mixture was quenched with sat. aq.
NH4Cl and was extracted with CHCl3 (3 × 20 mL). The organic layer
was washed with brine and dried over Na2SO4. Purification by short
column chromatography on silica gel (hexane/AcOEt = 2:1) yielded 3-
(2′-furyl)-5-phenyl-1H-pyrazole 3k (320 mg, 76%).
General Procedure for the Praparation of Substituted 1H-
Pyrazoles 3l, 3m (with Method C). A solution of n-BuLi (1.58 M in
hexane, 1.39 mL, 2.2 mmol) was added dropwise to phenylacetylene
1a (204 mg 2.0 mmol) in toluene (3 mL) at 0 °C, and then the
mixture was stirred at room temperature for 1.5 h. Propionaldehyde 2l
(151 μL, 2.1 mmol) was added to the mixture at 0 °C, and the
obtained mixture was stirred at room temperature for 1 h. Then, conc.
HCl aq. was added until the solution became acidic, and then
Fe(NO3)3·9H2O (81 mg, 0.2 mmol) and 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO, 31 mg, 0.2 mmol) were added, and the obtained
mixture was stirred for 24 h at room temperature. Then, the solvent
was removed, and then hydrazine monohydrate (194 μL, 4.0 mmol)
and t-BuOH (3 mL) were added, and the obtained mixture was stirred
for 1 h under refluxing conditions. The reaction mixture was quenched
with 4 M HCl aq. and was extracted with CHCl3 (3 × 20 mL). The
organic layer was washed with brine and dried over Na2SO4.
Purification by short column chromatography on silica gel (hexane/
AcOEt = 2:1) yielded 3-ethyl-5-phenyl-1H-pyrazole 3l (104 mg, 30%).
3-(4′-Methoxyphenyl)-5-phenyl-1H-pyrazole (3a). White solid
(434 mg, 86% yield): mp 165−166 °C (lit.,49 mp 156−158 °C); IR
CONCLUSION
■
3,5-Disubstituted pyrazoles and isoxazoles were prepared in
good yields with high regioselectivity in one pot by the
treatment of terminal alkynes with aromatic aldehydes,
molecular iodine (in some cases, DIB or Fe(NO3)3 in the
presence of TEMPO), and hydrazines, and of terminal alkynes
with aromatic aldehydes, molecular iodine (in some cases, DIB
or Fe(NO3)3 in the presence of TEMPO), and hydroxylamine,
respectively. The present reaction is a simple and practical
method for the preparation of various 1,3-disubstituted
pyrazoles and isoxazoles from easily available compounds.
EXPERIMENTAL SECTION
General Methods. H NMR spectra were measured on 500 and
■
1
(ATR) 3135, 2914, 1619, 1508, 1460, 1297, 1253, 1187 cm−1; H
1
NMR (400 MHz, CDCl3) δ = 3.81 (s, 3H), 6.73 (s, 1H), 6.88 (d, J =
8.7 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.62 (d,
J = 8.7 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 55.3, 99.4, 114.2, 123.9, 125.6, 126.9, 128.1, 128.8, 131.5,
159.6; HRMS (ESI) Calcd for C16H15ON2 (M + H)+ 251.1179, found
251.1172.
400 MHz spectrometers. Chemical shifts were recorded as follows:
chemical shift in ppm from internal tetramethylsilane on the δ scale,
multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m =
multiplet; br = broad), coupling constant (Hz), integration, and
assignment. 13C NMR spectra were measured on 125 and 100 MHz
spectrometers. Chemical shifts were recorded in ppm from the solvent
resonance employed as the internal standard (deuterochloroform at
77.0 ppm). High-resolution mass spectra (HRMS) were measured on
orbitrap mass spectrometers. Characteristic peaks in the infrared (IR)
spectra were recorded in wave numbers, cm−1. Melting points were
uncorrected. Thin-layer chromatography (TLC) was performed using
0.25 mm silica gel plates (60F-254). The products were purified by
short column chromatography on silica gel 60 (63−200 mesh).
General Procedure for the Preparation of 3,5-Disubstituted
1H-Pyrazoles 3a−3j, 3l−3q, 3s, 3t (with Method A). A solution of
n-BuLi (1.58 M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (206 mg 2.0 mmol) in THF (3 mL) at 0 °C, and
then the mixture was stirred at room temperature for 1.5 h. A solution
of 4-methoxybenzaldehyde 2a (286 mg, 2.1 mmol) in THF (2 mL)
was added to the mixture at 0 °C, and the obtained mixture was stirred
at room temperature for 2 h. Then, the solvent was removed, and I2
(812 mg, 3.2 mmol), K2CO3 (830 mg, 6.0 mmol), and t-BuOH (3
mL) were added to the residue, and the obtained mixture was stirred
for 2 h under refluxing conditions. Then, hydrazine monohydrate (194
μL, 4.0 mmol) was added, and the obtained mixture was stirred for 1 h
under refluxing conditions. The reaction mixture was quenched with
sat. aq. NH4Cl and was extracted with CHCl3 (3 × 20 mL). The
3-(4′-Methylphenyl)-5-phenyl-1H-pyrazole (3b). White solid
(469 mg, >99% yield): mp 177−178 °C (lit.,49 mp 170−172 °C); IR
1
(ATR) 3134, 2908, 1605, 1508, 1457, 1307, 1268, 1175 cm−1; H
NMR (400 MHz, CDCl3) δ = 2.39 (s, 3H), 6.82 (s, 1H), 7.24 (d, J =
8.0 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.61 (d,
J = 8.0 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ = 21.3, 99.9, 125.5, 125.6 128.2, 128.8, 129.6, 138.3; HRMS
(ESI) Calcd for C16H15N2 (M + H)+ 235.1230, found 235.1225.
3-(2′-Methylphenyl)-5-phenyl-1H-pyrazole (3c). White solid
(350 mg, 75% yield): mp 104−105 °C; IR (ATR) 3206, 3019, 1572,
1492, 1457, 1308, 1259, 1176 cm−1; 1H NMR (400 MHz, CDCl3) δ =
2.44 (s, 3H), 6.69 (s, 1H), 7.17−7.23 (m, 1H), 7.24−7.28 (m, 2H),
7.31 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 7.6 Hz,
1H), 7.75 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 20.8,
103.0, 125.6, 126.0, 128.0, 128.5, 128.7, 128.9, 130.9, 136.0; HRMS
(ESI) Calcd for C16H15N2 (M + H)+ 235.1230, found 235.1228.
3-(3′-Methylphenyl)-5-phenyl-1H-pyrazole (3d). White solid
(356 mg, 76% yield): mp 141−142 °C(lit.,50 mp 120−124 °C); IR
1
(ATR) 3204, 3030, 1566, 1457, 1293, 1268, 1162 cm−1; H NMR
(400 MHz, CDCl3) δ = 2.38 (s, 3H), 6.84 (s, 1H), 7.16 (d, J = 7.7 Hz,
1H), 7.27−7.36 (m, 2H), 7.39−7.44 (m, 2H), 7.52 (d, J = 7.7 Hz,
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1H), 7.55 (s, 1H), 7.75 (d, J = 7.7 Hz, 2H),; 13C NMR (100 MHz,
CDCl3) δ = 21.3, 99.7, 122.7, 125.5, 126.2, 127.7, 128.5, 128.6, 131.0,
131.3, 138.2, 148.6; HRMS (ESI) Calcd for C16H15N2 (M + H)+
235.1230, found 235.1227.
3,5-Diphenyl-1H-pyrazole (3e, Commercially Available).
White solid (388 mg, 88% yield): mp 196−197 °C (lit.,49 mp 197−
199 °C).
and then the mixture was stirred at room temperature for 1.5 h. A
solution of 4-methylbenzaldehyde 2b (252 mg, 2.1 mmol) in THF (2
mL) was added to the mixture at 0 °C, and the obtained mixture was
stirred at room temperature for 2 h. Then, the solvent was removed,
and I2 (812 mg, 3.2 mmol), K2CO3 (830 mg, 6.0 mmol), and t-BuOH
(3 mL) were added, and the obtained mixture was stirred for 2 h under
refluxing conditions. Then, methylhydrazine (209 μL, 4.0 mmol) was
added, and the obtained mixture was stirred for 1 h under refluxing
conditions. The reaction mixture was quenched with sat. aq. NH4Cl
and was extracted with CHCl3 (3 × 20 mL). The organic layer was
washed with brine and dried over Na2SO4. Purification by short
column chromatography on silica gel (hexane/CHCl3 = 1:1) yielded
1-methyl-3-(4′-methylphenyl)-5-phenyl-1H-pyrazole 5 (449 mg,
90%).
3-(4′-Chlorophenyl)-5-phenyl-1H-pyrazole (3f). White solid
(466 mg, 91% yield): mp 203−204 °C (lit.,49 mp 214−215 °C); IR
1
(ATR) 3141, 2923, 1733, 1567, 1456, 1308, 1270, 1184 cm−1; H
NMR (500 MHz, CDCl3) δ = 6.81 (s, 1H), 7.35−7.39 (m, 3H), 7.43
(t, J = 7.5 Hz, 2H), 7.66−7.70 (m, 4H); 13C NMR (125 MHz, DMSO-
d6) δ = 101.0, 126.0, 127.8, 129.1, 129.4, 129.9, 130.1, 133.4, 147.1,
147.2; HRMS (ESI) Calcd for C15H12N2Cl (M + H)+ 255.0684, found
255.0678.
1-Methyl-3-(4′-methylphenyl)-5-phenyl-1H-pyrazole (5).56
White solid (449 mg, 90% yield): mp 131−132 °C; IR (ATR)
3335, 2973, 2915, 1526, 1484, 1437, 1089, 1048 cm−1; 1H NMR (400
MHz, CDCl3) δ = 2.37 (s, 3H), 3.91 (s, 3H), 6.57 (s, 1H), 7.21 (d, J =
7.9 Hz, 2H), 7.39−7.48 (m, 5H), 7.72 (d, J = 7.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ = 21.2, 37.5, 103.0, 125.4, 128.5, 128.6, 128.7,
129.3, 130.7, 137.3, 144.9, 150.5; HRMS (ESI) Calcd for C17H17N2
(M + H)+ 249.1386, found 249.1385.
3-(4′-Trifluoromethylphenyl)-5-phenyl-1H-pyrazole (3g).
White solid (395 mg, 68% yield): mp 225−226 °C (lit.,51 mp 226 °C).
3-(3′,4′-Dimethoxyphenyl)-5-phenyl-1H-pyrazole (3h). White
solid (456 mg, 81% yield): mp 143−144 °C; IR (ATR) 3251, 2972,
1590, 1466, 1253, 1237, 1140 cm−1; 1H NMR (500 MHz, CDCl3) δ =
3.71 (s, 3H), 3.87 (s, 3H), 6.68 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 7.19
(d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.25−7.32 (m, 3H), 7.64 (d, J = 8.0
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 55.2, 55.7, 98.8, 108.4,
111.0, 118.0, 125.3, 127.7, 128.5, 131.1, 148.7, 148.8; HRMS (ESI)
Calcd for C17H17O2N2 (M + H)+ 281.1285, found 281.1279.
3-(1′-Naphthyl)-5-phenyl-1H-pyrazole (3i). White solid (411
mg, 76% yield): mp 145−146 °C(lit.,49 mp 140−142 °C).
5-Phenyl-3-(2′-thienyl)-1H-pyrazole (3j). White solid (377 mg,
83% yield): mp 184−185 °C (lit.,49 mp 187−188 °C).
General Procedure for the Preparation of 3,5-Disubstituted
1-Phenylpyrazole 6 (with Method A). A solution of n-BuLi (1.58
M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (205 mg 2.0 mmol) in THF (3 mL) at 0 °C,
and then the mixture was stirred at room temperature for 1.5 h. A
solution of 4-methylbenzaldehyde 2b (252 mg, 2.1 mmol) in THF (2
mL) was added to the mixture at 0 °C, and the obtained mixture was
stirred at room temperature for 2 h. Then, the solvent was removed,
and I2 (812 mg, 3.2 mmol), K2CO3 (830 mg, 6.0 mmol), and t-BuOH
(3 mL) were added, and the obtained mixture was stirred for 2 h under
refluxing conditions. Then, phenylhydrazine (394 μL, 4.0 mmol),
tetrabutylammonium iodide (74 mg, 0.2 mmol), and H2O (3 mL)
were added, and the obtained mixture was stirred for 5 h under
refluxing conditions. Then, p-toluenesulfonic acid monohydrate (951
mg, 5.0 mmol) was added, and the obtained mixture was stirred for 1 h
at room temperature. The reaction mixture was quenched with sat. aq.
Na2SO3 and was extracted with CHCl3 (3 × 20 mL). The organic layer
was washed with brine and dried over Na2SO4. Purification by short
column chromatography on silica gel (hexane/CHCl3 = 1:1) yielded
5-(4′-methylphenyl)-1,3-diphenyl-1H-pyrazole 6 (558 mg, 89%).
5-(4′-Methylphenyl)-1,3-diphenyl-1H-pyrazole (6). White
solid (558 mg, 89% yield): mp 110−111 °C (lit.,57 mp 174 °C); IR
3-(2′-Furyl)-5-phenyl-1H-pyrazole (3k). White solid (320 mg,
76% yield): mp 173−174 °C (lit.,49 mp 170−172 °C).
3-Ethyl-5-phenyl-1H-pyrazole (3l). White solid (104 mg, 30%
yield): mp 80−81 °C (lit.,52 mp 82.5 °C).
3-Cyclohexyl-5-phenyl-1H-pyrazole (3m). White solid (192
mg, 42% yield): mp 138 °C (lit.,49 mp 135−137 °C).
3-(tert-Butyl)-5-phenyl-1H-pyrazole (3n). White solid (286 mg,
71% yield): mp 118−119 °C (lit.,53 mp 119−120 °C).
5-(4′-Methoxyphenyl)-3-(4″-methylphenyl)-1H-pyrazole
(3o). White solid (443 mg, 83% yield): mp 167−168 °C (lit.,54 mp
170 °C).
3,5-Di(4′-methylphenyl)-1H-pyrazole (3p). White solid (469
mg, 94% yield): mp 220−221 °C (lit.,55 mp 221−223 °C).
5-(4′-Chlorophenyl)-3-(4″-methylphenyl)-1H-pyrazole (3q).
White solid (412 mg, 76% yield): mp 223−224 °C (lit.,51 mp 209
1
°C); IR (ATR) 3111, 2855, 1491, 1385, 1304, 1721, 1172 cm−1; H
1
(ATR) 3377, 3057, 2973, 1593, 1493, 1456, 1359, 1175 cm−1; H
NMR (500 MHz, CDCl3) δ = 2.40 (s, 3H), 6.79 (s, 1H), 7.26 (d, J =
7.8 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.71
(d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ = 20.8, 99.5,
125.0, 126.7, 128.6, 129.5; HRMS (ESI) Calcd for C16H14N2Cl (M +
H)+ 269.0840, found 269.0840.
NMR (400 MHz, CDCl3) δ = 2.34 (s, 3H), 6.78 (s, 1H), 7.11 (d, J =
8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 4H), 7.26−7.44 (m, 8H), 7.92 (d, J =
7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 21.2, 104.9, 125.3,
125.8, 127.3, 127.6, 127.9, 128.5, 128.6, 128.8, 129.1, 133.1, 138.2,
140.2, 144.4, 151.8; HRMS (ESI) Calcd for C22H19N2 (M + H)+
311.1543, found 311.1541.
3-(4′-Methylphenyl)-5-(2″-pyridyl)-1H-pyrazole (3r). White
solid (320 mg, 68% yield): mp 169 °C; IR (ATR) 3217, 3042,
1597, 1565, 1454, 1313, 1296, 1177 cm−1; 1H NMR (500 MHz,
CDCl3) δ = 2.39 (s, 3H), 7.04 (s, 1H), 7.22−7.26 (m, 3H), 7.74−7.77
(m, 4H), 8.69 (td, J = 4.9, 1.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ = 21.3, 100.2, 120.1, 122.9, 125.5, 129.4, 137.0, 137.8, 149.4; HRMS
(ESI) Calcd for C15H14N3 (M + H)+ 236.1182, found 236.1179.
5-Hexyl-3-(4′-methylphenyl)-1H-pyrazole (3s). White solid
(377 mg, 77% yield): mp 81−82 °C; IR (ATR) 3239, 2926, 2854,
1566, 1530, 1446, 1377, 1263, 1110 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 0.87 (t, J = 7.0 Hz, 3H), 1.22−1.36 (m, 6H), 1.61 (quin, J
= 7.7 Hz, 2H), 2.35 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 6.30 (s, 1H), 7.16
(d, J = 7.9 Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H),; 13C NMR (100 MHz,
CDCl3) δ = 14.0, 21.2, 22.5, 26.5, 29.0, 29.2, 31.6, 100,6, 125.6, 129.3,
137.4; HRMS (ESI) Calcd for C16H23N2 (M + H)+ 243.1856, found
243.1854.
General Procedure for the Preparation of 3,5-Disubstituted
1-Acetylpyrazoline 7 (with Method A). A solution of n-BuLi (1.58
M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (206 mg 2.0 mmol) in THF (3 mL) at 0 °C,
and then the mixture was stirred at room temperature for 1.5 h. A
solution of 4-methylbenzaldehyde 2b (252 mg, 2.1 mmol) in THF (2
mL) was added to the mixture at 0 °C, and the obtained mixture was
stirred at room temperature for 2 h. Then, the solvent was removed,
and I2 (812 mg, 3.2 mmol), K2CO3 (830 mg, 6.0 mmol), and t-BuOH
(3 mL) were added, and the obtained mixture was stirred for 2 h under
refluxing conditions. Then, acethydrazide (296 mg, 4.0 mmol) and
Et3N (279 μL, 4.0 mmol) were added, and the obtained mixture was
stirred for 5 h at refluxing conditions. The reaction mixture was
quenched with sat. aq. Na2SO3 and was extracted with CHCl3 (3 × 20
mL). The organic layer was washed with brine and dried over Na2SO4.
Purification by short column chromatography on silica gel (hexane/
CHCl3 = 1:3) yielded 1-acetyl-5-hydroxy-5-(4′-methylphenyl)-3-
phenyl-1H-pyrazoline 7 (423 mg, 71%).
General Procedure for the Prepration of 3,5-Disubstituted
1-Methylpyrazole 5 (with Method A). A solution of n-BuLi (1.58
M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (206 mg 2.0 mmol) in THF (3 mL) at 0 °C,
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1-Acetyl-5-hydroxy-5-(4′-methylphenyl)-3-phenyl-1H-pyra-
zoline (7). White solid (423 mg, 71% yield): mp 133−134 °C; IR
(ATR) 3374, 2974, 1650, 1600, 1434, 1360, 1329, 1243, 1173 cm−1;
1H NMR (400 MHz, CDCl3) δ = 2.33 (s, 3H), 2.43 (s, 3H), 3.35 (d, J
= 18.3 Hz, 1H), 3.69 (d, J = 18.3 Hz, 1H), 5.07 (s, 1H), 7.17 (d, J =
8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.38−7.43 (m, 3H), 7.68−7.72
(m, 2H); 13C NMR (100 MHz, CDCl3) δ =21.0, 22.3, 50.5, 93.8,
123.7, 126.5, 128.7, 129.4, 130.4, 131.1, 137.8, 140.9, 152.6, 170.8;
HRMS (ESI) Calcd for C18H19O2N2 (M + H)+ 295.1441, found
295.1441.
General Procedure for the Preparation of 3,5-Disubstituted
Isoxazoles 4a−4q, 4s, 4t (with Method A). A solution of n-BuLi
(1.58 M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (204 mg 2.0 mmol) in THF (3 mL) at 0 °C, and
then the mixture was stirred at room temperature for 1.5 h. A solution
of 4-methoxybenzaldehyde 2a (286 mg, 2.1 mmol) in THF (2 mL)
was added to the mixture at 0 °C, and the obtained mixture was stirred
at room temperature for 2 h. Then, the solvent was removed, and I2
(812 mg, 3.2 mmol), K2CO3 (830 mg, 6.0 mmol), and t-BuOH (3
mL) were added, and the obtained mixture was stirred for 2 h under
refluxing conditions. Then, hydroxylamine hydrochloride (348 mg, 5.0
mmol), tetrabutylammonium iodide (74 mg, 0.2 mmol), and H2O (3
mL) were added, and the obtained mixture was stirred for 5 h under
refluxing conditions. Then, p-toluenesulfonic acid monohydrate (951
mg, 5.0 mmol) was added, and the obtained mixture was stirred for 1 h
at room temperature. The reaction mixture was quenched with sat. aq.
Na2SO3 and was extracted with CHCl3 (3 × 20 mL). The organic layer
was washed with brine and dried over Na2SO4. Purification by short
column chromatography on silica gel (hexane/CHCl3 = 1:1) yielded
5-(4′-methoxyphenyl)-3-phenylisoxazole 4a (441 mg, 88%).
(hexane/CHCl3 = 1:1) yielded 5-ethyl-3-phenylisoxazole 4l (91 mg,
26%).
5-(4′-Methoxyphenyl)-3-phenylisoxazole (4a). White solid
(410 mg, 87% yield): mp 124 °C (lit.,58 mp 126−127 °C)
5-(4′-Methylphenyl)-3-phenylisoxazole (4b). White solid (441
mg, 88% yield): mp 135 °C (lit.,58 mp 135−136 °C).
5-(2′-Methylphenyl)-3-phenylisoxazole (4c). White solid (342
mg, 72% yield): mp 38−39 °C; IR (ATR) 3053, 1566, 1490, 1399,
1
1232 cm−1; H NMR (500 MHz, CDCl3) δ = 2.54 (s, 3H), 6.70 (s,
1H), 7.28−7.36 (m, 3H), 7.42−7.48 (m, 3H), 7.74 (d, J = 7.5 Hz,
1H), 7.87 (d, J = 7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.4,
100.5, 126.2, 126.8, 127.0, 128.4, 128.9, 129.1, 129.9, 130.0, 131.3,
136.2, 162.6, 170.5; HRMS (ESI) Calcd for C16H14ON (M + H)+
236.1070, found 236.1068.
5-(3′-Methylphenyl)-3-phenylisoxazole (4d). White solid (354
mg, 75% yield): mp 111−112 °C; IR (ATR) 3109, 1587, 1490, 1462,
1397, 1084 cm−1; 1H NMR (500 MHz, CDCl3) δ = 2.43 (s, 3H), 6.81
(s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.44−7.50
(m, 3H), 7.64 (d, J = 7.7 Hz, 1H), 7.66 (s, 1H), 7.85−7.88 (m, 2H);
13C NMR (125 MHz, CDCl3) δ = 21.4, 97.3, 123.0, 126.4, 126.8,
127.3, 128.9 (2C), 129.2, 130.0, 131.0, 138.8, 162.9, 170.6; HRMS
(ESI) Calcd for C16H14ON (M + H)+ 236.1070, found 236.1069.
3,5-Diphenylisoxazole (4e, Commercially Available). White
solid (420 mg, 95% yield): mp 138−139 °C (lit.,58 mp 140−141 °C).
5-(4′-Chlorophenyl)-3-phenylisoxazole (4f). White solid (369
mg, 72% yield): mp 175−177 °C (lit.,58 mp 177−179 °C).
5-(4′-Trifluoromethylphenyl)-3-phenylisoxazole (4g). White
solid (356 mg, 61% yield): mp 184−185 °C; IR (ATR) 3110, 1600,
1
1465, 1394, 1320, 1109 cm−1; H NMR (500 MHz, CDCl3) δ = 6.94
(s, 1H), 7.47−7.52 (m, 3H), 7.76 (d, J = 8.3 Hz, 2H), 7.85−7.89 (m,
2H), 7.96 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 79.0,
123.8 (q. JC−F = 272.3 Hz), 126.1, 126.2, 126.8, 128.9, 129.0, 130.2,
130.7, 132.1 (q, JC−F = 33.6 Hz), 163.2, 168.9; HRMS (ESI) Calcd for
C16H11ONF3 (M + H)+ 290.0787, found 290.0795.
General Procedure for the Preparation of 3,5-Disubstituted
Isoxazoline IIIr (with Method B). A solution of n-BuLi (1.58 M in
hexane, 1.39 mL, 2.2 mmol) was added dropwise to 2-pyridylacetylene
1e (207 mg 2.0 mmol) in THF (3 mL) at 0 °C, and then the mixture
was stirred at room temperature for 1.5 h. A solution of 4-
methylbenzaldehyde 2b (252 mg, 2.1 mmol) in THF (2 mL) was
added to the mixture at 0 °C, and the obtained mixture was stirred at
room temperature for 2 h. Then, the solvent was removed, and 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO, 31 mg, 0.2 mmol),
(diacetoxyiodo)benzene (2.4 mmol, 773 mg), and 1,2-dichloroethane
(3 mL) were added, and the obtained mixture was stirred for 2 h under
refluxing conditions. Then, hydroxylamine hydrochloride (348 mg, 5.0
mmol), tetrabutylammonium iodide (74 mg, 0.2 mmol), and H2O (3
mL) were added, and the obtained mixture was stirred for 5 h under
refluxing conditions. The reaction mixture was quenched with sat. aq.
Na2SO3 and was extracted with CHCl3 (3 × 20 mL). The organic layer
was washed with brine and dried over Na2SO4. Purification by short
column chromatography on silica gel (hexane/EtOAc = 4:1) yielded 5-
hydroxy-5-(4′-methylphenyl)-3-(2′-pyridyl)-1H-pyrazole IIIr (285
mg, 56%).
General Procedure for the Synthesis of Substituted
Isoxazoles 4l, 4m (with Method C). A solution of n-BuLi (1.58
M in hexane, 1.39 mL, 2.2 mmol) was added dropwise to
phenylacetylene 1a (204 mg 2.0 mmol) in toluene (3 mL) at 0 °C,
and then the mixture was stirred at room temperature for 1.5 h.
Propionaldehyde 2l (151 μL, 2.1 mmol) was added to the mixture at 0
°C, and the obtained mixture was stirred at room temperature for 1 h.
Then, conc. HCl aq. was added until the solution became acidic, and
then Fe(NO3)3·9H2O (81 mg, 0.2 mmol) and 2,2,6,6-tetramethylpi-
peridine 1-oxyl (TEMPO, 31 mg, 0.2 mmol) were added, and the
obtained mixture was stirred for 24 h at room temperature. Then, the
solvent was removed. Hydroxylamine hydrochloride (348 mg, 5.0
mmol), tetrabutylammonium iodide (74 mg, 0.2 mmol), t-BuOH (3
mL), and H2O (3 mL) were added, and the obtained mixture was
stirred for 5 h under refluxing conditions. Then, p-toluenesulfonic acid
monohydrate (951 mg, 5.0 mmol) was added, and the obtained
mixture was stirred for 1 h at room temperature. The reaction mixture
was quenched with 4 M HCl aq. and was extracted with CHCl3 (3 ×
20 mL). The organic layer was washed with brine and dried over
Na2SO4. Purification by short column chromatography on silica gel
5-(3′,4′-Dimethoxyphenyl)-3-phenylisoxazole (4h). White
solid (428 mg, 76% yield): mp 106−107 °C (lit.,59 mp 90 °C); IR
1
(ATR) 3126, 1605, 1505, 1468, 1399, 1251 cm−1; H NMR (500
MHz, CDCl3) δ = 3.94 (s, 3H), 3.97 (s, 3H), 6.73 (s, 1H), 6.95 (d, J =
8.3 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H),
7.45−7.50 (m, 3H), 7.85−7.88 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ = 55.9, 56.0, 96.4, 108.6, 111.2, 119.1, 120.4, 126.8, 128.9,
129.2, 129.4, 149.2, 150.7, 163.0, 170.3; HRMS (ESI) Calcd for
C17H16O3N (M + H)+ 282.1125, found 282.1124.
5-(1′-Naphthyl)-3-phenylisoxazole (4i). White solid (405 mg,
74% yield): mp 161−162 °C (lit.,60 mp 76 °C); IR (ATR) 3107, 1563,
1
1509, 1457, 1402, 1272 cm−1; H NMR (500 MHz, CDCl3) δ = 6.94
(s, 1H), 7.46−7.52 (m, 3H), 7.55 (dt, J = 9.5, 3.2 Hz, 2H), 7.86−7.95
(m, 6H), 8.36 (d, J = 8.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ =
97.8, 122.9, 124.7, 125.6, 126.8, 126.9, 127.3, 127.8, 128.7, 128.8,
128.9, 129.1, 130.0, 133.0, 133.9, 163.1, 170.4; HRMS (ESI) Calcd for
C19H14ON (M + H)+ 272.1070, found 272.1068.
3-Phenyl-5-(2′-thienyl)isoxazole (4j). White solid (340 mg, 75%
yield): mp 93−94 °C (lit.,61 mp 95−96 °C).
5-(2′-Furyl)-3-phenylisoxazole (4k). White solid (238 mg, 56%
yield): mp 76 °C (lit.,11 mp 76−77 °C).
5-Ethyl-3-phenylisoxazole (4l).62 Colorless oil (91 mg, 26%
1
yield): IR (ATR) 2978, 1601, 1578, 1471 1442, 1407, 1232 cm−1; H
NMR (400 MHz, CDCl3) δ = 1.35 (t, J = 7.4 Hz, 3H), 2.83 (t, J = 7.4
Hz, 2H), 6.29 (s, 1H), 7.41−7.48 (m, 3H), 7.76−7.82 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 11.7, 20.2, 98.1, 126.7, 128.8, 129.4,
129.7, 162.3, 175.3; HRMS (ESI) Calcd for C11H12ON (M + H)+
174.0913, found 174.0913.
5-Cyclohexyl-3-phenylisoxazole (4m). White solid (137 mg,
30% yield): mp 73−74 °C; IR (ATR) 2923, 1595, 1578, 1471, 1440,
1
1405, 1309 cm−1; H NMR (500 MHz, CDCl3) δ = 1.24−1.55 (m,
5H), 1.71−1.77 (m, 1H), 1.80−1.87 (m. 2H), 2.07−2.14 (m, 2H),
2.82 (tt, J = 11.2, 3.5 Hz, 1H), 6.25 (s, 1H), 7.40−7.46 (m, 3H), 7.78−
7.80 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 25.7, 25.8, 31.2, 36.4,
97.0, 126.7, 128.8, 129.5, 129.7, 162.1, 178.4; HRMS (ESI) Calcd for
C15H18ON (M + H)+ 228.1383, found 228.1381.
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5-(tert-Butyl)-3-phenylisoxazole (4n). White solid (361 mg,
90% yield): mp 49−50 °C (lit.,63 mp 41 °C); IR (ATR) 2971, 1594,
1576, 1465, 1438, 1402, 1275 cm−1; 1H NMR (500 MHz, CDCl3) δ =
1.40 (s, 9H), 6.25 (s, 1H), 7.40−7.46 (m, 3H), 7.78−7.80 (m, 2H);
13C NMR (125 MHz, CDCl3) δ = 28.9, 32.8, 96.4, 126.7, 128.8, 129.5,
129.7, 162.1, 181.7; HRMS (ESI) Calcd for C13H16ON (M + H)+
202.1226, found 202.1226.
3-(4′-Methoxyphenyl)-5-(4″-methylphenyl)isoxazole (4o).
White solid (456 mg, 86% yield): mp 149 °C (lit.,64 mp 150−150.5
°C).
2633. (d) Kumar, V.; Aggarwal, R.; Singh, S. P. Heterocycles 2008, 75,
2893. (e) Elguero, J. Comprehensive Heterocyclic Chemistry; Katrizky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol.
5. (f) Giomi, D.; Cordero, F.; Machetti, F. Comprehensive Heterocyclic
Chemistry III; Katrizky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor,
R. J. K., Joule, J., Eds.; Elsevier: Oxford, 2008; Vol. 4. (g) Katritzky, A.
R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171.
(2) (a) Elguero, J. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Shinkai, I., Eds.; Pergamon:
Oxford, U.K., 1996; Vol. 3, Chapter 3.01, p 1. (b) Eicher, T.;
Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.; Wiley-VCH:
New York, 2003; p 179. (c) Yet, L. Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Joule, J. A., Eds.; Pergamon-Elsevier: Oxford, U.K.,
2008; Vol. 4, Chapter 4.01, p 1. (d) Yet, L. Progress in Heterocyclic
Chemistry; Gribble, G. W., Joule, J. A., Eds.; Elsevier: Oxford, U.K.,
2008; Vol. 19, Chapter 5.4, pp 208−241. (e) Yet, L. Progress in
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Oxford, U.K., 2009; Vol. 20, Chapter 5.4, p 190.
3,5-Di(4′-methylphenyl)isoxazole (4p). White solid (431 mg,
86% yield): mp 149−150 °C (lit., mp 152−152.5 °C).
3-(4′-Chlorophenyl)-5-(4″-methylphenyl)isoxazole (4q).
White solid (407 mg, 75% yield): mp 193−194 °C (lit., mp 199.5−
200 °C); IR (ATR) 3111, 1601, 1497, 1428, 1379, 1262, 1093 cm−1;
1H NMR (500 MHz, CDCl3) δ = 2.42 (s, 3H), 6.74 (s, 1H), 7.29 (d, J
= 8.0 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.80
(d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 21.5, 96.7,
124.6, 125.8, 127.7, 128.0, 129.2, 129.7, 135.9, 140.7, 161.9, 170.9;
HRMS (ESI) Calcd for C16H13ONCl (M + H)+ 270.0680, found
270.0681.
5-Hydroxy-5-(4′-methylphenyl)-3-(2″-pyridyl)isoxazoline
(IIIr). White solid (285 mg, 56% yield): mp 123−124 °C; IR (ATR)
3198, 1573, 1476, 1443, 1286, 1179 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 2.36 (s, 3H), 3.56 (d, J = 18.3 Hz, 1H), 3.85 (d, J = 18.3
Hz, 1H), 4.21 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.28 (ddd, J = 7.8, 5.0,
1.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.72 (td, J = 7.8, 1.8 Hz, 1H),
8.03 (dt, J = 7.8, 1.1 Hz, 1H), 8.55 (dd, J = 5.0, 1.8 Hz, 1H), ; 13C
NMR (100 MHz, CDCl3) δ = 21.1, 48.2, 108.6, 121.7, 124.4, 125.5,
129.1, 136.5, 137.7, 138.6, 149.0, 149.2, 159.0; HRMS (ESI) Calcd for
C15H15O2N2 (M + H)+ 255.1128, found 255.1127.
3-Hexyl-5-(4′-methylphenyl)isoxazole (4s). White solid (335
mg, 69% yield): mp 38 °C; IR (ATR) 2927, 1602, 1516, 1468, 1421,
1421, 1264 cm−1; 1H NMR (500 MHz, CDCl3) δ = 0.89 (t, J = 7.0 Hz,
3H), 1.29−1.35 (m, 4H), 1.36−1.42 (m, 2H), 1.70 (quin, J = 7.7 Hz,
2H), 2.38 (s, 3H), 2.69 (t, J = 7.7 Hz, 2H), 6.31 (s, 1H), 7.24 (d, J =
8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H),; 13C NMR (125 MHz, CDCl3)
δ = 14.0, 21.4, 22.5, 26.1, 28.3, 28.9, 31.5, 98.5, 125.0, 125.6, 129.5,
140.1, 164.7, 169.6; HRMS (ESI) Calcd for C16H22ON (M + H)+
244.1696, found 244.1695.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of all pyrazoles and isoxazoles,
and X-ray analysis data of pyrazoles 6 and 7, and isoxazole 4f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Singh, S. P.; Naithani, R.; Aggarwal, R.; Prakesh, O. Indian J.
Heterocycl. Chem. 1992, 11, 27.
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Gyertyan, I.; Fischer, J. J. Med. Chem. 2009, 52, 4329. (b) Wu, C. H.;
Hung, M. S.; Song, J. S.; Yeh, T. K.; Chou, M. C.; Chu, C. M.; Jan, J. J.;
Hsieh, M. T.; Tseng, S. L.; Chang, C. P.; Hsieh, W. P.; Lin, Y.; Yeh, Y.
N.; Chung, W. L.; Kuo, C. W.; Lin, C. Y.; Shy, H. S.; Chao, Y. S.; Shia,
K. S. J. Med. Chem. 2009, 52, 4496.
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Bioorg. Med. Chem. 2009, 17, 5549.
AUTHOR INFORMATION
Corresponding Author
*E-mail: togo@faculty.chiba-u.jp. Tel: 81-43-290-2792. Fax: 81-
43-290-2792.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. 25105710) from the Ministry of Education,
Culture, Sports, Science, and Technology in Japan, and Iodine
Research Project in Chiba University is gratefully acknowl-
edged.
(12) Sliskovic, D. R.; Roth, B. D.; Wilson, M. W.; Hoefle, M. L.;
Newton, R. S. J. Med. Chem. 1990, 33, 31.
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