One-pot regioselective synthesis of substituted pyrazoles and isoxazoles in PEG-400/water medium by Cu-free nano-Pd catalyzed sequential acyl Sonogashira coupling-intramolecular cyclization

Article abstract of DOI:10.1039/c9cy01335k

Catalyst efficacy of in situ generated Pd-nanoparticles (PdNPs) in the regioselective one-pot synthesis of 3,5-di & 3,4,5-trisubstituted pyrazoles and 3,5-disubstituted isoxazoles in environmentally benign PEG-400/H₂O medium, which involves the sequential (i) Cu-free acyl-Sonogashira coupling (ASC) and (ii) intramolecular ynone-amine cyclization under PTC conditions was described. The results of controlled experiments support the operation of two sequential catalytic cycles (ASC/cyclization) and achievement of complementary/opposite regioselectivity via ynone-bound palladium in a one-pot approach. Moreover, the in situ PdNPs recovered after the first catalytic cycle of the one-pot reaction sequence have been reused again five times successively. Besides, prior to the above studies, the efficacy of some common Pd-N-heterocyclic carbene (Pd-NHC) complexes in catalyzing the same one-pot two-step reaction sequence (Cu-free ASC/cyclization) both in water and organic solvents was also optimized. In situ generation of PdNPs from above Pd-NHCs in water was also identified, but they are not reusable due to their large size distribution.

Full text of DOI:10.1039/c9cy01335k

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One-pot regioselective synthesis of substituted
pyrazoles and isoxazoles in PEG-400/water
medium by Cu-free nano-Pd catalyzed sequential
acyl Sonogashira coupling–intramolecular
cyclization†
Cite this: Catal. Sci. Technol., 2019,
9, 6471
a
a
b
Narasimha Swamy Thirukovela, Ramesh Balaboina, Vinayak Botla,
Ravinder Vadde, * Sreekantha Babu Jonnalagadda * and Chandra Sekhar Vasam *d
a
c
Catalyst efficacy of in situ generated Pd-nanoparticles (PdNPs) in the regioselective one-pot synthesis of
3,5-di & 3,4,5-trisubstituted pyrazoles and 3,5-disubstituted isoxazoles in environmentally benign PEG-400/
2
H O
medium, which involves the sequential (i) Cu-free acyl-Sonogashira coupling (ASC) and (ii)
intramolecular ynone–amine cyclization under PTC conditions was described. The results of controlled
experiments support the operation of two sequential catalytic cycles (ASC/cyclization) and achievement of
complementary/opposite regioselectivity via ynone-bound palladium in a one-pot approach. Moreover, the
in situ PdNPs recovered after the first catalytic cycle of the one-pot reaction sequence have been reused
again five times successively. Besides, prior to the above studies, the efficacy of some common Pd–N-
heterocyclic carbene (Pd–NHC) complexes in catalyzing the same one-pot two-step reaction sequence (Cu-
free ASC/cyclization) both in water and organic solvents was also optimized. In situ generation of PdNPs from
above Pd–NHCs in water was also identified, but they are not reusable due to their large size distribution.
Received 5th July 2019,
Accepted 30th September 2019
DOI: 10.1039/c9cy01335k
rsc.li/catalysis
6
7
coupling, (v) alkynylation of activated esters and (vi) direct
Introduction
8
aldehyde C–H alkynylation. Among all, the Pd-catalyzed acyl-
α,β-Unsaturated ynones (α,β-acetylenic ketones) are practical
Sonogashira coupling reaction i.e. coupling between acid-
chlorides and alkynes is relatively a facile route to obtain
ynones and subsequent N,O-cyclization in a one-pot approach.
Previously, the ASC reaction was investigated using different
electrophilic three-carbon building blocks for diverse
1
cyclization reactions to obtain bioactive N,O-heterocycles.
Besides, this approach could be a promising alternative to
Huisgen 1,3-dipolar cycloaddition for the regioselective
synthesis of 3,5-disubstituted azoles. Classical syntheses of
ynones involve reactions of various metal acetylides with
carbonyls or their derivatives, which however require harsh
4f–l
homogeneous/heterogeneous Pd-catalysts in the absence
or
4a–e
presence of copper as a co-catalyst.
Cu-catalyzed ASC reaction was also reported.
In addition, the Pd-free
4m,n
Nevertheless,
the choice of a solvent and a copper catalyst/co-catalyst seems
to be an important consideration in the Pd-catalyzed ASC
reaction to deal with the objectives of green chemistry.
Although Cu-mediated alkyne-transmetalation is beneficial to
the increase of the reactivity of the entire ASC system, the
reason for the Cu-free ASC reaction is suggested to prevent the
potential simultaneous Glaser type oxidative dimerization of
alkynes in the presence of air or other oxidizing agents.
Moreover, the presence of a Cu-cocatalyst may complicate the
sequential transformation of in situ generated ynones in one-
pot in the presence of a Pd-catalyst under aerobic conditions.
Considering the solvent factor, although the ASC reaction can
carry on smoothly even in less polar solvents to produce
ynones, the use of highly polar solvent/co-solvents was
2
reaction conditions. Thus, a variety of catalytic methods have
been explored to synthesize ynones such as (i)
3
4
propargylicalcohol oxidation, (ii) acyl-Sonogashira coupling,
(
5
iii) carbonylative-Sonogashira coupling, (iv) acyl-Negishi
a
Department of Chemistry, Kakatiya University, Warangal, T.S, India.
E-mail: ravichemkuc@gmail.com
b
IICT, Hyderabad, T.S, India. E-mail: vinnu.chemistry@gmail.com
c
School of Physics and Chemistry, University of Kwazulu-Natal, Westville
Campus, Chiltern Hills, Durban-4000, South Africa.
E-mail: jonnalagaddas@ukzn.ac.za; Fax: +27 31 260 3091;
Tel: +27 31 2607325/3090
d
Department of Pharmaceutical Chemistry, Telangana University, Nizamabad,
T.S, India. E-mail: csvasam@telanganauniversity.ac.in
4d,9
suggested for the subsequent N,O-cyclization.
Previously, we
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cy01335k
have reported the efficacy of palladiumIJII)–N-heterocyclic
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carbenes (Pd–NHCs) in catalyzing the Sonogashira coupling to
ii) Optimization of the Pd–NHC catalyzed Cu-free one-pot
sequential ASC reaction and cyclization in organic solvents as
well as in pure water for the synthesis of 3,5-diphenyl-1H-
pyrazole (6a).
iii) Optimization of the recyclable in situ PdNP catalyzed
Cu-free one-pot sequential ASC reaction and cyclization in
PEG-400/water for the synthesis of 3,5-di & 3,4,5-trisubstituted
pyrazoles and 3,5-disubstituted isoxazoles and achievement of
complementary regioselectivity thereof.
Firstly, we explored the Pd–NHC (3a) catalyzed Cu-free ASC
reaction of benzoyl chloride (1a) with phenylacetylene (2a) in
DCM using pyrrolidine base as a model reaction to optimize
the synthesis of corresponding 1,3-diphenylprop-2-yn-1-one
(4a). The details of reaction conditions and the results are
presented in Table 1. The Pd–NHC catalyst 3a was derived
synthesize internal alkynes under copper-free conditions in
10
dichloromethane (DCM). As emphasized in the literature,
due to their special steric and electronic properties the NHC
ligands can increase the efficacy of Pd-catalysts in almost all
1
1
cross-coupling reactions as compared to phosphines.
Nevertheless, a homogeneous or heterogeneous Pd-catalyzed
Cu-free ASC reaction followed by N,O-cyclization that was
performed entirely in pure water in a one-pot approach has not
been reported yet.
Herein, we report the development of a regioselective one-
pot synthesis of substituted pyrazoles and isoxazoles with a
broad substrate scope in environmentally benign polyethylene
glycol (PEG)-400/H O medium that involves the two-step
2
reaction sequence of (i) the in situ generated PdNP catalyzed
Cu-free ASC reaction to produce in situ ynones and (ii)
intramolecular cyclization of in situ ynones with hydrazines
and hydroxyl amine. The possibility of recovery and reuse of
the above in situ PdNPs for the next catalytic cycles was also
optimized. As well, prior to the above studies, we have also
obtained the results on the efficacy of some common Pd–NHCs
as homogeneous catalysts in catalyzing the same one-pot two-
step reaction method both in organic and pure water media.
from the NHC precursor (L ) shown in Fig. 1. According to the
1
results listed in Table 1, the Pd–NHC (3a) catalyzed Cu-free
ASC reaction that was conducted in DCM has provided 93%
yield of ynone 4a at RT after 2 hours (Table 1, entry 1). The
2 6
Pd–NHCs (3b–3f) derived from other NHC-precursors (L –L ,
Fig. 1) have also shown ability in catalyzing the same ASC
reaction in DCM in the presence of pyrrolidine to provide
high yields (82–89%) of 4a (Table 1, entries 2–6). Specifically,
those Pd–NHCs containing N-aryl substituents on the NHC
ring are found to be relatively effective (Table 1, entries 1 & 3).
Besides, it is also noticeable that there was no ASC reaction in
the absence of a catalyst (Table 1, entry 7), but low yields of 4a
was obtained when PdCl and PdIJOAc) were used as catalysts
Results and discussion
The results of following three studies are discussed in a
sequence:
2
2
(Table 1, entries 8–9).
i) Optimization of the Pd–NHC catalyzed Cu-free ASC
reaction for the synthesis of 1,3-diphenylprop-2-yn-1-one (4a)
in organic solvents.
Next, the effect of solvent and base was assessed in the
same ASC reaction. It was found that the reaction conducted
in toluene and MeCN can also provide relatively high yields
a
Table 1 Optimization of reaction conditions for the ASC between 1a and 2a
b
Entry
Catalyst
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
—
PdCl
PdIJOAc)
3a
3a
3a
3a
3a
3a
3a
3a
3a
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
93
87
89
86
82
84
N.R.
39
c
2
c
2
DCM
THF
46
10
11
12
13
14
15
16
17
18
83
81
85
89
91
93
90
91
89
1,4-Dioxane
MeOH
Toluene
MeCN
DCM
DCM
DCM
DCM
3
Et N
K
2
CO
Cs CO
AcONa
3
2
3
a
b
Reaction conditions: catalyst (0.03 mmol), 1a (1.2 mmol), 2a (1 mmol), base (2.0 mmol), 2 mL of solvent and RT. Isolated yields after
c
column chromatography. Reaction time was 12 hours. [Pd–NHC] catalysts were synthesized in situ at RT by mixing PdIJOAc)
2
(0.03 mmol),
NHC ligands (0.06 mmol) and DBU (0.072 mmol) in THF (1 mL) for 2 h, followed by the removal of the solvent under reduced pressure.
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MeOH & MeCN has provided high yields (71–73%) of 6a
(
Table 2, entries 3 and 5).This could be due to the increased
solubility of amine 5a in polar MeOH & MeCN compared to
other solvents used in the present study. Furthermore, the
addition of MeCN as a co-solvent to the DCM solvent also
enhanced the rate of cyclization to provide 75% yield of 6a
(
Table 2, entry 6).
The improved result of the one-pot reaction shown above
Fig. 1 NHC-ligand precursors used in the present work.
was investigated further in pure water to produce 6a to meet
green chemistry protocols. In order to avoid the acid-
hydrolysis side reaction, 30 mol% of tetrabutylammonium
bromide (TBAB) was used as a PTC. In reality, A PTC can play
multiple roles in catalyzed reactions as a co-catalyst and a
of 4a (Table 1, entries 13–14). Concerning the results of the
base effect, the use of mild organic bases is found to be
beneficial in obtaining high yields of ynone 4a under the
operating conditions of this work (Table 1, entries 1 & 15).
Having the optimized conditions of the ASC reaction,
ynone 4a was then subjected for subsequent cyclization with
hydrazine hydrate (5a) under two different conditions to
produce corresponding 3,5-diphenyl-1H-pyrazole (6a). In (i), in
situ 4a (monitored by TLC) was reacted with 5a in the same
pot (Scheme 1A) in DCM i.e. without separating the catalyst
1
3,b
stabilizing agent of intermediates and catalysts.
As a
result, the one-pot reaction sequence (ASC-cyclization) shown
above has occurred successfully in pure water to provide 6a
in higher yields (84%) than that conducted in organic
solvents (Table 2, entry 7). However, the ASC reaction
between 1a & 2a was unsuccessful using some Pd-sources like
PdCl
2 2
and PdIJOAc) in water even after 24 hours (Table 2,
entries 8 and 9).
3
a after the ASC reaction. In (ii), pre-synthesized 4a of the
It was mentioned in the previous literature that PdIJII)-
catalysts/pre-catalysts including PdIJII)–NHCs often exhibit
heterogeneous-type catalytic behaviour generally by
speciation to form PdNPs under normal experimental
ASC reaction was allowed to react with amine 5a in the
absence of Pd–NHC catalyst 3a in DCM (Scheme 1B). Since
5
a is an inorganic base, a slight excess quantity of 5a was
1
3
used to react with ynone 4a as followed in many previous
studies of cyclization.
conditions. This evidence has raised the question: which
are the original catalytic species in cross-coupling reactions.
It is also worth noting that homogeneously dispersed PdNPs
exhibit notable ability to catalyse coupling reactions
compared to PdIJII)-complex catalysts and also offer recycling
advantages depending on the conditions. Hence, the one-pot
reaction solutions of entries 1–7 in Table 2 were further
analyzed to know the nature of the catalysts. At this point, we
would like to mention that in our work, the Pd–NHC
catalyzed one-pot reaction conducted in the presence of TBAB
in pure water has shown the formation of some un-evenly
distributed in situ PdNPs (Fig. S1, ESI†) during the synthesis
of 6a, where the reaction solution colour was fairly
transparent brown (Table 2, entry 7). On the other hand, the
Pd–NHC catalyzed one-pot reaction conducted in pure
organic solvents has shown the formation of some Pd-black
but not the PdNPs at the end of the reaction (Table 2, entry
1–6). When we have tried to re-use the above un-evenly
distributed in situ PdNPs for the next cycle of the one-pot
reaction, a low yield of pyrazole 6a was obtained (Table 2,
entry 10). This observation indicates that the unevenly PdNPs
formed from Pd–NHC catalyst 3a used in the present work
are not well protected by either an NHC or a PTC present in
the reaction solution to achieve recyclability.
4
d,9a,d,12
It was our intention to see
whether the catalyst 3a has any decisive role also during the
cyclization of 4a with 5a in terms of reaction times and
yields. Since the substrates 4a and 5a are symmetrical ones,
the question of complementary regioselectivity does not arise
during the synthesis of 6a, although the catalyzed and un-
catalyzed cyclization paths are different as shown below.
However, according to our observation, the role of Pd–NHC
catalyst 3a is not so substantial in the second step i.e. ynone–
amine cyclization to increase the yield of 6a in DCM as
compared to the same product obtained from the un-
catalyzed path.
In addition, we have also conducted few other
supplementary experiments to assess the influence of solvent
polarity in the above one-pot sequential process. We have
noticed that the role of solvent polarity in the ASC reaction to
produce ynone 4a is not much significant (Table 1), but the
role of solvents is influential during the second step i.e. the
cyclization reaction of in situ ynone 4a with amine 5a in
producing the desired pyrazole 6a. Therefore, the entire one-
pot reaction (ASC-cyclization) conducted exclusively in polar
Based on the above observations, we intend to re-
investigate the above one-pot reaction sequence using well
dispersed in situ PdNPs obtained from PdCl in PEG-400/H O
2
2
medium. PEGs are known as effective, inexpensive and
soluble polymeric stabilizing agents and reducing agents for
1
4
well/homogeneously dispersed PdNPs. PEGs are also known
1
5
Scheme 1 Synthesis of 3,5-diphenyl-1H-pyrazole (6a).
as effective solvents for certain organic transformations.
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a
Table 2 Optimization of reaction conditions for the one-pot synthesis of 6a
b
Entry
Cat. Pd
Solvent
THF
1,4-Dioxane
MeOH
Toluene
MeCN
DCM
Time (h) step-i/step-ii
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
2/3.5
2/3.5
2/3
2/4
2/3
61
64
71
41
73
75
84
NR
NR
53
87
64
82
c
2/3
3/3
d
2
H O
2
H O
2
H O
2
H O
d
PdIJOAc)
PdCl
Isolated PdNPs
PdCl
PdIJOAc)
PdCl
Pre-prepared PdNPs
2
24/−
24/−
3/3.5
2.5/3
4/6
d
2
e
1
1
1
1
1
0
1
2
3
4
f
2
PEG-400/H
PEG-400/H
PEG-400
2
O
O
f
2
2
g
2
2.5/3.5
3/4
h
PEG-400/H
2
O
79
a
Reaction conditions: step 1: cat. Pd (0.03 mmol), 1a (1.2 mmol), 2a (1 mmol), pyrrolidine (2.0 mmol), 2 mL solvent, RT and 2 h. Step 2: 2
b
c
d
mmol (4a), 60 °C and 3 h. Isolated yields after column chromatography. In step 2, 1 mL of MeCN was added. TBAB (0.3 mmol) was added.
e
g
f
In situ PdNPs obtained from 3a in the presence of TBAB were isolated and then reused. 6 mL of PEG-400/H
2
O (2 : 1) and TBAB (0.3 mmol).
h
4
mL of PEG-400. Pre-prepared PdNPs. NR = no reaction.
Therefore, we thought that the combination of PEG-400 and
H O would provide synergistic effect i.e. effective
stoichiometric amount of nitrogen bases was also
investigated using in situ PdNPs and the results are presented
in the ESI.†
a
2
stabilization of PdNPs and a green reaction medium. It was
mentioned in the literature that the polar capping agent
forms a more open structure in water and in turn facilitates
1
6
Substrate scope and possibility of achieving complementary
regioselectivity
an easy contact between reactants and the metal surface.
Indeed such a situation is complementary in catalysis since
strong encapsulation could lead to loss of catalytic activity.
The one-pot reaction of 1a, 2a and 4a conducted in the
The catalytic conditions optimized with the in situ PdNPs
in PEG-400/water for the one-pot synthesis of 6a have
been extended further to make use of different acid halide
2 2
presence of PdCl /PEG-400/H O under PTC conditions has
generated in situ PdNPs, which have catalyzed the ASC/
cyclization sequence effectively to produce 6a in 87% yield
and
alkyne
substrates
to
generate
symmetrical/
unsymmetrical ynones (in situ) and their subsequent
cyclization with hydrazines and hydroxyl amine to produce
corresponding substituted pyrazoles (Table 3) and
isoxazoles (Table 4).
(
Table 2, entry 11). The formation of uniformly dispersed in
situ PdNPs (7–8 nm) after the first catalytic cycle was
confirmed by a TEM study (Fig. S2, ESI†). When PdIJOAc)
2
was used as a precursor for in situ PdNPs to catalyze the one-
pot reaction of 1a, 2a and 4a, only 64% yield of 6a was
Depending on the types of substrates (ynones/hydrazines/
hydroxyl amine), we have also observed the achievement of
complementary regioselectivity in the above substituted
pyrazole and isoxazole products. The results in
Tables 3 and 4 reveal that specifically the reaction of
unsymmetrical ynones with phenyl hydrazine and hydroxyl
amine has provided the complementary regioselectivity in the
corresponding pyrazole (Table 3, entries 6l–6s) and isoxazole
products (Table 4, entries 8b–8n) as compared to the
obtained indicating that PdIJOAc)
for in situ PdNPs in PEG-400/H O (Table 2, entry 12). Besides,
it is interesting to observe that the in situ PdNP (obtained
from PdCl only in PEG-400) catalyzed system has provided a
slightly less yield of 4a compared to the in situ PdNP
2
was not an effective source
2
2
(
(
obtained from PdCl2 in PEG-400/H O) catalyzed system
Table 2, entry 13). We have also conducted an additional
2
9
b,12a,18a
experiment for the one-pot synthesis of 4a using pre-
products obtained from the un-catalyzed reaction.
prepared PdNPs that were obtained from PdCl /PEG-400 i.e.
Other important observations concerning the substrate
scope experimentation areas shown below;
2
2
without the combination of H O according to a literature
1
7
procedure. This time 78% yield of 6a (Table 1, entry 14)
was obtained from the one-pot sequence. These results
suggested that the in situ generated Pd nanoparticles are
slightly more active catalysts than the pre-formed Pd
nanoparticles. Further, the effect of reaction parameters such
(i) When the ynones obtained from aromatic acid halides/
alkynes are used as substrates for cyclization, relatively better
yields of respective pyrazoles (Table 3, entries 6a and 6b &
6d–6j) and isoxazoles (Table 4, entries 8a–8l) were obtained
as compared to ynones obtained from aliphatic acid halides
and alkynes.
as temperature, the nature of PEG
& PTC and the
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Table 3 Synthesis of di- and tri-substituted pyrazolesa,b
6
6
a, 87%
c
6
6
b, 88%
6c, 77%
6d, 92%
e, 88%
f, 90%
6g, 88%
6h, 84%
d
6l, 83%
6
6
i, 86%
6j, 86%
c
6
k, 76%
d
m, 81%
d
d
d
6
6
n, 80%
6o, 78%
6p, 75%
d
6
q, 80%
d
d
r, 79%
6s, 81%
a
Reaction conditions: step 1: PdCl
2
(0.03 mmol), 6 mL of PEG-400/H
2
O (2 : 1), TBAB (0.3 mmol), 1a (1.2 mmol), 2a (1 mmol), pyrrolidine (2.0
b
c
mmol), RT and 2.5 h. Step 2: 2.0 mmol (5a), 60 °C, 3 h. Isolated yields after column chromatography. In step 1 the reaction time was 3 h.
d
In step 2 the reaction time was 5 h.
(ii) The presence of an electronic withdrawing group on
symmetrical/un-symmetrical ynone–hydrazones involved in
phenylacetylenes (Table 3, entries 6b & 6l–6m and Table 4,
entries 8b and 8c) and an electron releasing group and
benzoyl chlorides (Table 3, entries 6e–6h & 6s and Table 4,
entries 8h and 8i) has increased yields of corresponding
azoles from the ASC-cyclization sequence.
intramolecular cyclization to form tri-substituted ones was
1
8b
reported.
However, the role of a metal-catalyst including
PdNPs in catalyzing the sequential ASC and intramolecular
cyclization in one-pot to produce pyrazoles and isoxazoles
has not been described yet.
(
iii) The aryl bromide functionality remained unchanged
i.e. no coupling with terminal alkyne) during the ASC-
cyclization (Table 3, entry 6e).
iv) The reactivity of phenyl hydrazine was low as
Therefore, to understand this phenomenon, we have
carried out some controlled experiments. As shown in
Scheme 2, the reaction of pre-synthesized ynone (4b) with
phenyl hydrazine (5b) and hydroxyl amine (7) in the absence
of a Pd-catalyst at 60 °C did not form the expected pyrazole
and isoxazole, but did form intermediates (A & B) only via
cyclo-condensation. Upon dehydration in the presence of
(
(
compared to hydrazine hydrate with ynones and hence a
slight decrease in the yields of corresponding tri-substituted
pyrazoles has been found (Table 3, entries 6b & 6l and 6m
and Table 4, entries 6l–6s).
2 4
H SO , intermediates A & B were converted to 1,5-diphenyl-3-
(
(
p-tolyl)-1H-pyrazole (6q) and 5-phenyl-3-(p-tolyl)isoxazole
1
2a,18a
8h), respectively, as observed previously.
It is worth
Mechanism
noting that, when the above reaction was catalyzed by PdNPs,
Previously, the mechanism of the Cu-free Pd-catalyzed ASC
the reaction occurred via intramolecular cyclization and
4
f,h–i
reaction was described.
Pd-Catalyzed activation of
provided
1,3-diphenyl-5-(p-tolyl)-1H-pyrazole
(6m)
and
symmetrical/un-symmetrical ynone–oxime involved in
3-phenyl-5-(p-tolyl)isoxazole (8b) as sole products. This means
that the products obtained via the catalyzed path are
complementary to the products obtained via the un-catalyzed
intramolecular cyclization to form the isoxazoles was also
1
8a,19
reported.
Besides,
a
Cu-catalyzed activation of
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Table 4 Synthesis of di-substituted isoxazolesb
8a, 85%
a
8
8
b, 86%
8c, 89%
8d, 82%
8g, 79%
f, 84%
8
8
e, 81%
h, 83%
8
8
i, 81%
8j, 91%
8k, 92%
c
c
m, 76%
8n, 79%
8l, 84%
a
2 2
Reaction conditions: step 1: PdCl (0.03 mmol), 6 mL of PEG-400/H O (2 : 1), TBAB (0.3 mmol), 1a (1.2 mmol), 2a (1 mmol), pyrrolidine (2.0
b c
mmol), RT and 2.5 h. Step 2: 7 (2.0 mmol), AcONa (2.4 mmol), 60 °C and 5 h. Isolated yields after column chromatography. Step 1: Reaction
time was 3 h.
path. The structures of 6q, 8h, 6m and 8b were analysed by
physical state and melting point that consistent with previous
report (see experimental section).
optimized conditions there was no substantial influence on
the catalytic activity.
In continuation, we have also added different quantities
of carbon disulfide (0, 0.65, 1 and 1.5 equivalents to that of
palladium) to the reaction mixture of Scheme 3. We have
noticed that in the presence of 0 and 0.65 equivalents of CS2,
both ASC and intramolecular cyclitization reactions were still
operative and gave the desired product 6m in the range of
77–81% yields, (entries 1 and 2, Scheme 4). However, when
Although the in situ generated PdNPs have shown good
catalytic activity, we didn't know whether the catalysis
occurred either on the surface of the cluster or by leached Pd
2
0
species. Therefore, we have carried out some controlled
experiments to evaluate the homogeneous/heterogeneous
nature of the active PdNP catalytic system (Scheme 3). When
1
00 equivalents of Hg(0) (relative to palladium) was added to
the amount of CS
the ASC reaction between 1a and 2b was almost non-existent
entries 3 and 4, Scheme 4). These observations suggest that
the active catalytic system is very likely to be homogeneous in
2
was increased to 1.0 and 1.5 equivalents,
the one-pot two step reaction of 1a, 2b and 5b under the
(
2
1
nature.
Based on the above controlled experiments and from the
4
f,h–i,14a,b,18,19,22
literature
a plausible catalytic cycle has been
proposed. According to Scheme 5, initially, aroyl halides
undergo oxidative addition with the in situ generated Pd(0)
NPs catalytic system to form aroyl-PdIJII)–Cl intermediate A.
Scheme
2 Controlled experiments and achievement of opposite
regioselectivity in the uncatalyzed versus catalyzed reaction.
Scheme 3 Hg poisoning test.
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Fig. 2 Data showing the recyclability of in situ PdNPs.
2
Scheme 4 CS poisoning test.
which may be due to aggregation after the 6th catalytic run
Fig. S3, ESI†).
(
Conclusions
In conclusion, our results have demonstrated the first
example of in situ PdNPs catalyzed regioselective one-pot
synthesis of various substituted pyrazoles and isoxazoles in
an environmentally benign PEG-400/water system. A plausible
mechanism has been proposed by considering the outcome
of controlled experiments and literature studies explaining
the operation of two sequential Pd-catalytic cycles (ASC/
intramolecular cyclization) for the synthesis of ynones and
the subsequent conversion to pyrazoles and isoxazoles. It is
interesting to note that opposite regioselectivity was observed
between the catalyzed reaction products and the un-catalyzed
reaction products. The recovery of PEG-supported PdNPs
obtained from the first phase of catalytic cycles has shown
remarkable recyclable catalytic activity up to five successive
catalytic cycles.
The results of present one-pot methodology (ASC-
cyclization) are comparable or relatively better than the
previous studies conducted in pure organic or mixed organic
solvent systems. Besides, the optimization of Cu-free Pd-
catalyzed ASC in pure water for the synthesis of various
symmetric/asymmetric ynones, the first of its kind, offers a
broad substrate scope for the development of other
cyclization to obtain a variety of heterocycles in water. Our
mechanistic studies suggest a typical heterogeneous reaction
process that is unlikely to be in operation.
Scheme 5 A plausible reaction mechanism.
Later Pd–alkyne coordination takes place in the presence of a
pyrrolidine base, which in turn forms Pd–alkyne complex C
through the transitory intermediate B. Finally, the reductive
elimination of intermediate C facilitates the formation of
ynone D and regeneration of Pd(0)NPs. These regenerated
PdNPs again start the second catalytic cycle through their
coordination with the C–C triple bond of in situ formed
ynone D. The resulting activated ynone–palladium
intermediate E then converts to ynone–hydrazone/ynone–
oxime intermediate F by reacting with hydrazines/hydroxyl
amine. Then, the 5-endo-dig cyclization of intermediate F
occurs to form pyrazolyl–palladium/isoxazolyl–palladium
intermediate G. Finally, the substituted pyrazole/isoxazole
products were obtained regioselectively upon the subsequent
deprotonation and depalladation–protonation process.
Experimental
General information
Recyclability of the in situ PdNP (PdCl /PEG-400) catalytic
system
All commercially available reagents were used without further
purification. The purity of the compounds was checked by
TLC using Merck 60F254 silica gel plates. Transmission
electron microscopy (TEM) analysis was performed using a
PHILIPS instrument-CM 200 with an operating voltage of 20–
2
The reusability efficiency of the PEG-PdNPs in the one-pot
synthesis of pyrazole 6l was investigated (Fig. 2). After the
formation of 6l in the first catalytic cycle, the reaction
mixture was extracted with diethyl ether (4 × 10 mL) and the
solidified PdNPs were reused for the next catalytic run. It was
observed that the recycled PdNPs have shown significant
catalytic efficiency up to 5 successive catalytic runs. The TEM
studies reveal that the PdNP sizes were increased to 20 nm
1
13
200 kV and a resolution of 2.4 Å. H & C NMR spectra were
recorded with a Mercury Plus spectrometer (operating at 500/
1
13
400/300 MHz for H & 125/100/75 MHz for C) and chemical
shifts were referenced to TMS.
Ex situ nanoparticles were synthesized according to a
1
7
literature procedure. PdCl (3 mol%) was added into PEG-
2
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00 (4 g) present in a 25 mL round bottom flask and was
isoxazoles. It has been noticed that the reaction time was 5
hours in the second step.
allowed to stirr at room temperature for overnight. After the
completion of the reaction, the colour of the solution turned
from light yellow to dark, indicating the formation of
palladium nanoparticles. Then, these PdNPs were used to
catalyze the one-pot three-component reaction of 1a, 2a and 5a.
Hg(0) poisoning test. As per the general procedure for the
synthesis of 6m, PdCl (0.03 mmol), benzoyl chloride 1a (1.2
2
mmol), TBAB (0.3 mmol), pyrrolidine (2.0 mmol) 4-ethynyl
toluene 2b (1.0 mmol) and 6 mL of PEG-400/H O (2 : 1)
2
solution with the addition of elemental Hg (3 mmol, 100
equivalent to that of relative palladium) were successively
added and the resulting reaction mixture was stirred at RT
for 2.5 hours. After the in situ formation of ynone,
phenylhydrazine 5b (2.0 mmol) was added. The resulting
mixture was stirred for additional 5 hours at 60 °C to achieve
General procedure for the synthesis of 4a & 4b
Synthesis of 1,3-diphenylprop-2-yn-1-one (4a). To a 10 mL
round bottom flask containing 1 mL of dry THF, 0.03 mmol
of PdIJOAc)
2
, 0.06 mmol of NHC precursor L
1
and 0.072 mmol
atmosphere and
of DBU were successively added under a N
2
7
8% yield of 6m indicating that the reaction was not
inhibited by introducing Hg(0).
CS poisoning test. As per the general procedure for the
the mixture was allowed to stir at room temperature for 2 h.
Later the solvent was removed under reduced vacuum. Then,
benzoyl chloride 1a (1.2 mmol), pyrrolidine (2.0 mmol) and
phenylacetylene 2a (1.0 mmol) in 2 mL DCM were added and
the whole reaction mixture was stirred at RT for 2 hours. The
completion of the reaction was monitored by TLC, and the
crude reaction mixture was extracted twice with DCM/H O (5
2 4
mL). The combined organic layers were dried over Na SO ,
filtered and concentrated under reduced pressure to give the
crude product. The crude product was further analyzed by
column chromatography using (10 : 1) hexane : ethyl acetate
2
synthesis of 6m, PdCl (0.03 mmol), benzoyl chloride 1a (1.2
2
mmol), TBAB (0.3 mmol), pyrrolidine (2.0 mmol) 4-ethynyl
toluene 2b (1.0 mmol) and 6 mL of PEG-400/H O (2 : 1)
2
solution were employed as a control. CS (0 equivalent & 0.65
2
2
equivalent to that of palladium) correspondingly was added
to the above reaction mixtures and stirred at RT for 2.5 h.
After the in situ formation of ynone, phenylhydrazine 5b (2.0
mmol) was added. The resulting mixture was allowed to stir
for further 5 hours at 60 °C to afford 77–81% yield of 6m.
When we carried out the same reaction using 1.0 and 1.5
as an eluent to give the pure product 4a.
4
1
,3-Diphenylprop-2-yn-1-one (4a). 93% yield; white solid;
2
equivalents of CS there was no ASC reaction. Successive
investigations of the reactions recommend that the reactions
1
M.P. 42–44 °C; H NMR (400 MHz, CDCl
3
) δ 8.20 (dd, J = 7.9,
1
7
1
8
.5 Hz, 1H), 7.63–7.57 (m, 2H), 7.55 (t, J = 8.1 Hz, 1H), 7.33–
.25 (m, 2H) ppm; C NMR (400 MHz, CDCl ): δ 178.5,
37.4, 134.5, 133.7, 131.4, 130.1, 129.4, 129.1, 120.1, 93.5,
7.4 ppm.
are totally inhibited when we added ≥1.0 equivalents of CS2.
1
3
3
General procedure for the recyclability of PEG-PdNPs
4
1
-(4-Methylphenyl)-3-phenylpropynone (4b). 91% yield;
After the first experimentation, the reaction mixture was
extracted with diethyl ether (4 × 10 mL) and the solidified
PdNPs were exposed to a second catalytic run using the same
1
white solid; M.P. 85–86 °C; H NMR (400 MHz, CDCl
3
) δ 8.02
(d, J = 8.5 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.45–7.38 (m, 3H),
1
3
7
.25 (d, J = 8.5 Hz, 2H), 2.35 (s, 3H) ppm; C NMR (400
) δ 177.8, 145.4, 134.7, 133.4, 131.2, 129.8, 128.7,
20.2, 93.2, 87.3, 22.7 ppm.
substrates in a 1 : 2 ratio of the PEG-400/H O solvent system
2
MHz, CDCl
1
3
under the optimized conditions.
2
3
3
,5-Diphenyl-1H-pyrazole (6a). 85% yield; white solid; M.
1
P. 191–193 °C; H NMR (CDCl , 400 MHz) δ 7.74 (d, J = 7.2
3
General procedure for the one-pot synthesis of substituted
pyrazole and isoxazoles
13
Hz, 4H), 7.33–7.40 (m, 6H), 6.88 (s, 1H) ppm; C NMR
(
DMSO-d , 100 MHz) δ 128.9, 127.9, 125.2, 99.8 ppm.
6
9
a
Synthesis of 3,5-diphenyl-1H-pyrazole (6a). To a 25 mL
round-bottom flask containing 6 mL of PEG-400/H
3-Phenyl-5-p-tolyl-1H-pyrazole (6b). 87% yield; white
1
2
O (2 : 1)
solid; M.P. 160–162 °C; H NMR (CDCl
3
, 400 MHz) δ 7.76 (d,
solution, PdCl (0.03 mmol), benzoyl chloride 1a (1.2 mmol),
J = 4.2 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.23–7.46 (m, 5H),
2
1
3
TBAB
(0.3
mmol),
pyrrolidine
(2.0
mmol)
and
6.84 (s, 1H), 2.39 (s, 3H) ppm; C NMR (DMSO-d , 100 MHz)
6
phenylacetylene 2a (1.0 mmol) were successively added and
the whole reaction mixture was stirred at RT for 2.5 hours.
The formation of in situ ynone 4a was confirmed by TLC, and
hydrazine hydrate 5a (2.0 mmol) was then added and stirring
was continued for further 3 hours at 60 °C. Then, the
reaction mixture was cooled to RT and extracted with diethyl
ether (4 × 10 mL). The organic layers were combined and the
volatile components were evaporated under reduced pressure.
Finally, the crude product was purified by column
chromatography (silica gel 60–120 mesh size) using ethyl
acetate/hexane (1 : 4) as an eluent to obtain 87% yield of (6a).
A similar procedure was used to synthesize 3,5-disubstituted
δ 129.3, 128.7, 125.05, 125.02, 99.2, 20.8 ppm.
2
3
5-Butyl-3-phenyl-1H-pyrazole (6c) . 77% yield; yellow oil;
1
H NMR (400 MHz, CDCl ) δ 7.63–7.49 (m, 2H), 7.44–7.31 (m,
3
3H), 6.41 (s, 1H), 2.73 (t, J = 8.0 Hz, 2H), 1.66 (p, J = 7.9 Hz,
2H), 1.44–1.31 (m, 2H), 0.94 (t, J = 6.6 Hz, 3H) ppm; C NMR
1
3
(DMSO-d , 100 MHz) δ 128.6, 125.4, 100.4, 31.3, 22.1, 13.9
6
ppm.
2
3
3-(4-Fluorophenyl)-5-phenyl-1H-pyrazole (6d). 92% yield;
1
white solid; M.P. 168–170 °C; H NMR (CDCl , 500 MHz) δ
3
7.77–7.72 (m, 3H), 7.50–7.38 (m, 4H), 7.10 (t, J = 8.1 Hz, 2H),
1
3
6.83 (s, 1H) ppm; C NMR (DMSO-d , 125 MHz) δ 131.5,
6
129.7, 128.4, 127.7, 127.6, 125.6, 116.3, 116.0, 100.1 ppm.
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2
3
3
-(4-Bromophenyl)-5-phenyl-1H-pyrazole (6e). 88% yield;
δ 152.4, 143.3, 139.7, 132.7, 131.6, 130.1, 129.4, 128.6, 128.2,
1
white solid; M.P. 217–219 °C; H NMR (400 MHz, CDCl ) δ
.65–7.58 (m, 4H), 7.49 (d, J = 7.7 Hz, 2H), 7.47–7.41 (m, 3H),
.82 (s, 1H) ppm; C-NMR (DMSO-d , 100 MHz) δ 132.0,
127.6, 125.7, 125.1, 122.3, 105.4 ppm.
3
2
4
7
6
1
5-(4-Chlorophenyl)-1,3-diphenyl-1H-pyrazole
(6o). 78%
1
3
1
yield; white solid; M.P. 104–106 °C; H NMR (400 MHz, CDCl )
6
3
31.0, 129.9, 128.6, 127.8, 127.5, 125.9, 100.1 ppm.
δ 7.93 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.35–7.19 (m,
2
3
13
3
-(4-Chlorophenyl)-5-phenyl-1H-pyrazole (6f). 90% yield;
8H), 7.10 (d, J = 8.2 Hz, 2H), 6.84 (s, 1H) ppm; C NMR (100
1
white solid; M.P. 216–218 °C; H-NMR (400 MHz, CDCl ) δ
MHz, CDCl ) δ 152.1, 143.2, 139.9, 134.4, 132.9, 130.0, 129.1,
3
3
7
.72–7.64 (m, 4H), 7.56–7.48 (m, 4H), 7.38–7.30 (m, 1H), 6.83
129.0, 128.7, 128.1, 127.7, 125.9, 125.4, 105.3 ppm.
1
3
24
(
1
s, 1H) ppm; C-NMR (DMSO-d
25.0, 99.2 ppm.
-(5-Phenyl-1H-pyrazol-3-yl)benzonitrile (6g). 88% yield;
6
, 100 MHz) δ 128.7, 126.9,
5-(4-Nitrophenyl)-1,3-diphenyl-1H-pyrazole
(6p). 75%
1
yield; white solid: M.P. 135–137 °C; H NMR (400 MHz,
2
3
4
CDCl ) δ 8.23 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 7.6 Hz, 2H),
3
1
13
yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.77 (q, J = 7.8 Hz,
7.45–7.25 (m, 10H), 6.94 (s, 1H) ppm; C NMR (100 MHz,
4
7
H), 7.62 (dd, J = 7.6, 1.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H),
CDCl ) δ 152.6, 147.4, 142.2, 139.8, 136.8, 132.4, 129.3, 128.7,
3
1
3
.37–7.30 (m, 1H), 6.87 (s, 1H) ppm; C-NMR (DMSO-d , 100
128.3, 125.9, 125.4, 123.7, 106.4 ppm.
6
2
4
MHz) δ 157.6, 146.8, 133.0, 130.1, 129.8, 128.9, 127.4, 125.6,
19.1, 110.1, 100.1 ppm.
-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole
1,5-Diphenyl-3-(p-tolyl)-1H-pyrazole
(6q). 80%
yield;
1
1
white solid; M.P. 126–128 °C; H NMR (400 MHz, CDCl ) δ
3
2
3
3
(6h). 84%
7.81 (d, J = 7.7 Hz, 2H), 7.34–7.10 (m, 12H), 6.80 (s, 1H), 2.38
1
13
yield; white solid; M.P. 144–146 °C; H NMR (400 MHz,
3
(s, 3H) ppm; C NMR (100 MHz, CDCl ) δ 152.2, 144.1,
CDCl ) δ 7.74 (d, J = 7.1 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H),
140.4, 137.7, 130.6, 130.1, 129.5, 128.9, 128.4, 127.6, 125.7,
125.2, 104.8 ppm.
3
7
6
.38–7.30 (m, 2H), 7.37–7.31 (m, 1H), 6.91 (d, J = 8.6 Hz, 1H),
1
3
25
.72 (s, 1H), 3.86 (s, 1H) ppm; C NMR (DMSO-d
6
, 100 MHz)
3-(4-Methoxyphenyl)-1,5-diphenyl-1H-pyrazole (6r). 79%
1
δ 129.4, 127.2, 125.3, 114.6, 99.6, 55.5 ppm.
yield; white solid; M.P. 143–144 °C; H NMR (400 MHz,
1
2a
5
-Phenyl-3-(m-tolyl)-1H-pyrazole (6i).
86% yield; white
solid; M.P. 176–178 °C; H NMR (500 MHz, CDCl ) δ 7.75–
.68 (m, 2H), 7.54 (t, J = 1.9 Hz, 1H), 7.44–7.37 (m, 3H), 7.35–
3
CDCl ) δ 7.87 (d, J = 8.1 Hz, 2H), 7.42–7.24 (m, 10H), 6.97 (d,
1
13
3
J = 8.1 Hz, 2H), 6.75 (s, 1H), 3.83 (s, 3H) ppm; C NMR (100
7
7
1
1
MHz, CDCl ) δ 159.8, 151.6, 144. 6, 140.2, 130.7, 128.9, 127.5,
3
1
3
.21 (m, 2H), 6.82 (s, 1H), 2.33 (s, 3H) ppm; C NMR (CDCl
00 MHz) δ 148.7, 138.1, 131.3, 128.7, 128.4, 127.8, 126.2,
3
,
125.8, 125.2, 114.3, 104.6, 55.6 ppm.
2
4
3-(4-Chlorophenyl)-1,5-diphenyl-1H-pyrazole
(6s). 81%
yield; white solid; M.P. 138–139 °C; H NMR (400 MHz,
CDCl ) δ 7.91 (d, J = 7.7 Hz, 2H), 7.45–7.23 (m, 12H), 6.82 (s,
1H) ppm; C NMR (100 MHz, CDCl
1
25.6, 122.7, 99.6, 21.4 ppm.
3
2
3
-(Furan-2-yl)-5-phenyl-1H-pyrazole
(6j). 86%
yield;
) δ
.59–7.72 (m, 3H), 7.47–7.31 (m, 3H), 6.81 (s, 1H), 6.71 (dd, J
3
1
13
yellow solid; M.P. 172–174 °C; H NMR (400 MHz, CDCl
3
3
) δ 150.7, 144.7, 139.8,
7
=
133.6, 131.5, 130.3, 129.2, 128.9, 128.3, 127.8, 127.3, 125.4,
104.9 ppm.
1
3
7.8, 1.9 Hz, 1H), 6.49 (t, J = 7.8 Hz, 1H) ppm; C NMR
, 100 MHz) δ 148.4, 146.8, 142.4, 129.4, 128.7,
28.3, 125.8, 111.7, 106.5, 99.6 ppm.
-Cyclohexyl-5-phenyl-1H-pyrazole (6k).
2
5
(
DMSO-d
6
3,5-Diphenylisoxazole (8a). 85% yield; white solid; M.P.
1
1
141–142 °C; H NMR (CDCl , 400 MHz) δ 7.80–7.86 (m, 4H),
3
1
2a
13
3
76% yield; white
, 400 MHz) δ 7.73
dd, J = 7.7, 1.8 Hz, 1H), 7.37–7.24 (m, 3H), 6.33 (s, 1H), 3.32–
7.42–7.51 (m, 6H), 6.80 (s, 1H) ppm; C NMR (100 MHz,
1
solid; M.P. 137–138 °C; H NMR (CDCl
3
CDCl
126.8, 125.6, 97.1 ppm.
3-Phenyl-5-(p-tolyl)isoxazole (8b). 86% yield; yellow solid;
3
) δ 170.4, 162.7, 130.2, 129.8, 129.1, 128.8, 128.7, 127.5,
(
2
6
3
.25 (m, 1H), 2.68–2.59 (m, 1H), 2.03–1.91 (m, 2H), 1.38–1.24
1
3
1
(m, 6H) ppm; C NMR (100 MHz, CDCl
3
) δ 152.5, 149.8,
3
M.P. 137–138 °C; H NMR (400 MHz, CDCl ) δ 7.86 (dd, J =
1
32.7, 128.6, 127.9, 125.5, 99.7, 35.8, 32.7, 26.4, 26.2 ppm.
7.9, 1.9 Hz, 2H), 7.70 (d, J = 8. 1 Hz, 2H), 7.51–7.45 (m, 2H),
7.34–7.25 (m, 3H). 6.79 (s, 1H), 2.40 (s, 1H) ppm; C NMR
2
2
13
5
-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole (6l). 82%
1
yield; white solid; M.P. 77–78 °C; H NMR (400 MHz, CDCl
δ 7.91 (d, J = 7.8 Hz, 2H), 7.42–7.20 (m, 10H), 6. 86 (d, J = 8.1
3
)
(100 MHz, CDCl
127.6, 125.7, 124.6, 97.2, 21.7 ppm.
5-(4-Methoxyphenyl)-3-phenylisoxazole (8c). 89% yield;
3
) δ 170.9, 163.1, 140.9, 130.3, 129.9, 129.3,
1
3
27
Hz, 2H), 6.75 (s, 1H), 3.82 (s, 3H) ppm; C NMR (100 MHz,
CDCl ) δ 159.5, 151.6, 144.4, 140.1, 133.2, 130.3, 128.8, 128.1,
27.2, 125.8, 125.2, 123.1, 114.2, 104.4, 55.6 ppm.
1
3
white solid; M.P. 126–127 °C; H NMR (400 MHz, CDCl
3
) δ
1
7.86–7.78 (m, 4H); 7.51–7.40 (m, 3H); 6.95 (d, 2H, J = 8.7 Hz),
2
4
13
1
,3-Diphenyl-5-(p-tolyl)-1H-pyrazole (6m). 81% yield;
3
6.79 (s, 1H); 3.82 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ 1
1
yellow solid; M.P. 114–116 °C; H NMR (400 MHz, CDCl
3
) δ
70.4, 163.1, 161.3, 129.9, 129.4, 128.8, 127.4, 126.5, 120.2,
114.1, 96.9, 56.0 ppm.
7
.91 (d, J = 7.6 Hz, 2H), 7.39–7.16 (m, 10H), 7.11 (d, J = 7.9
1
3
27
Hz, 2H), 6.80 (s, 1H), 2.37 (s, 3H) ppm; C NMR (100 MHz,
CDCl ) δ 151.7, 144.4, 140.5, 138.3, 133.4, 129.1, 128.8, 128.1,
27.6, 127.3, 125.7, 125.1, 104.9, 21.4 ppm.
-(4-Bromophenyl)-1,3-diphenyl-1H-pyrazole
5-(4-Chlorophenyl)-3-phenylisoxazole (8d). 82% yield;
1
3
colourless solid; M.P. 176–178 °C; H NMR (400 MHz, CDCl
3
)
C
1
3
1
δ 7.96–7.86 (m, 4H), 7.49–7.37 (m, 5H), 6. 83 (s, 1H) ppm;
NMR (100 MHz, CDCl ) δ 170.6, 163.2, 136.4, 130.3, 129.1,
128.6, 127.1, 126.4, 125.7, 97.9 ppm.
5-(3-Chlorophenyl)-3-phenylisoxazole (8e). 81% yield;
2
4
5
(6n). 80%
3
1
yield; yellow solid; M.P. 129–131 °C; H NMR (400 MHz,
CDCl ) δ 7.90 (d, J = 7.8 Hz, 2H), 7.46–7.17 (m, 10H), 7.05 (d,
J = 7.8 Hz, 2H), 6.84 (s, 1H) ppm; C NMR (100 MHz, CDCl
2
5
3
1
3
1
3
)
3
white solid; M.P. 105–107 °C; H NMR (400 MHz, CDCl ) δ
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1
1
.89–7.83 (m, 3H); 7.74 (s, 1H); 7.44–7.35 (m, 5H), 6.86 (s, Acknowledgements
1
3
H) ppm; C NMR (100 MHz, CDCl ) δ 169.6, 163.4, 135.3,
3
The authors are thankful to UGC, New Delhi, India [F.No. 17-
80/2009IJSA-I)], DST (SERB), New Delhi, India [F.No. SR/S1/IC-
31/2011] and DST-India (DST/INT/SA/P-15/2011 Indo-South
Africa project) for financial support.
30.8, 130.1, 129.2, 126.7, 125.9, 124.2, 98.2 ppm.
2
5
5
-(4-Bromophenyl)-3-phenylisoxazole (8f). 84% yield;
1
white solid; M.P. 155–157 °C; H NMR (400 MHz, CDCl ) δ
3
7
6
1
.80–7.71 (m, 4H), 7.63 (d, J = 7.8 Hz, 1H), 7.49–7.42 (m, 3H),
1
3
.82 (s, 1H) ppm; C NMR (100 MHz, CDCl ) δ 169.3, 163.1,
3
32.5, 130.3, 129.1, 127.5, 126.8, 126.4, 124.5, 97.7 ppm.
Notes and references
2
5
5
-(3-Nitrophenyl)-3-phenylisoxazole
(8g). 79%
yield;
1
white solid; M.P. 167–169 °C; H NMR (400 MHz, CDCl ) δ
1 (a) A. Jeevanandam, K. Narkunan and Y.-C. Ling, J. Org.
Chem., 2001, 66, 6014; (b) A. V. Kelin and V. Gevorgyan,
J. Org. Chem., 2002, 67, 95; (c) H. Arzoumanian, M. Jean, D.
Nuel, A. Cabrera, J. L. G. Gutierrez and N. Rosas,
Organometallics, 1995, 14, 5438; (d) B. G. VandenHoven, B. El
Ali and H. Alper, J. Org. Chem., 2000, 65, 4131; (e) V. Lellek
and H.-J. Hansen, Helv. Chim. Acta, 2001, 84, 3548; ( f ) M.
Hojo, K. Tomita and A. Hosomi, Tetrahedron Lett., 1993, 34,
485; (g) R. K. Dieter and K. Lu, J. Org. Chem., 2002, 67, 847;
(h) D. B. Grotjahn, S. Van, D. Combs, D. A. Lev, C. Schneider,
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Chem., 2002, 67, 9200; (i) X. Wang, J. Tan and L. Zhang, Org.
Lett., 2000, 2, 3107; ( j) A. V. Kelin, A. W. Sromek and V.
Gevorgyan, J. Am. Chem. Soc., 2001, 123, 2074; (k) A. S. Karpov
and T. J. J. Muller, Org. Lett., 2003, 5, 3451; (l) M. C. Bagley,
D. D. Hughes and P. H. Taylor, Synlett, 2003, 259; (m) C. G.
Savarin, J. A. Murry and P. G. Dormer, Org. Lett., 2002, 4,
2071; (n) M. C. Bagley, D. D. Hughes, R. Lloyd and V. E. C.
Powers, Tetrahedron Lett., 2001, 42, 6585; (o) D. D. Hughes
and M. C. Bagley, Synlett, 2002, 1332; (p) A. Arcadi, F.
Marinelli and E. Rossi, Tetrahedron, 1999, 55, 13233.
3
9
7
.05 (s, 1H), 8.64 (d, 1H, J = 3.7 Hz), 8.11 (d, 1H, J = 7.8 Hz),
1
3
.92–7.84 (m, 2H), 7.39–7.25 (m, 4H), 6.91 (s, 1H) ppm;
C
NMR (100 MHz, CDCl ) δ 163.7, 148.9, 132.2, 131.4, 130.7,
1
3
29.4, 128.3, 127.2, 125.4, 120.7, 100.3 ppm.
2
5
5
-Phenyl-3-(p-tolyl)isoxazole (8h). 83% yield; white solid;
M.P. 141–142 °C; 7.86–7.81 (m, 2H); 7.74 (d, 2H, J = 8.2 Hz);
.45–7.33 (m, 3H); 7.29 (d, 2H, J = 7.8 Hz); 6.81 (s, 1H), 2.36
7
1
3
(s, 3H) ppm; C NMR (100 MHz, CDCl
3
) δ 170.2, 163.2, 140.3,
1
30.4, 129.9, 129.2, 127.5, 126.9, 126.2, 125.4, 97.7, 21.8 ppm.
2
5
3
-(4-Methoxyphenyl)-5-phenylisoxazole (8i). 81% yield;
1
white solid; M.P. 129–130 °C; H NMR (400 MHz, CDCl
3
) δ
7
6
1
1
.84–7.76 (m, 4H), 7.52–7.42 (m, 3H), 6.98 (d, 2H, J = 8.8 Hz),
1
3
3
.76 (s, 1H), 3.84 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ
70.3, 162.6, 161.3, 130.4, 129.2, 128.5, 127.6, 125.8, 121.6,
14.2, 97.2, 55.7 ppm.
2
6
3
-(4-Chlorophenyl)-5-phenylisoxazole (8j). 92% yield;
1
3
yellow solid; M.P. 172–174 °C; H NMR (500 MHz, CDCl ) δ
1
3
7
.83–7.75 (m, 1H), 7.48–7.11 (m, 5H), 6.84 (s,1H) ppm;
C
3
NMR (125 MHz, CDCl ) δ 170.9, 162.2, 136.3, 130.3, 129.4,
1
28.2, 127.4, 127.1, 125.8, 97.8 ppm.
-(4-Fluorophenyl)-5-phenylisoxazole (8k). 92% yield;
2
5
3
2 (a) R. J. P. Corriu, V. Huynh and J. J. E. Moreau, Tetrahedron
Lett., 1984, 25, 1887; (b) D. R. M. Walton and F. Waught,
J. Organomet. Chem., 1972, 37, 45; (c) M. W. Logue and K.
Teng, J. Org. Chem., 1982, 47, 2549.
1
white solid; M.P. 165–166 °C; H NMR (400 MHz, CDCl
3
) 7.88–
7
1
1
.81 (m, 4H), 7.45–7.34 (m, 3H), 7.17 (t, 2H, J = 8.8 Hz), 6.80 (s,
H) ppm, C NMR (100 MHz, CDCl ) δ 170.8, 163.4, 161.4,
30.5, 129.3, 128.9, 127.4, 125.8, 125.4, 116.2, 116.0, 97.5 ppm.
13
3
3 Y. Maeda, N. Kakiuchi, S. Matsumura, T. Nishimura, T.
Kawamura and S. Uemura, J. Org. Chem., 2002, 67, 6718.
4 (a) L. Chen and C.-J. Li, Org. Lett., 2004, 6, 3151; (b) R. J.
Cox, D. J. Ritson, T. A. Dane, J. Berge, J. P. H.
Charmantcand and A. Kantacha, Chem. Commun.,
2005, 1037; (c) R. E. Islas, J. Cardenas, R. Gavino, E. G.
Rios, L. L. Romero and J. A. M. Serna, RSC Adv., 2017, 7,
9780; (d) Q. Chen, F. Yao, L. Yin and M. Cai,
J. Organomet. Chem., 2016, 804, 108; (e) B. Huang, L. Yin
and M. Cai, New J. Chem., 2013, 37, 3137; ( f ) S. Atobe,
H. Masuno, M. Sonoda, Y. Suzuki, H. Shinohara, S.
Shibata and A. Ogawa, Tetrahedron Lett., 2012, 53, 1764;
(g) D. A. Alonso, C. Najera and M. C. Pacheco, J. Org.
Chem., 2004, 69, 1615; (h) S. Santra, K. Dhara, P. Ranjan,
P. Bera, J. Dash and S. K. Mandal, Green Chem., 2011, 13,
3238; (i) R. K. Sharma, M. Yadav, R. Gaur, R. Gupta, A.
Adholeya and M. B. Gawande, ChemPlusChem, 2016, 81,
1312; ( j) M. Bakherad, A. Keivanloo, B. Bahramian and
M. Rajaie, Tetrahedron Lett., 2010, 51, 33; (k) P. R. Likhar,
M. S. Subhas, M. Roy, S. Roy and M. L. Kantam, Helv.
Chim. Acta, 2008, 91, 259; (l) C. Kang, J. Huang, W. He
and F. Zhang, J. Organomet. Chem., 2010, 695, 120; (m) W.
2
3
5
-Phenyl-3-(pyridin-2-yl)isoxazole (8l). 84% yield; white
1
solid; M.P. 126–127 °C; H NMR (500 MHz, CDCl ) δ 8.67
3
(dd, J = 7.8, 1.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H) 7.86–7.75 (m,
1
3
3
H), 7.46–7.25 (m, 4H), 7.21 (s, 1H) ppm; C NMR (125
MHz, CDCl ) δ 170.9, 163.6, 149.6, 148.4, 136.8, 130.7, 129.4,
1
3
27.7, 125.8, 124.4, 121.8, 98.7 ppm.
2
5
1
3
-Hexyl-5-phenylisoxazole (8m). 84% yield; red oil;
H
NMR (500 MHz, CDCl ) δ 7.77 (d, 2H, J = 7.6 Hz); 7.51–7.36
3
(m, 3H), 6.38 (s, 1H), 2.75 (t, J = 7.6 Hz, 2H), 1.79–1.71 (m,
1
3
1
H), 1.42–1.26 (m, 6H), 1.01–0.91 (m, 3H) ppm; C NMR
(125 MHz, CDCl ) δ 173.8, 162.5, 129.6, 128.5, 126.6, 98.3,
3
3
1.6, 28.7, 27.4, 26.4, 22.2, 13.8 ppm.
1
2a
5
-Ethyl-3-phenylisoxazole (8n).
84% yield; colourless oil;
1
H NMR (500 MHz, CDCl ) δ 7.81–7.76 (m, 2H), 7.48–7.40 (m,
3
3
H), 6.28 (s, 1H), 2.82 (q, J = 6.9 Hz, 1H), 1.33 (t, J = 6.9 Hz,
1
3
3
H) ppm; C NMR (125 MHz, CDCl
3
) δ 174.9, 162.2, 129.8,
1
29.3, 128.7, 126.5, 97.8, 20.3, 11.8 ppm.
Conflicts of interest
There are no conflicts to declare.
6480 | Catal. Sci. Technol., 2019, 9, 6471–6481
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