Synthesis of 4-hydroxy-7-dimethylamino-3-pyrazolinylcoumarins and their polarity-sensitive properties

Article abstract of DOI:10.1016/j.tetlet.2011.11.142

Four 4-hydroxy-3-pyrazolinylcoumarin derivatives were synthesized and their UV-vis spectra in various compositions of MeOH and CH₂Cl₂ were measured. Among the prepared compounds, only one was found to exist mainly in the enol form in

Full text of DOI:10.1016/j.tetlet.2011.11.142

Tetrahedron Letters 53 (2012) 778–782
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 4-hydroxy-7-dimethylamino-3-pyrazolinylcoumarins
and their polarity-sensitive properties
⇑
Jiun-Han Lin, Chi-Hui Lin, Ding-Yah Yang
Department of Chemistry, Tunghai University, No. 181, Section 3, Taichung Port Road, Taichung City 40704, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Four 4-hydroxy-3-pyrazolinylcoumarin derivatives were synthesized and their UV–vis spectra in various
compositions of MeOH and CH2Cl2 were measured. Among the prepared compounds, only one was found
to exist mainly in the enol form in nonpolar solvents and the keto form in protic solvents, whereas the
others are exclusively present in the enol forms regardless of solvent polarity. This polarity-sensitive
property of 3-pyrazolinylcoumarins can be controlled by the electronic nature of the substituent at the
7-position of coumarin, the 1-position (nitrogen atom) of pyrazoline as well as the para-position of the
benzene moiety.
Received 6 October 2011
Revised 26 November 2011
Accepted 30 November 2011
Available online 8 December 2011
Keywords:
Coumarin
Pyrazoline
Ó 2011 Elsevier Ltd. All rights reserved.
Keto-enol tautomerization
Introduction
OH
O
O
O
O
OH
O
4-Hydroxycoumarin-based diketone lactones and their deriva-
tives have been known for their extensive application as biologi-
cally active substances1 as well as organic functional materials.2
They exist in different tautomeric forms under different solvent
polarities, and this property plays a major role in determining their
chemical, biological and therapeutic activities. Previous studies3
have demonstrated that 4-hydyroxycoumarin-based diketone lac-
tones exist mainly in the endocyclic-enol form in nonpolar solvents
and the exocyclic-enol form in protic solvents. For instance, the
major tautomer for 3-acyl-4-hydroxycoumarin (1) in methylene
chloride is the endocyclic enol form, whereas the dominant tauto-
mer for the same compound in methanol is the exocyclic enol
form, as shown in Scheme 1. A similar polarity-sensitive property
for 4-hydroxy-3-pyrazolinylcoumarin 3 has also recently been
reported by Traven and coworkers4 (Scheme 1). This compound
exists mainly in the enol tautomer 3 in nonpolar solvents such as
CCl4 and the enol tautomer 4 in polar solvents such as DMF. While
various 4-hydyroxycoumarin-based diketone lactones and their
derivatives have been reported to possess the solvent-sensitive
properties, factors that affect this intriguing enol-keto tautomer-
ization in different solvent polarities are rarely explored.
Understanding or control of the tautomeric forms of diketone
lactones may not only provide valuable information regarding
their biological and pharmacological properties,5 but also facilitate
further development of the coumarin-based organic functional
materials such as polarity-sensitive fluorescent probes.6 Here we
O
2
1
dominant exocyclic enol
tautomer in MeOH
dominant endocyclic enol
tautomer in CH2Cl2
N
N
OH
O
N
O
O
O
HN
O
OMe
OMe
4
3
dominant enol tautomer in CCl4
dominant keto tautomer in DMF
Scheme 1. Enol-keto tautomerization of 1 and 3 in different solvents.
report the synthesis of four 4-hydroxy-3-pyrazolinylcoumarins
with different substituents and their UV–vis spectra in solvents
with different polarities were measured. Our studies suggest that
the polarity-sensitive property of these compounds is highly
dependent on the electronic nature of the substituents at the cou-
marin, pyrazoline, and benzene moieties.
Results and discussion
Scheme
2 shows the preparation of 4-hydroxy-3-pyra-
⇑
zolinylcoumarins 5–8 and 4-methoxy-3-pyrazolinylcoumarin 9. It
started with a base-catalyzed condensation of 3-acetyl-7-dimethyl-
Corresponding author. Tel.: +886 4 2359 7613; fax: +886 4 2359 0426.
E-mail address: yang@thu.edu.tw (D.-Y. Yang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.142

J.-H. Lin et al. / Tetrahedron Letters 53 (2012) 778–782
779
OH
O
O
O
OH
O
O
OHC
piperidine
toluene
Dean-Stark trap
14 h
N
R
N
O
R
10
13, R= N(CH3)2, 90%
14, R= NO2, 75%
11, R= N(CH3)2
12, R= NO2
NH2NH2 or NH2NHPh
HOAc
reflux, 3 h
R1
N
Ac
N
OH
O
N
O
O
N
CH2N2
CH2Cl2 0 oC, 6 h,
60%
R
N
N
O
N
O
5, R= N(CH3)2, R1= Ph, 94%
6, R= NO2, R1= Ph, 80%
7, R= NO2, R1 = Ac, 77%
8, R= N(CH3)2, R1= Ac, 88%
9
Scheme 2. Preparation of compounds 5–9.
Figure 1. ORTEP crystal structures of 5 and 8.
amino-4-hydroxycoumarin (10)7 with 4-dimethylaminobenzalde-
hyde (11) or 4-nitrobenzaldehyde (12) to give the ,b-unsaturated
solvent-sensitive properties. Compounds 5–7 were found to be
present in the enol form in solution regardless of solvent polarity.
Figure 2 shows the absorption spectra of 5 in various compositions
of CH2Cl2 and MeOH. No conspicuous absorption change was
observed when the solvent polarity was increased from 100%
CH2Cl2 to 100% MeOH. Obviously compound 5 does not exhibit
enol-keto tautomerization properties and exists exclusively in enol
form either in CH2Cl2 or MeOH, that is, compound 15 is not formed
as shown in Scheme 3. Since the major structural difference
between 3 and 5 is that the latter has an extra dimethylamino
group at 7-position of the coumarin moiety, we speculate that this
a
ketones 13 and 14, respectively. The subsequent coupling of ketone
13 or 14 with hydrazine or phenylhydrazine in acetic acid under
reflux conditions yielded 4-hydroxy-3-pyrazolinylcoumarins 5–8.8
Final methylation of 8 with diazomethane in methylene chloride
afforded the corresponding 4-methoxy-3-pyrazolinylcoumarin 9.
The molecular structures of 5 and 8 were elucidated by 1H and 13
C
NMR spectroscopy as well as by X-ray crystallography as shown in
Figure 1,9 which clearly reveal a coumarin and dimethylaminoben-
zene substituted pyrazoline skeleton. Both compounds 5 and 8 were
found to exist in the endocyclic-enol form in the solid state. The
intramolecular hydrogen bonding (the distance between the hydro-
xyl hydrogen and pyranzoline nitrogen atom) for 5 and 8 was mea-
sured to be 1.620 and 1.614 Å, respectively.
electron-donating substituent on the coumarin moiety of
5
substantially strengthens the enol form’s hydrogen bond, which
results in 5 to be less susceptible to eno-keto tautomerization in
protic solvents.
Having characterized the structures of these 4-hydroxy-3-pyra-
zolinylcoumarins 5–8, we turned our attention toward their
Interestingly, compound 8 was found to possess solvent-sensi-
tive properties. Figure 3 shows the absorption spectra of 8 in

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J.-H. Lin et al. / Tetrahedron Letters 53 (2012) 778–782
Figure 2. UV–vis spectra of 5 (2.9 Â 10À5 M) in various compositions of CH2Cl2 and MeOH.
N
N
O
O
HN
O
OH
O
N
O
N
N
N
N
5
15
not observed
enol tautomer in both CH2Cl2 and MeOH
Scheme 3. No enol-keto tautomerization was observed for 5.
Figure 3. UV–vis spectra of 8 (4.5 Â 10À5 M) in various compositions of CH2Cl2 and MeOH.
various compositions of CH2Cl2 and MeOH. With the increase of
the solvent polarity, the absorption bands with the peak wave-
length around 397 and 413 nm gradually decrease and the absorp-
tion band at 350 nm gradually increases. An isosbestic point was
observed at approximately 366 nm, which indicates the intercon-
version of two different tautomeric forms. Scheme 4 shows the
proposed enol-keto tautomerization between 8 and 16. The enol
form 8 is more stable in nonpolar solvents such as methylene
chloride because it contains a strong hydrogen bond between
4-hydroxy hydrogen atom and 3-hydrazono nitrogen atom. When
the solvent polarity is increased, the keto form 16 emerges
presumably because polar solvents such as methanol weaken the

J.-H. Lin et al. / Tetrahedron Letters 53 (2012) 778–782
781
Ac
N
Ac
N
O
O
HN
O
OH
O
N
O
N
N
N
N
8
16
dominant keto tautomer in MeOH
dominant enol tautomer in CH2Cl2
Scheme 4. Enol-keto tautomerization between 8 and 16.
Figure 4. Partial proton NMR spectra of 8 in (a) CD3OD, (b) DMSO-d6, and (c) CD2Cl2.
Figure 5. Emission spectra of 8 (2.0 Â 10À6 M) obtained in various compositions of MeOH and CH2Cl2.
aforementioned hydrogen bond. Since the NMR spectroscopy often
provides useful information on keto-enol tautomerism and E–Z
isomerization of the appropriate coumarin derivatives,10 the
proton NMR of compound 8 in three different solvents (CD3OD,
DMSO-d6, CD2Cl2) was recorded as shown in Figure 4. Unfortu-
nately, the chemical shifts of the exchangeable (OH or NH) protons,
which form intramolecular hydrogen bonds were found to be
located in a narrow region between 13.348 and 13.299 ppm, which
is too close to be differentiated by solvent titration. Nevertheless,
the occurrence of enol-keto tautomerization in different solvent
polarities of 8 can still be supported by the variation of the fluores-
cence intensity. Figure 5 shows the emission spectra of 8 in various
compositions of MeOH and CH2Cl2. Compound 8 is non-emissive in
MeOH since it mainly exists in the keto form 16. When the solvent
polarity decreases (by adding CH2Cl2), the fluorescence intensity of
8 increases due to the presence of the N,N-dimethylaminocouma-
rin fluorophore in its enol form and the discernible brightness
enhancement can be detected even with a slight solvent polarity

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J.-H. Lin et al. / Tetrahedron Letters 53 (2012) 778–782
change. The fluorescence quantum yield (Uf) of 8 in CH2Cl2 was
measured to be 0.11, whereas compounds 5–7 were essentially
non-fluorescent in CH2Cl2 with Uf values of less than 0.01.
Understandably, when 3-pyrazolinylcoumarin 8 was methylated
to the corresponding 4-methoxy-3-pyrazolinylcoumarin 9, the
polarity-sensitive property of the resulting compound was no
longer observed simply because no hydrogen atom is available
for the intramolecular proton transfer process. Since compound 8
is highly sensitive to the surrounding solvent systems and is prone
to undergo keto-enol tautomerization in nonpolar solvents, we
envision that it may have the potential to function as a fluores-
cence probe to determine the solvent polarities empirically as well
as and to evaluate ‘polarity’ of protein and enzyme binding sites.11
Among the prepared 4-hydroxy-3-pyrazolinylcoumarins 5–8,
only 8 was found to exist in the enol form in nonpolar solvents
and the keto form in protic solvents, whereas others are
exclusively present in the enol form regardless of solvent polarity.
The structural comparison between the solvent-sensitive 8 and
solvent-insensitive 5 implies that the electron-withdrawing acetyl
group at the N-3 position of the pyrazole moiety of 8 plays an
important role in controlling the enol-keto tautomerization
process. Furthermore, the fact that compound 7 with a nitro group
at the para-position of the benzene moiety fails to exhibit the
solvent-sensitive properties also suggests that the enol-keto tauto-
merization can be manipulated by an electron-withdrawing group
on the benzene ring. Our studies suggest that the polarity-sensitive
property of 3-pyrazolinylcoumarins is highly dependent upon the
electronic nature of the substituents on coumarin, pyrazoline,
and benzene moieties. The equilibrium between enol and keto
forms can be pulled to favor one or be pushed to favor the other
via the incorporation of suitable electronic groups on each side of
the hydrogen bond donor and acceptor.
incorporation of suitable electron-donating or withdrawing sub-
stituents on each side of the hydrogen bond donor and acceptor.
Acknowledgment
We thank the National Science Council of the Republic of China,
Taiwan, for financially supporting this research under Contract No.
NSC 98-2113-M-029-003-MY2.
Supplementary data
Supplementary data (synthesis of compounds 5–9, 13, and 14
experimental details, and additional spectra. X-ray structure de-
tails for 5, 8, and 13 (CIF).) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.11.142.
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In summary, four 4-hydroxy-3-pyrazolinylcoumarin derivatives
were synthesized to evaluate their polarity-sensitive properties.
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