Synthesis of Functionalized Pyrazoles via Vanadium-Catalyzed C-N Dehydrogenative Cross-Coupling and Fluorescence Switch-On Sensing of BSA Protein

Article abstract of DOI:10.1021/acs.orglett.5b02669

Vanadium-catalyzed C-N dehydrogenative cross-coupling of alkenyl hydrazones leading to functionalized pyrazoles is described in a 1:1 mixture of toluene/H₂O using air as the terminal oxidant. Significant practical features include use of the commercial nontoxic VOSO₄ as a recyclable catalyst, mild reaction conditions, scalability, and the broad substrate scope. Some of the product pyrazoles exhibit interesting photophysical properties. Fluorescence light-up sensing of BSA protein by one of the pyrazoles is also highlighted.

Full text of DOI:10.1021/acs.orglett.5b02669

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Pyrazoles via Vanadium-Catalyzed C−N
Dehydrogenative Cross-Coupling and Fluorescence Switch-On
Sensing of BSA Protein
†
,†
Dinabandhu Sar, Raghunath Bag, Afsana Yashmeen, Subhendu Sekhar Bag,*
and Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India
*
S Supporting Information
ABSTRACT: Vanadium-catalyzed C−N dehydrogenative cross-coupling of alkenyl hydrazones leading to functionalized
pyrazoles is described in a 1:1 mixture of toluene/H O using air as the terminal oxidant. Significant practical features include use
2
of the commercial nontoxic VOSO as a recyclable catalyst, mild reaction conditions, scalability, and the broad substrate scope.
4
Some of the product pyrazoles exhibit interesting photophysical properties. Fluorescence light-up sensing of BSA protein by one
of the pyrazoles is also highlighted.
8
ransition-metal-catalyzed oxidative C−H functionalization
their widespread potential biological applications. Also9,
pyrazoles are known to bind strongly with biomolecules.
Thus, synthesis of functionalized pyrazoles with a mild, atom
economic, and simple process, and a study of their interaction
properties with biomolecules such as bovine serum albumin
(BSA) could find useful application in synthetic and medicinal
T
affords a powerful tool for regioselective C−C and C−
1
heteroatom bond formation. Transition metals such as Rh, Ru,
1
Pd, and Cu have been significantly investigated for this purpose.
Vanadium is nontoxic, readily available, cheap, and also present
2
in biological molecules. Thus, its exploration for regioselective
10
C−H functionalization via dehydrogenative cross-coupling,
sciences.
3
employing air as the oxidant under environmentally benign
We first commenced our optimization studies using α,β-
unsaturated ketone 1a and phenylhydrazine hydrochloride 2a as
model substrates with V catalysts (Supporting Information,
Table 1). Gratifyingly, the reaction readily occurred to provide
the functionalized pyrazole 3a in 70% yield when the substrates
1a and 2a were stirred with NaOAc in a 1:1 mixture of toluene/
H O at 60 °C for 1 h followed by rt for 18 h with 20% VOSO ,
4
aqueous organic reaction conditions, would be valuable
(
Scheme 1a). Herein, we report the condensation of α,β-
Scheme 1. Vanadium-Catalyzed Dehydrogenative Coupling
Reactions
2
4
using air as the oxidant (entry 1). Subsequent screening of
VO(acac) and V O as the catalysts produced the target
2
2
5
heterocycle 3a in 55% and 54% yield, respectively (entries 2 and
3
). Yet, lowering the quantity of VOSO to 5 mol % led to an
4
increase in the yield to 73% (entries 4−5). The reaction under N
2
provided 3a in trace amount (entry 6). Control experiments
confirmed that in the absence of a V catalyst the target
heterocycle 3a was not formed (entry 7).
Having identified the optimal reaction conditions, the scope of
the procedure was explored. First, the reaction of a series of
methyl alkenyl ketones 1b−p was screened with phenyl-
hydrazine 2a (Scheme 2). The substrate 1b underwent reaction
to afford 3b in 48% yield. The reactions of substrates 1c−j
unsaturated ketones with aryl hydrazines followed by the C−N
5
dehydrogenative cross-coupling of alkenyl hydrazones using
water-soluble VOSO as the recyclable catalyst, leading to highly
4
functionalized pyrazoles in a 1:1 mixture of toluene/water under
6
,7
air at room temperature (Scheme 1b).
Functionalized
Received: September 15, 2015
pyrazoles are the subject of recent research interest due to

Organic Letters
Letter
Scheme 2. Reaction of Different Methyl Alkenyl Ketones 1b−
Scheme 3. Reaction of Methyl Alkenyl Ketones with Different
Aryl Hydrazines 2b−e
a
−
c
−
a c
p with Phenylhydrazine 2a
a
Reaction conditions: ketone (1.0 mmol), aryl hydrazines 2b−e (1.2
mmol), toluene (1.5 mL), 60 °C, 1 h; VOSO (0.05 mmol), H O (1.5
4
2
b
c
mL), rt, air. Isolated yield. Accompanied 5−10% unreacted
substrates.
Scheme 4. Reaction of α,β-Unsaturated Ketones 1r−s with
Hydrazines 2a and 2f
a
Reaction conditions: 1b−p (1.0 mmol), 2a (1.2 mmol), NaOAc (2.9
mmol) toluene: H O (1:1, 3 mL), 60 °C, 1 h; VOSO (0.05 mmol), rt,
2
4
b
c
air. Isolated yield. Accompanied by ∼5−10% unreacted 1b−p and
2
a.
bearing substituted aryl rings with 2-bromo, 2-methoxy, 2-
methyl, 4-bromo, 4-cyano, 4-fluoro, 4-methyl, and 4-methyl
carboxylate functionalities produced the corresponding pyr-
azoles 3c−j in 38−66% yields, while 1k−l having 2,4-dimethoxy
and 3,4,5-trimethoxy substituents in the aryl ring underwent
reaction to furnish 3k−l in good yields. In addition, the reaction
of 1m−p bearing cyclohexyl, isobutyl, sec-butyl, and isopropyl
substituents in the alkenyl position readily occurred to furnish
the corresponding pyrazoles 3m−p in 54−64% yields.
The reaction of 1a with 2a was also studied in gram scale as a
representative example (Supporting Information (SI), Scheme
S1). As mentioned above, the reaction took place readily to
produce 3a in 65% yield. Furthermore, the aqueous layer having
the vanadium catalyst could be easily separated and recycled. For
example, the reaction of 1a with 2a was studied over three runs
with >64% yield (SI, Scheme S2).
Recrystallization of 3a from CH CN gave a single crystal
3
whose structure was determined by X-ray analysis.
Next, the utility of the protocol was extended to the reaction of
methyl alkenyl ketones 1a−b, 1i, 1f, 1l−m, and 1q with different
aryl hydrazines 2b−e (Scheme 3). Ketones 1i and 1m underwent
a reaction with (4-bromophenyl)hydrazine 2b to give pyrazoles
The proposed catalytic cycle is shown in Scheme 5.
Condensation of the ketones with aryl hydrazines may give
3
q and 3r in 74% and 61% yield, respectively, while 1b, 1q, and 1l
with (4-chlorophenyl)hydrazine 2c produced the desired
pyrazole derivatives 3s−u in 48−71% yields. The reaction of
the ketone 1i with (4-methoxyphenyl)hydrazine 2d gave 3v in
hydrazones a, which may react with VOSO to yield the
4
Scheme 5. Proposed Reaction Pathway
68% yield, whereas 1f and 1a with (2,4-dichlorophenyl)-
hydrazine 2e furnished pyrazoles 3w and 3x in 58% and 63%
yields, respectively. Also, the reaction of the chalcone 1r with 2a
produced pyrazole 3y in 72% yield (Scheme 4), whereas
trifluoromethyl ketone with a p-tolyl substituent in the alkenyl
position 1s underwent reaction with hydrazine 2f to produce
celebrex 3z in 45% yield. These results suggest that this
procedure can be employed for the reactions of a broad range of
substrates to afford diverse functionalized pyrazoles in good
yields.
B
DOI: 10.1021/acs.orglett.5b02669
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Organic Letters
Letter
2
a
intermediate b. Concerted metalation−deprotonation (CMD)
of b may give the cyclic vanadium intermediate c, which may
undergo reductive elimination to produce the target pyrazole
derivatives and V(II) species. The latter with air may oxidize to
active catalysts via the peroxo species d and e to complete the
catalytic cycle.
state complex formation between 3y and BSA (Figure 1a).
Moreover, the nonperturbed nature of the isosbestic point
Finally, we studied the UV−visible and fluorescence photo-
physical properties of some of the synthesized pyrazoles and
interaction of two of the compounds with the BSA biomolecule.
Thus, pyrazole 3a exhibited strong absorption bands at 260 and
3
02 nm as was revealed from UV−visible spectra. When excited
at 302 nm it showed strong red-shifted emission (31 nm) at
around 363−394 nm. In contrast, 3u, in which the N-1 of
pyrazole was substituted by the electron-withdrawing group,
chlorophenyl, showed red-shifted (24 nm) emission at around
Figure 1. (a) UV−visible titration of probe 3y with various
concentrations of BSA. (b) Fluorescence titration of probe 3y with
various concentrations of BSA (5 mM phosphate buffer, pH 7.0, rt, λ =
ex
3
45 nm).
367−391 nm with decreased intensity as the solvent polarity
increased when excited at its strong charge transfer absorption
band at 301 nm. The emission was characterized as ICT
emission. However, when pyrazole N-1 was substituted by the
electron-withdrawing group, dichlorophenyl, the compound 3x
showed very weak emission with a strong red shift in the polar
solvents compared to highly nonpolar hexane. The pyrazole
derivative 3k exhibited strong absorbance in various organic
solvents at around 265 nm. Upon excitation at individual
absorption maxima (λex = 263−272 nm) of each solvent, 3k
showed strong emission behavior at around 365 nm with
increased intensity as the solvent polarity increases from hexane
to methanol. On the other hand, pyrazole 3l containing the
trimethoxyphenyl donor exhibited absorbance at around 265 and
suggested only one binding stoichiometry. The Job plot for both
probes suggested a 1:1 binding complex between probes and
BSA (SI, Figure 16).
To investigate the protein sensing ability and insight into the
binding event of the probes, we then investigated the change in
fluorescence upon addition of increasing concentrations of BSA
to the individual probe’s solution. Thus, it was observed that both
the fluorescence intensity and quantum yield of the probe
pyrazole 3a decreased slowly with a small blue shift of emission
maxima when excited at 302 nm (SI, Figure 2a) indicating a
binding of the probe in a relatively hydrophobic site of the BSA.
This observation was also evident from a blue-shifted emission of
the probe 3a in various organic solvents as the solvent polarity
325 nm. The charge transfer band at 325 nm showed increased
1
0,11
intensity with red shifting behavior as solvent polarity was
increased. However, upon excitation at around 260−270 nm it
showed strong emission at around 370 nm in various organic
solvents with no regular trend. The compound 3y showed
stronger absorbance at 255 and 335 nm than 3l. The charge
transfer band at 335 nm showed decreased intensity with a red
shift as the solvent polarity was increased. Upon excitation at a
longer absorption band, it showed strong red-shifted emission,
characteristic of ICT at around 400 nm with a red shift of 39 nm
as the solvent polarity was increased. The compound 3v showed
absorption at 260 nm in less polar solvent such as hexane with a
shoulder at around 300 nm in polar solvents. It showed irregular
emission behavior at around 373 nm when excited as 260 nm. On
the other hand, compound 3q showed a strong absorption band
at around 262 nm which when excited at 262 nm showed
structureless emission at around 375 nm with a red shift of 15 nm
and decreased intensity as solvent polarity was decreased.
Looking at the microenvironment sensitive emission charac-
teristics of pyrazoles, 3a and 3y, we were next interested in
studying the interaction behavior with bovine serum albumin
decreases (SI, Figure 2c−d).
In contrast, upon excitation at
3
35 nm, a gradual increase in fluorescence intensity at about 420
nm was the result when an increasing concentration of BSA
solution was added gradually to a solution of probe pyrazole 3y
(Figure 1b). This result indicated a binding interaction between
the pyrazole 3y and the BSA. Next, the fluorescence anisotropy
was measured to confirm the binding event further. Thus, an
enhancement of fluorescence anisotropy for the probe 3a from
0.01 in aqueous buffer to 0.10 in the presence of BSA was
observed. This indicated that the probe 3a bound strongly inside
the hydrophobic pocket of BSA and experienced a highly
12
restricted rotational motion (SI, Figure 13). On the other hand,
upon addition of BSA to a solution of 3y, the anisotropy value
increased initially from 0.18 to 0.31 indicating a strong binding
12
between BSA and the probe (SI, Figure 17). An increase in the
% α-helicity of BSA was observed from the CD spectra in the
presence of both pyrazoles. This indicated a possible conforma-
tional adjustment of BSA upon association with the pyrazoles
10,11
(SI, Figure 18).
The association constant of probe pyrazoles
3a and 3y with BSA was also determined fluorimetrically by a
Stern−Volmer plot SI, Figure 11) and Benesi−Hildebrand plot
1
0
(
BSA). The absorption spectra of free 3a and 3y in phosphate
3
buffer (20 mM, pH 7.0) showed maxima (λmax) near 245, 299 nm
and 243, 336 nm, respectively. Thus, upon addition of increasing
concentration of BSA to the solution of pyrazole probe 3a, we
observed a hyperchromicity with a strong red shift of 12 nm in
the UV−vis spectra indicating interactions between BSA and 3a
(SI, Figure 15) respectively, which were found to be 4.9 × 10
4
−1
and 1.64 × 10 M respectively. The association constants
reflected that the compound 3y binds with BSA more strongly
than 3a. Therefore, it is clear from the above findings that the
probe pyrazole 3y is more efficient compared to 3a in sensing the
BSA protein biomolecule via the generation of enhanced
fluorescence intensity. The low fluorescence intensity of the
probe in phosphate buffer in the absence of biomolecules may be
attributed to a radiationless channel assisted by intermolecular
hydrogen bonding present in aqueous solution. However, in the
presence of BSA the nonradiative channels are possibly blocked
and are less effective, as the probe interacts strongly with the
(SI, Figure 10a). On the other hand, pyrazole probe 3y exhibited
strong hypochromism with a red shift of about 8−10 nm of the
absorbance band in the UV−vis spectra upon gradual addition of
BSA. The band in the UV−visible spectra at around 335 nm
vanished when the BSA concentration was 9 times the
concentration of the probe. All these observations, along with
an isosbestic point at 298 nm, clearly indicated strong ground
C
DOI: 10.1021/acs.orglett.5b02669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02669.
2
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(
AUTHOR INFORMATION
Corresponding Authors
■
̈
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Synth. Commun. 2009, 39, 2169. (d) Neumann, J. J.; Suri, M.; Glorius, F.
Angew. Chem., Int. Ed. 2010, 49, 7790. (e) Hu, J.; Chen, S.; Sun, Y.; Yang,
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*
E-mail: ssbag75@iitg.ernet.in.
E-mail: tpunni@iitg.ernet.in.
*
Author Contributions
†A.Y. and S.S.B. contributed equally to the photophysical studies.
Notes
(
(
k) Hamada, N. M. M.; Abdo, N. Y. M. Molecules 2015, 20, 10468.
l) Bharathiraja, G.; Sengoden, M.; Kannan, M.; Punniyamurthy, T. Org.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
(
We gratefully acknowledge the Science and Engineering
Research Board (SR/S1/OC-55/2011) and Council of Scientific
and Industrial Research (02(0088)/12/EMR-II) for financial
support. D.S. thanks CSIR for an SRF Fellowship. We also thank
Central Instrumental Facility, IIT Guwahati for NMR facilities.
(
(9) (a) Baraldi, P. G.; Balboni, G.; Pavani, M. G.; Spalluto, G.; Tabrizi,
M. A.; Clercq, E. D.; Balzarini, J.; Bando, T.; Sugiyama, H.; Romagnoli,
R. J. Med. Chem. 2001, 44, 2536. (b) Kulkarni, N. V.; Kamath, A.;
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