One-flask synthesis of pyrazolone thioethers involving catalyzed and uncatalyzed thioetherification pathways of pyrazolones

Article abstract of DOI:10.1039/c7ob01754e

A one-flask thioetherification of pyrazolones has been demonstrated by transforming several pyrazolones to their corresponding 4-mercaptopyrazolone derivatives and employing them towards cross-coupling with various aromatic and heteroaromatic iodides by applying Pd(OAc)₂/xantphos as the catalytic system. The coupling ability of these thiol intermediates with 2,3-dichloropyrazine through an aromatic S_N2 pathway has also been established. This methodology provides the use of inexpensive starting materials along with a short reaction time.

Full text of DOI:10.1039/c7ob01754e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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One-flask synthesis of pyrazolone thioethers involving catalyzed
and uncatalyzed thioetherification pathways of pyrazolones
Received 00th January 20xx,
Accepted 00th January 20xx
Prasun Mukherjee and Asish R. Das*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
one-flask thioetherification of pyrazolones has been Recently, sulphenylation of pyrazolones with sulphenyl
demonstrated by transforming several pyrazolones to their chlorides, hydrazides, thiols and disulphides have been
corresponding 4-mercaptopyrazolone derivatives and employing recognized as additional routes to synthesize pyrazolone
those towards cross-coupling with various aromatic and thioethers (Scheme 1).6 Still, instability of the starting
heteroaromatic iodides by applying Pd(OAc)2/Xantphos as the materials, use of expensive and less available aromatic and
catalytic system. The coupling ability of these thiol intermediates heterocyclic thiols, requirement of stoichiometric amount of
with 2,3-dichloropyrazine through aromatic SN2 pathway have reagent and narrow substrate scope of those methodologies
also been established. The methodology provides use of essentially demand an alternative and efficient protocol to
inexpensive starting materials along with a short reaction time.
synthesize these valuable pyrazolone thioethers.
Introduction
Pyrazolones represent
a
significant class of nitrogen
heterocycles, due to their occurrence as the key structural
core in numerous natural products and synthetic compounds
with broad range of biological activities.1 As
a result,
tremendous efforts have been made over the past decades in
academic and medicinal fields to synthesize numerous
functionalized pyrazolone scaffolds to access potent bioactive
entities.2 On the other hand, heterocyclic thioethers are
abundant among natural products and artificial compounds
with ample biological, pharmaceutical and material
significance.3 In particular, pyrazolone thioethers have been
recognized as promising herbicidal agents and antioxidants.4
Consequently, several protocols have been established in
order to access these thioethers, such as, the condensation of
phenylhydrazine with methyl 3-oxo-2-(phenylthio) butanoate4
and reaction of alkyl or aryl thioacetates with acylchlorides
followed by the treatment with hydrazine derivatives.5
However, less availability of the starting materials,
requirement of strong base and less efficiency of the
condensation steps have restricted the use of those protocols.
Department of Chemistry, University of Calcutta, Kolkata-700009, India
*Corresponding
Author,
Tel.:
+913323501014,
+919433120265;
fax:
+913323519754; E-mail: ardchem@caluniv.ac.in, ardas66@rediffmail.com.
Electronic Supplementary Information (ESI) available: [Materials, method, general
synthetic procedures. X-ray crystallography data of compounds 2s and 3a and 1H
and 13C NMR spectra of all compounds (file type pdf) and X-ray crystallography
data of compound 2s and 3a (file type cif)]. See DOI: 10.1039/x0xx00000x
Scheme 1 Synthesis of pyrazolone thioethers
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Palladium-catalyzed cross-coupling has emerged as a key system to promote an unparalleled cross-coupling of 4-
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DOI: 10.1039/C7OB01754E
method to construct C-S bond along with other carbon- mercapto pyrazolones with aromatic and heteroaromatic
heteroatom
bonds
in
general
organic
synthesis, iodides. In addition, the coupling of 4-mercapto pyrazolone
pharmaceutical industry and material science.7 After the first intermediates with 2,3-dichloropyrazine through aromatic SN2
report of Migita8, several efforts have been made in pathway has also been materialized in this present report
generalizing the palladium catalyzed thioetherification.9 (Scheme 1).
Bidentate ligands, for instance, Xantphos, dppf, CyPF-t-Bu,
DPEphos have been revealed to provide excellent results for
carbon-sulfur along with other cross-coupling reactions.10 In
this context, we anticipated that if pyrazolones can be
transformed to the corresponding 4-mercapto pyrazolones
then those thiol derivatives inturn can be employed in cross-
coupling reaction with several readily available aromatic and
hetero aromatic halides to synthesize the desired pyrazolone
thioether derivatives with a broad substrate scope. As part of
our ongoing efforts towards the transition metal catalyzed
formation of carbon-carbon and carbon-heteroatom bonds,11
herein, we wish to report a practical methodology for the one-
pot synthesis of pyrazolone thioethers based on conversion of
the pyrazolone derivatives to 4-mercapto pyrazolones
followed by Pd-catalyzed coupling of these thiol intermediates
with a wide range of activated and deactivated aryl iodides
(Scheme 1). In this report, the combination of Pd(OAc)2 and
Xantphos has been demonstrated as the efficient catalytic
Results and discussion
Initially 1.0 mmol of 5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one 1a and iodobenzene were employed as the
model substrates. From literature review, we have found the
synthesis of 4-mercapto-5-methyl-2,4-dihydro-3H-pyrazol-3-
one from 5-methyl-2,4-dihydro-3H-pyrazol-3-one using
elemental sulfur and triethylamine.12 Applying that procedure
for substituted pyrazolones, we have then treated 1.5 mmol of
1a with elemental sulfur (1.3 equiv) and catalytic amount of
triethylamine (one drop) in ethanol (2 ml) medium. After 40
min the complete conversion of 1a took place and the volatiles
were removed under vacuum. Then to the same reaction flask,
1.0 mmol of iodobenzene, Pd(OAc)2 (5 mol%), Xantphos (5
mol%), Cs2CO3 (1.2 equiv) and DMSO (2 ml) were added under
Table 1 Optimization of the reaction conditions for palladium catalyzed pyrazolone thioether synthesisa,b
Entry
Catalyst (mol%)
Ligand (mol%)
Base (1.2
equiv)
Solvent (ml)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(6)
Xantphos (5)
dppf (5)
Cs2CO3
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (2)
2.5
2.5
12
88
86
-
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOBut
K3PO4
PPh3 (10)
(rac)BINAP(5)
Xantphos (5)
Xantphos (5)
Xantphos (5)
Xantphos (6)
12
10
70
50
78
87
2.5
2.5
2.5
2.5
Cs2CO3
2 | J. Name., 2012, 00, 1-3
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9
Pd(OAc)2(2)
Pd(OAc)2(1)
Pd(OAc)2(2)
Pd(OAc)2(2)
PdCl2(2)
Xantphos (2)
Xantphos (1)
Xantphos (2)
Xantphos (2)
Xantphos (2)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO (2)
DMSO (2)
DMF (2)
2.5
90
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10
11
12
13
2.5
5
84
70
66
60
NMP (2)
5
DMSO (2)
2.5
14
15
PdCl2dppf(2)
Pd(OAc)2(2)
-
Cs2CO3
Cs2CO3
DMF (2)
2.5
8
66
Xantphos (2)
DMSO (2)
70d
16
17
CuI (20)
-
1,10-phen (20)
-
Cs2CO3
KOBut
DMSO (2)
DMSO (2)
12
12
-
-
a 1.5 mmol of 1a was taken in all the cases. b iodobenzene (1 mmol), Argon atmosphere. c Yield, d reaction temperature 110 oC.
argon atmosphere and the mixture was allowed to stir at 130 purpose, a variety of pyrazolone derivatives were synthesized
oC (Table 1, entry 1). In our delight, complete conversion of the by condensing variety of phenyl hydrazines (having electron
starting material was observed after 2.5 h and the product 2a donating as well as withdrawing groups to the phenyl ring),
was obtained in 88% yield (Table 1, entry 1). With this with ethyl acetoacetate.13 The synthesized pyrazolones were
excellent result, we have then performed this reaction under treated with elemental sulfur (1.3 equiv) in presence of
varied reaction conditions in order to maximize the product catalytic amount of Et3N to transform those to their
yield (Table 1). Different ligands such as dppf, PPh3 and rac- corresponding 4-mercapto-5-methyl-2,4-dihydro-3H-pyrazol-3-
BINAP were employed for this reaction. Dppf was found to be one derivatives. After the complete conversion of the starting
equally efficient as Xantphos for this particular cross-coupling material the solvent was removed under vacuo and the thiol
reaction providing 1a in 86% yield. However, PPh3 was found intermediates were then subjected to cross-coupling with a
to be ineffective to promote this thioetherification reaction wide range of aromatic and heteroaromatic iodides in
and rac-BINAP has provided very small amount of 2a after a presence of Pd(OAc)2 (2 mol% ) - Xantphos (2 mol% )
prolonged time (Table 1, entry 3 and 4). Further improvement containing catalytic system and 1.2 equiv Cs2CO3 in 2 ml of
of the product yield was yet to observe carrying out the DMSO. In all cases the products were obtained in excellent
reaction in the presence of different bases such as K2CO3, yields within a short reaction time (Table 2, entry 2a-s).
KOBut and K3PO4 (Table 1, entry 5-7). An increase in the Interestingly, the steric effect of the adjacent carbonyl and
amount of catalyst loading did not afford any better result methyl groups in the thiol intermediates have not affected the
(Table 1, entry 8). Interestingly, 2a was obtained in 90% yield efficiency of this catalytic system and all 4-
when 2 mol% of Pd(OAc)2 and 2 mol% of Xantphos were mercaptopyrazolone intermediates have shown excellent
employed (Table 1, entry 9). However further improvement of reactivity
towards
unsubstituted
and
substituted
the product yield was not detected by lowering the amount of iodobenzenes along with heteroaromatic iodide in this
catalyst loading from 2 mol% to 1 mol% (Table 1, entry 10). particular cross-coupling reaction (Table 2). The protocol has
Replacing the solvent DMSO by DMF or NMP was unable to provided excellent product yield in case of electron rich aryl
generate any promotional result (Table 1, entry 11 and 12). iodides (Table 2, entry 2e-g). The presence of different
Different palladium salts such as PdCl2 and PdCl2dppf have functional groups in ortho, meta and para positions of the
failed to show any superior catalytic activity for this particular aromatic iodides have not affected the product yields to a
cross coupling reaction (Table 1, entry 13 and 14). Moreover great extent (Table 2, entry 2e-k, 2m-s). It is worth mentioning
o
when this reaction was performed at 110 C, 2a was obtained that only the mono substituted thioethers were obtained
in 70% yield (Table 1, entry 15). The reaction did not proceed exclusively when 1,2-diiodobenzene was subjected in this
at all when CuI (20 mol%) and 1,10-phenanthroline (20 mol%) particular reaction (Table 2, entry 2m
-
r
). On the other hand,
proceeded almost
were used as the catalyst system (Table 1, entry 16). this
thioetherification
reaction
Additionally, the reaction failed to move forward when KOBut quantitatively in case of 4-nitroiodobenzene (Table 2, entry
was used as the base in DMSO (2 ml) solvent employing no 2h). All the synthesized pyrazolone thioethers were well
catalyst (Table 1, entry 17).
characterized through spectral (1H, 13C, HRMS and IR) analysis
Having optimized reaction condition in hand, we have then and finally the structural motif of these thioethers have been
analyzed the scope and limitation of this protocol. In this
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established by analyzing the X-ray crystallography data of an uncatalyzed aromatic SN2 pathway. All theVieswynArttihcleesOinzleinde
13
compound 2s (CCDC 1557690).
We have then tried to extend the scope of this protocol by
thioethers were well characterized throDuOghI: 1s0p.1e0c3t9r/aCl7O(1BH0,1754CE,
HRMS and IR) analysis and finally the structural motif of the
compound 3a has been established by analyzing the X-ray
crystallography data obtained from the single crystal of 3a
(CCDC 1557692).
Table
2 Substrate scope for the palladium catalyzed synthesis of pyrazolone
thioethersa,b
Table 3 Substrate scope for the synthesis of pyrazolone thioethersa, b
a
b
reaction condition: 1 (1.5 mmol), S8 (1.3 equiv), 2 ml ethanol. reaction
condition: 2,3-dichloropyrazine (1 mmol), Cs2CO3 (1.2 equiv), DMSO (2 ml), 80 oC,
reaction time 20 min. c Yield.
A plausible mechanism for the palladium catalyzed synthesis of
pyrazolone thioethers has been depicted in scheme 2. Initially
1
is transformed to the 4-mercapto pyrazolone 1a' in presence
of elemental sulfur and catalytic amount of triethylamine. It is
worth mentioning here that the formation of 1a' was
confirmed through HRMS analysis taking small amount of
a
b
reaction condition: 1 (1.5 mmol), S8 (1.3 equiv), 2 ml ethanol. reaction
condition: aryl iodide (1 mmol), Pd(OAc)2 (2 mol%), Xantphos (2 mol%), Cs2CO3
(1.2 equiv), DMSO (2 ml), 130 oC, Argon atmosphere, reaction time 2.5 h. c Yield.
replacing aromatic iodides with 2,3-dichloropyrazine. In this
case, the reaction between thiol intermediates and 2,3-
dichloropyrazine proceeded essentially in an aromatic SN2
pathway in presence of 1.2 equiv of Cs2CO3 in DMSO without
the requirement of any metal catalyst (Scheme 1). By
producing comparable results as above, this one-pot protocol
also provided excellent product yields for various pyrazolone
derivatives within a noticeably short period of time (Table 3,
Scheme 2 Mechanism of the palladium catalyzed thioetherification
entry 3a
atoms in the pyrazine ring, activates the C2 position of 2,3-
dichloropyrazine to be highly electrophilic and hence
-f). In this endeavour, the presence of two nitrogen
aliquot from the reaction mixture after the first step. In the
next step oxidative insertion of Pd(0) species14 into the C-I
bond of Ar-I leads to the formation of intermediate 1c'. The
facilitates its reaction with 4-mercapto pyrazolones following
4 | J. Name., 2012, 00, 1-3
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Lao, T. K. Loe, V. Leko, A. Thalhofer, A. D. SchuleVri,ewA.ABrtieclde aOlnolivne
and J. A. Simon, J. Med. Chem., 2014, 5D7O, 3I:2108.310–3392/9C47O. (Bd0)1Y75.4E
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initially formed 1a' then reacts with 1d' in presence of caesium
carbonate to generate the intermediate 1d'. Finally, 1d'
follows reductive elimination pathway and generates the
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In conclusion we have demonstrated a versatile route for one-
pot synthesis of a wide variety of biologically relevant
pyrazolone thioethers by transforming several pyrazolones to
their corresponding 4-mercapto pyrazolone derivatives and
employed them first time towards cross-coupling reaction with
various easily available aromatic and heteroaromatic iodides,
using Pd(OAc)2 / Xantphos as the catalytic system. The coupling
ability of this thiol intermediates with 2,3-dichloropyrazine
through aromatic SN2 pathway have been also established. The
unique conveniences offered by these thioetherification
reactions are, use of inexpensive starting material, exploitation
of elemental sulfur as the sulfur source and requirement of
short reaction time. Extension and development of this
protocol in other active methylene group containing molecules
and aromatic halides are in progress.
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We acknowledge the financial support from the Centre of CAS-
V (Synthesis and functional materials) (support offered by
UGC, New Delhi) of the department of Chemistry, University of
Calcutta. P.M. thanks U.G.C. New Delhi, India, for the grant of
his Senior Research Fellowship. Crystallography was performed
at the DST-FIST, India-funded Single Crystal Diffractometer
Facility at the Department of Chemistry, University of Calcutta.
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Organic & Biomolecular Chemistry
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COMMUNICATION
Journal Name
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DOI: 10.1039/C7OB01754E
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01754E
Graphical Abstract:
One-pot thioetherification of pyrazolones through cross-coupling as well as aromatic SN2 pathway using
elemental sulfur as the sulfur source.