Phosphine- and copper-free palladium catalyzed one-pot four-component carbonylation reaction for the synthesis of isoxazoles and pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2015.11.053

The palladium catalyzed one-pot synthesis of isoxazoles and pyrazoles from aryl iodides, terminal alkynes, chromium hexacarbonyl and hydroxylamine hydrochloride or aqueous hydrazine solution is described. The Sonogashira carbonylative coupling intermediate was trapped in situ by hydroxylamine hydrochloride or aqueous hydrazine to deliver isoxazoles or pyrazoles, respectively, in high yields. This efficient method proceeds at atmospheric pressure and moderate temperature and does not require the use of copper, phosphine ligands or gaseous carbon monoxide.

Full text of DOI:10.1016/j.tetlet.2015.11.053

Accepted Manuscript
Phosphine- and copper-free palladium catalyzed one-pot four-component car-
bonylation reaction for the synthesis of isoxazoles and pyrazoles
Nasser Iranpoor, Habib Firouzabadi, Elham Etemadi-Davan
PII:
S0040-4039(15)30361-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.053
TETL 46993
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
9 April 2015
20 August 2015
18 November 2015
Please cite this article as: Iranpoor, N., Firouzabadi, H., Etemadi-Davan, E., Phosphine- and copper-free palladium
catalyzed one-pot four-component carbonylation reaction for the synthesis of isoxazoles and pyrazoles, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.053
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Phosphine- and copper-free palladium
catalyzed one-pot four-component
carbonylation reaction for the synthesis of
isoxazoles and pyrazoles
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Nasser Iranpoor, Habib Firouzabadi, Elham Etemadi-Davan

1
Tetrahedron Letters
Phosphine- and copper-free palladium catalyzed one-pot four-component carbonylation reaction for
the synthesis of isoxazoles and pyrazoles
Nasser Iranpoor,a,  Habib Firouzabadia,  and Elham Etemadi-Davan
aDepartment of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The palladium catalyzed one-pot synthesis of isoxazoles and pyrazoles from aryl iodides,
terminal alkynes, chromium hexacarbonyl, and hydroxylamine hydrochloride or aqueous
hydrazine solution is described. The Sonogashira carbonylative coupling intermediate was
trapped in situ by hydroxylamine hydrochloride or aqueous hydrazine to deliver isoxazoles or
pyrazoles respectively in high yields. . This efficient method proceeds at atmospheric pressure
and moderate temperature and does not require the use of copper, phosphine ligands or gaseous
carbon monoxide.
Available online
Keywords:
Four-component carbonylation
Ligand-free
Copper-free
PdCl2
2009 Elsevier Ltd. All rights reserved.
Isoxazole
Pyrazole
———
 Corresponding author. Tel.: +98 361 7104; e-mail: iranpoor@chem.susc.ac.ir
 Corresponding author. Tel.: +98 3613 7135; e-mail: firouzabadi@chem.susc.ac.ir

2
Tetrahedron Letters
followed by cyclization to offer both isoxazole and pyrazoles
under both copper- and ligand-free conditions.
Palladium-catalyzed carbonylative coupling reactions are
We initially examined the synthesis of isoxazoles via the Pd-
catalyzed reaction of iodobenzene, phenyl acetylene, Cr(CO)6,
and hydroxylamine hydrochloride at 100 ˚C at atmospheric
pressure. Screening different bases and solvents showed that in
the presence of KOAc in DMF, the desired isoxazole was
obtained in 90% yield (Table 1, entry 5). Further optimization
showed that decreasing the temperature to 70 ˚C did not have a
detrimental effect on the reaction time and the product was
obtained in 95% yield (Table 1, entry 9). The use of different
P(III) ligands gave almost the same yields as the phosphine-free
conditions (Table 1, entries 10, 11). The most efficient amount of
PdCl2 was found to be 5.0 mol% and performing the reaction in
the presence of 2.5 mol% PdCl2 lead to a lower yield (Table 1,
entry 12). Employing Pd(OAc)2 instead of PdCl2 as the catalyst
was almost the same in terms of yield, therefore PdCl2 was
selected as the catalyst due to its low cost in comparison to
Pd(OAc)2 (Table 1, entry 14). In addition we employed 1-hexyne
instead of phenylacetylene under these conditions to determine
whether alkynes with an aliphatic substituent would react to give
the desired isoxazole. Indeed, the desired isoxazole was obtained
in 88% yield which showed the applicability of this method
towards alkynes with an aliphatic substituent (Table 1, entry 15).
considered a promising strategy for the straightforward formation
of several bonds to provide highly functionalized products.1 The
reaction can be performed in one-pot over multiple steps without
the need for purification or isolation of the intermediates.2 The
synthesis of varied heteroaromatic compounds is important due
to their biological activities.3 Pyrazoles4 and isoxazoles5 are
important classes of five-membered heterocyclic compound with
applications as drugs showing analgesic, anti-inflammatory,
antiarrhythmic, antidiabetic and antibacterial activities.6
Considering their important applications, the development of new
methodologies for their synthesis is worthwhile.
The general methods for synthesizing isoxazoles include: the
[3 + 2] cycloaddition of alkynes with nitrile oxides in which the
starting material is difficult to synthesize and not readily
available (Scheme 1, A),7 and the cyclization of hydroxylamines
with a three-carbon atom component (Scheme 1, B).8
Pyrazoles are generally synthesized using the classical Knorr
pyrazole synthesis in which an acid catalyst is used for
converting hydrazine derivatives and a 1,3-dicarbonyl compound
into the pyrazole ring. However, this transformation suffers from
a lack of regioselectivity (Scheme 1, C).9 Alternatively a one-pot,
three-component approach which includes the condensation of an
aromatic aldehyde with tosylhydrazine, followed by
cycloaddition with terminal alkynes has been described (Scheme
1, D).10 Finally, formation of pyrazoles via the Sonogashira
carbonylation of aryl iodides followed by tandem cyclization has
been reported but is less well studied (Scheme 1, E).11 This
transformation, developed by Mori in 2005, utilises PdCl2(Ph3P)2
for the coupling of a terminal alkyne, hydrazine, carbon
monoxide, and an aryl iodide to obtain pyrazoles (or isoxazoles)
at ambient pressures of CO.11a Later, in 2013, a Pd nanoparticle
catalyst supported on N-doped carbon was used for the domino
carbonylative synthesis of pyrazoles.11c
We were also interested to see if pyrazoles could be
synthesized using the optimised conditions by replacement of
hydroxylamine hydrochloride for hydrazine. Since hydrazine
could act as a base, the reaction was initially employed in the
absence of KOAc. Remarkably, the desired pyrazole was
obtained in 90% yield (Table 1, entry 16). Conducting the
reaction in the presence of 1-hexyne also afforded the desired
pyrazole in 88% yield (Table 1, entry 17). Therefore, pyrazoles
could be obtained in high yields under our optimized conditions
in the presence of alkynes with aromatic or aliphatic substituents.
Table 1. Optimization of the reaction parameters for the copper-
and ligand-free Pd catalyzed carbonylation reaction for the
synthesis of isoxazoles and pyrazolesa
Entry
Solvent
Base
Temp. Time Yield
(˚C)
100
100
(h)
18
18
(%)
30
5
1
Dioxane
Dioxane
KOAc
Et3N
2
Table 1
(continued)
Scheme 1. Representative methods for the synthesis of
isoxazoles and pyrazoles
3
Dioxane
Dioxane
DMF
K2CO3
100
18
18
18
18
18
18
18
18
18
18
10
15
90
30
40
30
95
88
90
65
The synthesis of these heterocycles via Sonogashira
carbonylation followed by tandem ring closure remains an
challenge for chemists. Only a few protocols have been
reported11 and they require the use of gaseous carbon monoxide
which is difficult to handle in the laboratory. In this regard,
employing reagents that can act as a substitute for CO has
attracted much attention. There is only one report in the literature
regarding pyrazole formation in the presence of Mo(CO)6 as the
CO source.12 In this method, a palladium-catalyst was used in
conjunction with base, ligand and copper proceeding with long
reaction times and moderate yields. However, there has been no
report regarding the application of this methodology for
isoxazole synthesis. In a continuation of our studies on
carbonylation reactions,13 we report the applicability of Cr(CO)6
as a solid source of CO for the carbonylation aryl iodides,
4
Cs2CO3 100
5
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
100
100
100
100
70
6
H2O
7
o-Xylene
Diglyme
DMF
8
9
10b
11c
12d
DMF
80
DMF
70
DMF
70

3
13
DMF
DMF
DMF
DMF
DMF
KOAc
40
70
70
70
70
18
18
18
6
60
91
88
90
88
With regards to the results shown in Scheme 2, we were able
to synthesize variety of substituted isoxazoles and pyrazoles
under ligand- and copper-free conditions from iodoarenes in high
yields. Both alkynes with aliphatic- and aromatic-substituents
were reactive for both transformations. Substrates with electron-
withdrawing and electron-donating groups gave the products in
high yields. In addition, sterically hindered substrates also
reacted under the optimal conditions.
14e
15f
16g
17h
KOAc
KOAc
-
-
8
a Base was only required in the presence of H2NOH.HCl (entries 1-15). In
entries 16 and 17 aq. hydrazine solution was used
In addition, this reaction showed that Cr(CO)6 was an efficient
substituent for gaseous CO for the synthesis of isoxazoles and
pyrazoles proceeding under mild conditions. Our methodology
also has the advantage of proceeding in the absence of copper
and ligand to give the desired products in high yields.
b Ph3P ligand.
c dppf ligand
d 2.5mol% PdCl2
e 5.0 mol% Pd(OAc)2
f 1-Hexyne
Furthermore, methyl hydrazine, a monosubstituted hydrazine,
was also examined under our optimized condition. The reaction
with phenylacetylene produced the desired pyrazole 2’a in 88%
isolated yield (Scheme 2). When the reaction was performed with
1-hexyne, a 3:1 regioisomeric mixture of the desired pyrazoles
was formed (Scheme 2, 4’a). Guanidine hydrochloride was also
tested, but only 10% of the desired product was obtained.
g aq. hydrazine and phenylacetylene
h aq. hydrazine and 1-hexyne
With this protocol in hand, a variety of aryl iodides were
subjected to the optimized conditions for isoxazole and pyrazole
synthesis (Scheme 2).

4
Tetrahedron Letters
Scheme 2. Copper- and ligand-free PdCl2-catalyzed one-pot four-component carbonylation reactions for the synthesis of isoxazoles and
pyrazoles
Entry Ar-I M(CO)6
Base
[Cu]
Ligand
Yield
(%)
The efficiency of our protocol for the synthesis of pyrazoles
was compared with the method reported in the literature by
Stonehouse12 (Table 2).
1a
2a
3a
1a
1c
1a
Cr(CO)6
Cr(CO)6
Mo(CO)6
none
none
none
none
none
none
None
None
none
2a: 90
2c: 86
2a: 78
Table 2. Comparison of the reaction of aryl iodides with M(CO)6
for pyrazole synthesis

5
4b
1a
1c
Mo(CO)6
Mo(CO)6
Cs2CO3
Cs2CO3
CuI
CuI
tBu3P
tBu3P
2a: 53
2c: 54
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5b
a
Present method: Reaction conditions: M(CO)6 (1.0 mmol), aq. hydrazine
solution (1.5 mmol), phenylacetylene (1.4 mmol), PdCl2 (5.0 mol%), DMF
(3.0 mL), 70 ˚C. 1a: 6 h (entry 1), 1c: 8 h (entry 2), 1a: 6 h (entry 3)
5.
6.
b Stonehouse’s conditions: Mo(CO)6 (1.5 mmol), aq. hydrazine solution (2.5
mmol), phenylacetylene (1.5 mmol), Pd(OAc)2 (5.0 mol%), CuI (2.0 mol%),
Cs2CO3 (2.5 mmol), toluene:CH3CN (1: 1), 80 ˚C, 18 h12
According to the results shown in Table 2, the corresponding
pyrazoles (entries 1, 2) were obtained in high yields and with
shorter reaction times using our optimized conditions in
comparison to the literature protocol (entries 4, 5).12 In addition,
we applied Mo(CO)6 instead of Cr(CO)6 under our optimized
condition (entry 3). In this case, the desired pyrazole was
obtained in lower yield (78%) along with the formation of an
unidentified side product (10%).
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In summary, we have developed a one-pot four-component
ligand- and copper-free Pd-catalyzed procedure for the formation
of pyrazoles and isoxazoles in high yield from the ring closure of
hydrazine derivatives or hydroxylamine hydrochloride with the
in situ generated Sonogashira carbonylative coupling product
under mild reaction conditions. The difficulty in handling of
gaseous CO is avoided by employing Cr(CO)6 as a solid source
of CO.
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Acknowledgments
We gratefully acknowledge the partial financial support of this
study by the Shiraz University Research Council and the grant
from Iran national elite foundation.
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