Catalyst-Free One-Pot Access to Pyrazoles and Disulfide-Tethered Pyrazoles via Deamidative Heteroannulation of β-Ketodithioesters with Semicarbazide Hydrochloride in Water

Article abstract of DOI:10.1002/adsc.201701595

An operationally simple, mild, and catalyst-free one-pot protocol to access privileged pyrazoles and disulfide-tethered pyrazoles has been devised by [3+2] heteroannulation of β-ketodithioesters with semicarbazide hydrochloride in water under open air. The pH of the medium played a key role toward the selectivity switch, as refluxing in water led to the formation of pyrazoles, whereas addition of sodium acetate in water enabled the formation of disulfide-tethered pyrazoles. Notably, this protocol involves a tandem sequence of amination/cyclization/dehydration/hydrodesufurization/hydrolysis/deamidative reactions. A mechanistic rationale for this regio-/chemoselective domino reaction is outlined, which is well supported and validated by density functional theory calculations. (Figure presented.).

Full text of DOI:10.1002/adsc.201701595

Title: Catalyst-Free One-Pot Access to Pyrazoles and Disulfide-
Tethered Pyrazoles via Deamidative Heteroannulation of β-
Ketodithioesters with Semicarbazide Hydrochloride in Water
Authors: MAYA SINGH, Suvajit Koley, Sumit Kumar Panja, and Sonam
Soni
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701595
Link to VoR: http://dx.doi.org/10.1002/adsc.201701595

10.1002/adsc.201701595
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalyst-Free One-Pot Access to Pyrazoles and Disulfide-
Tethered Pyrazoles via Deamidative Heteroannulation of β-
Ketodithioesters with Semicarbazide Hydrochloride in Water
Suvajit Koley,a Sumit Kumar Panja,b Sonam Soni,a and Maya Shankar Singh a,*
a
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
E-mail: mayashankarbhu@gmail.com; mssingh@bhu.ac.in
Inorganic and Physical Chemistry Department, Indian Institute of Science, Bengaluru 560012, India
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
(NHCs),[9b] and directing groups for C-H
Abstract: An operationally simple, mild, and catalyst-free
one-pot protocol to access privileged pyrazoles and
disulfide-tethered pyrazoles has been devised by [3 + 2]
heteroannulation of -ketodithioesters with semicarbazide
hydrochloride in water under open air. The pH of the
medium played a key role toward the selectivity switch, as
refluxing in water led to the formation of pyrazoles,
whereas addition of sodium acetate in water enabled the
formation of disulfide-tethered pyrazoles. Notably, this
activations.[9c,d] Because of these facts, the
development of efficient methods for the synthesis of
pyrazoles is always a hot topic to synthetic
chemists.[10]
In general, substituted hydrazones have been
commonly utilized as starting materials for the
preparation of pyrazoles employing condensation or
cycloaddition reactions.[11] Some selected examples
involve the cyclization of -unsaturated hydrazones
by Xiao,[12] Chen[13] and Huang,[14] the [4+1]
cyclization of hydrazones by Glorius,[15a] Ji,[15b] and
protocol
involves
a
tandem
sequence
of
amination/cyclization/dehydration/hydrodesufurization/hy
drolysis/deamidative reactions. A mechanistic rationale
for this regio-/chemoselective domino reaction is outlined,
which is well supported and validated by density
functional theory calculations.
Wang,[16]
the
cyclization
of
-
alkynyltosylhydrazones by Tsui,[17] as well as
Zn(OTf)2-promoted cyclization of tosylhydrazones
with 2-(dimethylamino)malononitrile by Zhang and
co-workers.[18] However, the use of expensive
reagents, carcinogenic organic solvents, limited
substrate scope, and multistep sequences limit the
importance of these approaches to a great extent. To
the best of the authors’ knowledge, there is paucity of
reports on one-step procedure for the synthesis of
pyrazole derivatives from readily available starting
materials.
Keywords: Pyrazole; disulfane; pH selective reaction;
deamidation in water; density functional theory
calculation
Functionalized pyrazoles represent the core unit of
numerous biologically active molecules, and have
been
pharmaceutical/agrochemicals
chemical
laboratories.[1]
profoundly
targeted
by
the
industries
and
Over the past decades, a huge quantity of waste is
being attributed in the environment by the use of
organic solvents.[19] Therefore, there is increasing
demand to perform organic reactions in non-
hazardous media.[20] To this end, water is not only the
most abundant and viable solvent, but is a ultimate
choice of nature for biochemical and chemical
reactions. Due to its non-toxic, non-flammable, cheap,
environmentally benign nature as well as relatively
high vapour pressure as compared to organic solvents,
water has gained special attention as a solvent for
various organic syntheses during recent past.[21]
Additionally, the chemical and physical properties of
water could lead to unique selectivity and/or
reactivity that might be tough to accomplish in
organic solvents.[22] Herein, we disclose an
operationally simple domino protocol to access
Suitably
substituted
pyrazoles show a wide range of biological activities,
such
as
analgesic,[2]
antipyretic,[3]
anti-
hyperglycemic,[4] anti-inflammatory,[5a] and anti-
viral[5b] properties. Some of the accepted drugs are
celecoxib,[6a,b]
mavacoxib,[6c,d]
razaxaban,[6e]
fipronil,[6f] and rimonabant[6g]. Moreover, some
pyrazole derivatives have also been employed as
selective protein kinase inhibitors,[7a] and were among
the top 200 brand name drugs by total US
prescriptions in 2012.[7b] On the other hand,
appropriately substituted pyrazoles could serve as
optical
brighteners,[8a]
UV
stabilizers,[8b]
photoelectron-induced electron-transfer systems,[8c]
building blocks in supramolecular assemblies,[8d] and
indispensable intermediates for various chemical
syntheses. Besides, the tautomeric nature of pyrazole
facilitates its applicability as ligand in coordination
compounds,[9a] precursors to N-heterocyclic carbenes
pyrazoles
and
1,2-bis(pyrazol-5-yl)disulfanes
employing -ketodithioesters and semicarbazide
1
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10.1002/adsc.201701595
Advanced Synthesis & Catalysis
hydrochloride for the first time in water simply by
regulating the pH of the medium under catalyst-free
conditions (Scheme 1).
To optimize the reaction conditions for the
synthesis of pyrazoles, methyl 3-hydroxy-3-
phenylprop-2-enedithioate (1a) and semicarbazide
hydrochloride (2) were taken as the model substrates.
The effects of different promoters, solvents and
temperature were examined on the model reaction
and the results are listed in Table 1. Initially, a
mixture of 1a (1 mmol) and 2 (1 mmol) in 5 mL
ethanol was stirred at room temperature. No reaction
was observed even after 48 h and the starting
materials remained completely unconsumed (Table 1,
entry 1). With this failure, we carried out the above
model reaction at reflux temperature. To our
satisfaction, the reaction proceeded smoothly and
provided the desired product 3a in 70% yield (Table
1, entry 2). Next, we performed the reaction in
methanol at reflux temperature, which decreased the
yield of 3a to 54% (Table 1, entry 3). Keeping in
mind the benefits of water as solvent, we carried out
above test reaction in water at reflux temperature.
Delightedly, the reaction proceeded in a very clean
manner furnishing the desired product 3a in 90%
yield (Table 1, entry 4). Reducing the temperature of
the reaction decreased the yield (Table 1, entry 5).
Next, we executed the model reaction under solvent-
free conditions. Work up of the reaction afforded the
product 3a in 32% yield only (Table 1, entry 6).
Further to increase the efficiency of the reaction, we
added 1.0 equiv of NaOAc into the above test
reaction under water reflux conditions. To our
surprise, we observed an unexpected result enabling
the formation of 1,2-bis(pyrazol-5-yl)disulfane 4a in
55% yield along with desired product 3a in 40% yield
(Table 1, entry 7).
The applicability of β-ketodithioesters as unique
synthons and versatile intermediates for the
construction of various heterocycles have been well
recognized.[23] Our group has a long standing interest
in exploiting the unique reactivity of β-
ketodithioesters towards the construction of
numerous heterocyclic scaffolds.[24] Recently, we
developed a concise and direct one-pot annulative
strategy
to
access
fully
cycloamino/alkylaminopyrazoles[25a]
and
substituted thiazoles[25b] from β-ketodithioesters.
However, the synthetic efficacy of β-ketodithioesters
toward semicarbazide hydrochloride in water has not
yet been reported. Considering the benefits of domino
annulation in water, we envisioned to explore the
direct coupling of inexpensive and readily available
semicarbazide hydrochloride with β-ketodithioesters
to construct relevant pyrazoles and disulfide-tethered
pyrazoles.
Scheme 1. Construction of pyrazoles and 1,2-bis(pyrazol-
5-yl)disulfanes in water under catalyst-free conditions.
Table 1. Optimization of reaction conditions for the synthesis of compounds 3 and 4.[a]
Entry
1
Promoter (equiv)
none
Solvent
(5 mL)
Temp
(ºC)
Time
(h)
Yield[b]
(%)
3a
-
4a
-
[c]
EtOH
rt
48
2
3
4
5
6
7
8
9
10
11
12
13
none
none
none
none
EtOH
MeOH
H2O
H2O
none
H2O
H2O
H2O
H2O
H2O
H2O
none
reflux
reflux
reflux
80
15
24
8
24
6
8
8
8
8
70
54
90
35
32
40
15
10
trace
trace
trace
trace
-
-
-
-
none
100
-
NaOAc (1)
NaOAc (2)
NaOAc (3)
NaOAc (5)
NaOH (1)
KOH (1)
NaOAc (5)
reflux
reflux
reflux
reflux
reflux
reflux
100
55
78
82
85
50[d]
45[d]
34
8
8
8
[a] Reactions were performed with 1.0 mmol of each 1 and 2.
[b] Isolated yield.
[c] Starting materials remained unconsumed.
[d] Benzoic acid (8-10%) was isolated at the end of the reaction.
2
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10.1002/adsc.201701595
Advanced Synthesis & Catalysis
Remarkably, by increasing the amount of NaOAc
medium played a key role for this selectivity switch.
As evident from Table 3 and 4, all reactions
proceeded smoothly enabling the formation of
corresponding products 3 and 4 in good to excellent
yields.
(up to 5 equiv) increased the yield of compound 4a
up to 85%, whereas the yield of compound 3a
decreased significantly (Table 1, entries 8-10). The
pH of the reaction mixture was measured at 30 ºC
after the addition of sodium acetate in different
equivalents (Table 2). Next, some Brønsted bases like
NaOH and KOH were also screened, which could not
provide the better result (Table 1, entries 11 and 12).
Under above both conditions, we isolated 8-10% of
benzoic acid at the end of the reaction that could be
due to the hydrolysis of β-ketodithioester 1a. The
reaction of 1a with 2 in presence of NaOAc (5 equiv)
under solvent-free conditions afforded 3a only in
trace amount and 4a in 34% yield (Table 1, entry 13).
Thus, the optimum conditions for the formation of 3a
was identified as 1a (1.0 mmol), 2 (1.0 mmol) in 5
mL of water at reflux temperature (Table 1, entry 4).
The optimum conditions for 4a was found to be 1a
(1.0 mmol), 2 (1.0 mmol) and NaOAc (5 equiv) in 5
mL of water at reflux temperature (Table 1, entry 9).
However, aliphatic congeners of β–ketodithioester
are unable to provide any of the pyrazole products
since under refluxing in water, most of the starting
material
(3-hydroxy-3-alkylprop-2-enedithioate)
evaporated from the reaction vessel and remaining
amount undergoes decomposition.
Table 3. Substrate scope for the formation of 3.[a]
Table 2. pH of the medium on the addition of different
amount of NaOAc.[a]
NaOAc (eqv)
pH[b]
0
1.9
1
3.7
2
4.4
3
4.7
5
5.0
[a]
Reactions were performed with 1 mmol of both 1 and 2
in 5 mL of water.
[b] pH was measured at 30 ºC.
With the established optimal conditions in hand,
we then explored the generality and scope of the
protocol by using a range of structurally diverse β-
ketodithioesters 1. The results are summarized in
Table 3 and Table 4. To address the factors that
control the reaction, the electronic and steric
properties of the substituents R1 and R2 at β-
ketodithioesters were varied. R1 as various aromatic
groups with electron-donating or electron-
withdrawing substituents, regardless of their positions,
afforded the corresponding pyrazoles 3 in high yields,
revealing no obvious electronic impact. The various
substituents like Me, OMe, Cl and Br group on
phenyl ring (R1) were found to be compatible under
standard conditions (Table 3, 3d-3k). Importantly, β-
ketodithioesters 1 bearing heteroaromatic groups such
as 2-furyl, 2-thienyl and 3-pyridyl at R1 were also
tolerated well under optimal conditions affording the
corresponding products in high yields (Table 3, 3l-
3o). Replacing the R2 methyl with other groups such
as n-Pr, benzyl, Et, i-Bu, and n-Bu were fruitfully
amenable to this novel protocol affording
corresponding pyrazoles 3 in high yields (Table 3).
As shown in Table 4, a variety of β-
ketodithioesters 1 were applicable for this cyclization
and unexpected dimerization reaction, and most of
the substrates tested could afford the expected
products 4 in good yields. Thus, a broad spectrum of
1, bearing R1 as aryl and hetaryl groups could be
employed to afford disulphide-tethered pyrazoles 4 in
the presence of 5 equiv of NaOAc. The pH of the
[a] Reactions have been done with 1 mmol of each 1 and 2.
[b] Isolated yield.
Table 4. Substrate scope toward the formation of 4.[a]
[a] Reactions have been done with 1 mmol of each 1 and 2.
[b] Isolated yield.
The structures of all 1H pyrazoles 3a-o and 4a-h
were deduced from their satisfactory spectroscopic
1
data (IR, H, &13C NMR and MS) and structure
3
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10.1002/adsc.201701595
Advanced Synthesis & Catalysis
confirmation of 3 was further supported by X-ray
single crystal diffraction analysis of the
representative molecule 3g.[26]
Scheme 3. Control experiment.
To better understand the mechanistic rationale of
this domino protocol, we performed DFT studies.
From the mechanistic point of view, the nucleophile
(semicarbazide) could attack at two different
electrophilic carbonyl and thiocarbonyl carbons of β-
ketodithioesters resulting in the formation of two
intermediates C1-K and C2-SK having their
tautomeric enolic forms C1-E and C2-SE,
respectively (Figure 2). From the theoretical
calculations, it is evident that the enolic forms are
less stable than their corresponding keto-forms.
Furthermore, it could be specified that between C2-
SK and C1-K, the C2-SK is energetically more
stable than the C1-K (E is 5.82 kcalmol-1). However,
two positional isomers K-int and SK-int would give
same product after hydrolysis and subsequent
deamidation.
Figure 1. ORTEP diagram of 3g.
Taking into consideration the entire experimental
outcomes,
a
plausible mechanism for this
deamidative one-pot protocol is depicted in Scheme 2.
At first step, regioselective nucleophilic addition of
semicarbazide 2 onto electrophilic carbonyl carbon of
1 leads to the formation of open chain adduct C.
Adduct C undergoes intramolecular N-cyclization
enabling the cyclic intermediate D, which suffers
dehydration to give the intermediate E. Subsequently,
intermediate E undergoes elimination of either H2S or
R2SH forming 1H-pyrazole-1-carboxamides F and G,
respectively. Finally, intermediate F undergoes
hydrolysis followed by deamidation to give the
desired pyrazole 3. Since compound G bears free
thiol group at position 5 of the pyrazole ring, under
open air it undergoes oxidative dimerization leading
to disufide intermediate H,[27] which upon hydrolysis
followed by deamidation produced compound 4.
Figure 2. Energy level diagram of the adducts from DFT
calculation.
From DFT calculations (see SI Table S1), it is
perceived that these two positional isomers (K-int
and SK-int) have almost comparable energy (E is
2.47 kcal/mol). The CSR2 bond length is a bit
shorter (1.84 Å) in K-int than in SK-int (1.88 Å). But
CSR2 bond is reasonably elongated in C1-E (1.85
Å) than C2-SE (1.78 Å) (see SI Table S1). From
optimized structure of K-int, it is evident that the
elimination of SR2 is not facile, enabling the
formation of SK product exclusively. As the CSR2
bond length of SK-Intermediate is longer than that of
K-Intermediate, exclusive formation of SK product
occurs in more acidic medium, whereas formation of
K happens in less acidic/basic conditions. Both the
products SK and K have been isolated from the
reaction. Thus, from both experimental and
theoretical outcomes, it could be expected that the
desired products are formed exclusively through SK-
int intermediate (D in Scheme 2), not from the K-int
intermediate.
Scheme 2. Plausible mechanism.
To have deep insight into the mechanism, we
performed a control experiment by putting a reaction
of 3a in the presence of excess of NaOAc (5 equiv)
under water reflux to check the possibility of
conversion of 3a into 4a. But no trace of 4a was
observed and the starting material 3a remained
completely unconsumed (Scheme 3).
In summary, we have developed a catalyst-free
strategy to access diverse pyrazoles and disulfide-
tethered pyrazoles by the reaction of β-
ketodithioesters with semicarbazide hydrochloride in
water. This tandem [3 + 2] heteroannulation features
4
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10.1002/adsc.201701595
Advanced Synthesis & Catalysis
inexpensive and easily available substrates, broad
substrate scope, and good yields. During the course
of the transformations pH of the medium played a
key role toward switching selectivity. Based on our
experimental outcomes, a mechanistic rationale for
this cascade reaction is outlined, which is well
supported and validated by DFT calculations.
Notably, this chemistry is general, mild and low cost,
making this protocol a good alternative to existing
ones. The anti-cancer activity of the prepared
pyrazoles and disulfanes are under investigation in
our lab.
[5] a) M. A. A. El-Sayed, N. I. Abdel-Aziz, A. A. M.
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Experimental Section
General procedure for the synthesis of 5-thioalkyl-3-
aryl-1H-pyrazoles (3a-o) and 1,2-bis(3-aryl-1H-pyrazol-
5-yl)disulfane (4a-h).
In a round-bottomed flask -ketodithioesters 1 (1.0 mmol)
and semicarbazide hydrochloride 2 (1.0 mmol) were mixed
and 5 mL of H2O was added and it was heated to 100 °C.
After completion of the reaction (monitored by TLC), the
reaction mixture was cooled to room temperature and more
water (20 mL) was added to the followed by extraction
with ethyl acetate (2 × 10 mL). The combined organic
layer was dried over anhydrous Na2SO4 and evaporated in
vacuum. The crude residue was purified by column
chromatography over silica gel using ethyl acetate/hexane
as eluent to afford pure 5-thioalkyl-3-aryl-1H-pyrazoles 3.
In case of compound 4, in a round-bottomed flask -
ketodithioesters
1
(1.0
mmol),
semicarbazide
hydrochloride 2 (1.0 mmol) and sodium acetate (5.0 mmol)
were mixed and 5 mL of H2O was added and it was heated
to 100 °C. Purification and isolation of 1,2-bis(3-aryl-1H-
pyrazol-5-yl)disulfanes 4 have been done follownig the
same procedure like compound 3.
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Acknowledgements
The authors gratefully acknowledge the generous financial
support from the Science and Engineering Research Board, New
Delhi (SERB/EMR/2015/002482), the Council of Scientific and
Industrial Research (02(0263)/16/EMR-II), New Delhi, India.
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5
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10.1002/adsc.201701595
Advanced Synthesis & Catalysis
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10.1002/adsc.201701595
Advanced Synthesis & Catalysis
COMMUNICATION
Catalyst-Free One-Pot Access to Pyrazoles and
Disulfide-Tethered Pyrazoles via Deamidative
Heteroannulation of β-Ketodithioesters with
Semicarbazide Hydrochloride in Water
Adv. Synth. Catal. Year, Volume, Page – Page
Suvajit Koley,a Sumit Kumar Panja,b Sonam Soni,a
and Maya Shankar Singh a,*
7
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