Laccase-catalyzed reaction of 3-tert-butyl-1H-pyrazol-5(4H)-one with substituted catechols using air as an oxidant

Article abstract of DOI:10.1016/j.tet.2013.03.023

The laccase-catalyzed reaction of 3-tert-butyl-1H-pyrazol-5(4H)-one with a number of catechols and aerial oxygen as an oxidant selectively affords 4-substituted 3-tert-butyl-1H-pyrazol-5-ol derivatives with yields ranging from 77 to 99%.

Full text of DOI:10.1016/j.tet.2013.03.023

Tetrahedron 69 (2013) 3664e3668
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Laccase-catalyzed reaction of 3-tert-butyl-1H-pyrazol-5(4H)-one
with substituted catechols using air as an oxidant
a
b
b
b,
*
€
ꢀ
€
€
Safiye Emirdag-Ozturk , Szilvia Hajdok , Jurgen Conrad , Uwe Beifuss
a
_
Department of Chemistry, Faculty of Science, Ege University, Bornova, Izmir 35100, Turkey
Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstr. 30, D-70599 Stuttgart, Germany
b
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
The laccase-catalyzed reaction of 3-tert-butyl-1H-pyrazol-5(4H)-one with a number of catechols and
aerial oxygen as an oxidant selectively affords 4-substituted 3-tert-butyl-1H-pyrazol-5-ol derivatives
with yields ranging from 77 to 99%.
Received 17 December 2012
Received in revised form 20 February 2013
Accepted 5 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 13 March 2013
Keywords:
1H-Pyrazol-5(4H)-one
Catechol
Laccase
1. Introduction
catalyzed oxidative couplings of electron rich phenols,10,12 oxida-
tive aromatizations,10,13 and oxidative cleavages10,14 the focus is on
Pyrazolones are very well known for their analgesic, antipyretic,
and antiinflammatory properties.1,2aed There are also renowned for
their antitumor2eeh and hypoglycemic2i,j activities. For a couple of
years, the potent radical scavenger edaravone (3-methyl-1-phenyl-
2-pyrazolin-5-one) is in use as a neuroprotective agent for treat-
ment of acute cerebral infarction in several countries.3 A number
of pyrazolones find use as herbicides.4 Moreover, substituted
pyrazolones have been applied for the synthesis of dyes.5 The nu-
merous applications for pyrazolones are the reason for the
continuing interest in the development of new methods for their
efficient preparation.6
In organic synthesis, there is an urgent need for the development
of environmentally benign oxidations.7 Molecular oxygen repre-
sents an ideal alternative to traditionally used oxidants.8 This is why
enzyme-catalyzed oxidations using aerial oxygen as the oxidant
have received increasing attention.9 Recently, there are consider-
able attempts to use laccases as catalysts for selective and efficient
oxidations with O2.10 Laccases are produced by fungi, plants, and
prokaryotes. They can easily be isolated and some laccases are even
commercially available. Laccases (benzenediol: O2 oxidoreductase
EC 1.10.3.2.) are multicopper oxidases, which can catalyze the oxi-
dation of a number of substrates using O2 as the oxidant with si-
multaneous reduction of O2 to give H2O.11 Apart from laccase-
laccase-catalyzed oxidations of catechols and hydroquinones to the
corresponding benzoquinones and their reactions with C-nucleo-
philes.10,15 Typical examples include the reactions of catechols with
cyclic 1,3-dicarbonyls to yield 3,4-dihydro-7,8-dihydroxy-2H-di-
benzofuran-1-ones as the result of
a domino oxidation/in-
termolecular 1,4-addition/oxidation/intramolecular 1,4-addition
(Scheme 1).15h As an extension of this work, we became interested
in using 1,3-dicarbonyl equivalents as substrates.
O
O
OH
1. oxidation
OH
OH
+
2. 1,4-addition
OH
OH
OH
1
2a
3
O
OH
OH
3. oxidation
4. 1,4-addition
O
4
Scheme 1. Synthesis of 3,4-dihydro-7,8-dihydroxy-2H-dibenzofuran-1-one (4) by
laccase-catalyzed domino oxidation/intermolecular 1,4-addition/oxidation/intra-
molecular 1,4-addition.
Here, we report on the laccase-catalyzed reaction between 3-
* Corresponding author. E-mail address: ubeifuss@uni-hohenheim.de (U. Beifuss).
tert-butyl-1H-pyrazol-5(4H)-one (5) and unsubstituted catechol 2a,
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.023

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3-substituted catechols 2bee and 4-substituted catechols 2feh
(Fig. 1) using air as an oxidant.
OH
OH
N
HN
OH
OH
O
8
R2
N
O
N
R1
2a-h
Fig. 2. Structure of the expected cyclization product 8 from the reaction of 5 with 2a.
H
5
as the formation of product mixtures, which could not be sepa-
rated, was observed.
2a
2b
2c
2d
2e
R1 = H
R2 = H
R2 = H
R2 = H
R2 = H
R2 = H
2f
R1 = H
R1 = H
R1 = H
R2 = CH3
R1 = CH3
R1 = OCH3
R1 = F
2g
2h
R2 = C2H5
R2 = NO2
The next set of experiments was devoted to the reactions be-
tween the 3-tert-butyl-pyrazol-5-one (5) and several mono-
substituted catechols 2bee (Scheme 4, Table 1, Fig. 3). Depending
on whether the intermolecular 1,4-addition of the nucleophile
occurs at C-40 or C-50 of the corresponding o-benzoquinone in-
termediates 7bee (Scheme 4), either products of type 9 or type 10
were formed. The reaction of 3-tert-butyl-pyrazol-5-one (5) with 3-
methylcatechol (2b) delivered 98% of a 91:9 mixture of 9b and 10b
(Table 1, entry 2). In the reaction with 3-methoxycatechol (2c) the
1,4-adduct 9c, i.e., the product resulting from an attack at C-50 of 7c,
was isolated with 80% (Table 1, entry 3). When 5 was reacted with
3-fluorocatechol (2d), the regioselectivity was less pronounced.
Here, a 60:40 mixture of the two regioisomers 9d and 10d was
isolated in 98% yield (Table 1, entry 4). In contrast, upon reaction of
5 with 3-bromocatechol (2e) the regioisomer resulting from an 1,4-
attack of 5 at C-40 of 7e was formed exclusively. The corresponding
product 10e was obtained with 96% yield (Table 1, entry 5). The
regioselectivity of these reactions may be rationalized in such a way
that the 1,4-addition exclusively takes place at the more electro-
philic carbon atom of the corresponding o-benzoquinones 7
(Scheme 4).
R1 = Br
Fig. 1. Substrates for the laccase-catalyzed transformations.
2. Results and discussion
First, the laccase-catalyzed reaction between 3-tert-butyl-1H-
pyrazol-5(4H)-one (5) and the unsubstituted catechol (2a) was
studied using aerial oxygen as the oxidant (Scheme 2). After some
experimentation it was found that 6a can be isolated in 95% yield
when 1 equiv of 5 and 1.1 equiv of 2a were reacted in the presence
of laccase from Agaricus bisporus in phosphate buffer (pH 6.0) at
room temperature.
OH OH
cat. laccase
air, rt
OH
OH
N
O
buffer, pH 6.0
N
H
N
95%
OH
6a
5
2a
N
H
OH
Scheme 2. Laccase-catalyzed reaction between 5 and 2a.
OH
OH OH
R1
2b-e
It is assumed that the first step of the transformation is the
laccase-catalyzed oxidation of catechol (2a) with O2 to o-benzo-
quinone (7a), which then undergoes an intermolecular 1,4-addition
with the CH-acidic 3-tert-butyl-1H-pyrazol-5(4H)-one (5) as a nu-
cleophile to yield 6a (Scheme 3).
R1
5´
cat. laccase
air, rt
N
N
buffer, pH 6.0
OH
N
H
9b-d
O
O
5´
OH
OH
OH
OH
O
O
N
4´
O
- 2H
- 2e ,
N
H
R1
7b-e
R1 = CH3, OCH3, F, Br
4´
2a
7a
R1
OH
10b,d,e
5
OH OH
N
H
O
1,4-addition
N
+
O
H
N
H
Scheme 4. Laccase-catalyzed synthesis of 9 and 10.
O
6a
7a
N
5
Finally, the reactions with some 4-substituted catechols, i.e., 4-
methylcatechol (2f), 4-ethylcatechol (2g), and 4-nitrocatechol
(2h), were conducted (Scheme 5, Table 2, Fig. 4). The trans-
formations of 2f and 2g gave the products arising from attack of 5 at
C-50 of the o-benzoquinone intermediate 7. The yield of 11f
amounted to 99% (Table 2, entry 1) and 11g was isolated in 96%
(Table 2, entry 2). However, when 5 was treated with the nitro-
substituted catechol 2h, the 1,4-addition took place at C-30 of the
intermediate 7h. As a result, the regioselective formation of 12h in
77% was observed.
OH
N
H
Scheme 3. Plausible reaction mechanism for the formation of 6a.
It should be noted that the only product formed was the 1,4-
adduct 6a and that not even a trace of the expected cyclization
product 8 could be observed (Fig. 2). This result is quite astonishing
as the laccase-catalyzed reaction of 2a with other CH-acidic com-
pounds, such as 1,3-diketones and
the corresponding cyclization products.15 Their formation is based
on domino oxidation/intermolecular 1,4-addition/oxidation/
intramolecular 1,4-addition process.
In addition, catechol (2a) was also reacted with other
substituted pyrazolones. The results, however, were not satisfying
b-ketoesters, exclusively yields
a
Again, the regioselectivity of these three reactions may be ra-
tionalized in such a way that the 1,4-addition exclusively occurs at
the more electrophilic carbon atom of the corresponding o-ben-
zoquinones 7 (Scheme 5).

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Table 1
HO
OH
HO
OH
6´
5´
Laccase-catalyzed reaction of 5 with catechol (2a) and 3-substituted catechols 2bee
using air as an oxidanta
6´
6´
3´
3´
O2N
N
OH
Entry
2
R1
Time (h)
Product
Ratiob 9:10
Yield (%)
OH
OH
CH3
C2H5
1
2
3
4
5
a
b
c
d
e
H
17
15
15
15
17
9a
9b, 10b
9c
9d, 10d
10e
d
95
98
80
98
96
N
N
CH3
OCH3
F
91:9
d
OH
11f
OH
11g
N
N
H
N
H
H
60:40
d
12h
Br
a
Reactions were performed with 1.5 mmol 5 and 1.7 mmol 2.
The ratio 9:10 was determined by 1H NMR of the crude product.
Fig. 4. Products from the laccase-catalyzed reaction of 5 with 2feh.
b
The structures of all products were unambiguously elucidated
by mass spectrometry and NMR spectroscopic methods. The re-
actions between 3-tert-butyl-1H-pyrazol-5(4H)-one (5) and
OH OH
OH
OH OH
6´
substituted catechols
2 result in the formation of different
6´
5´
6´
CH3
OH
CH3
OH
OCH3
regioisomers, in which the pyrazole moiety is attached at C-30, C-40
4´
4´
OH
9c
or C-50 of the catechol moiety.
In the reaction of 5 with 3-methylcatechol (2b) a mixture of two
isomers was obtained. The 1H NMR spectrum of the 91:9 mixture of
9b and 10b shows two sets of doublets in the aromatic region. The
N
N
N
N
OH
N
H
N
N
H
H
9b
OH OH
10b
OH
OH
protons at
d
¼6.34 ppm and ¼6.45 ppm reveal a small coupling
d
OH
OH
constant of J¼1.8 Hz indicating a meta coupling between these
protons, which can be attributed to 40-H and 60-H of the major
component 9b. Furthermore, strong 3J HMBC correlations from 40-H
to C-4 and from 60-H to C-4 demonstrate that the pyrazole ring is
attached at C-50 of the catechol. The second set of doublets in 1H
6´
6´
5´
6´
5´
F
4´
F
Br
N
N
OH
OH
OH
N
H
N
H
N
H
NMR spectrum of the mixture at
d
¼6.37 ppm and ¼6.55 ppm
d
sharing a coupling constant of J¼8.1 Hz can be attributed to the
ortho-positioned 50-H and 60-H of the minor component 10b. A 3J
HMBC correlation from 50-H to C-4 indicates that the pyrazole ring
is attached at C-40 of the catechol.
10d
10e
9d
Fig. 3. Products of the laccase-catalyzed reaction between 5 and 2bee.
In the 1H NMR spectrum of 9c, two doublets (40-H at
OH
d
¼6.21 ppm and 60-H at
¼6.24 ppm) with a coupling constant of
d
J¼1.5 Hz and HMBC correlations similar to 9b provide evidence for
R2
OH
OH
R2
HO
the structure assigned. The structure of 10e was proven by the
2f-h
occurrence of the 50-H (
d
¼6.53 ppm) and 60-H (
d
¼6.71 ppm) pro-
cat. laccase
air, rt
tons as doublets with a coupling constant of 3J(5 -H,6 -H)¼8.3 Hz and
0
0
5´
HMBC correlation from 50-H to C-4.
buffer, pH 6.0
N
In the reaction between 5 and 2d a 60:40 mixture of the two
regioisomers 9d and 10d was obtained. The structures of 9d and
10d were deduced by analysis of their NMR spectra. In the major
OH
N
H
O
O
5´
11f,g
N
O
R2
component 9d, protons 40-H and 60-H both appear as doublets of
N
H
3´
R2
N
OH
doublets with coupling constants for 40-H [ J(4 -H,6 -H)¼2.0 Hz, 3J(4 -
4
0
0
0
5
3´
¼11.5 Hz] and for 60-H [ J(4 -H,6 -H)¼2.0 Hz, 5J(6 -H,F)¼2.0 Hz], that
4
0
0
0
H,F)
OH
OH
7f-h
R2 = CH3, C2H5, NO2
clearly establish the structure assigned. In the minor component
N
H
10d, the protons 50-H and 60-H also occur as doublets of doublets.
12h
3
4
Here, the coupling constants for 50-H [ J(5 -H,6 -H)¼8.3 Hz, J(5 -
0
0
0
¼8.0 Hz] and for 60-H [ J(5 -H,6 -H)¼8.3 Hz, 5J(6 -H,F)¼1.5 Hz] prove
3
Scheme 5. Laccase-catalyzed synthesis of 11 and 12.
0
0
0
H,F)
that in 10d the pyrazole is attached to C-40 of the catechol ring.
The structures of 11f are proven by the two singlets of the
protons 30-H and 60-H (
d
¼6.54 ppm and ¼6.46 ppm) and the
d
Table 2
strong 3J(H,C) HMBC correlations between 60-H and C-4 and 30-H and
the carbon of the methyl group. The structure elucidation of 11g is
Laccase-catalyzed reaction of 5 with 4-substituted catechols 2feh using air as an
oxidanta
similar to 11f: two singlets for 30-H at
d
¼6.57 ppm and for 60-H at
Entry
2
R
Time (h)
Product
Yield (%)
3
d
¼6.44 ppm and J(H,C) HMBC correlations between 60-H and C-4
1
2
3
f
g
h
CH3
18
17
15
11f
11g
12h
99
96
77
C2H5
NO2
and 30-H and the CH2 of the ethyl group. The structure of 12h fol-
lows from the two doublets at
d
¼7.37 ppm and at ¼6.84 ppm,
d
which were assigned to 50-H and 60-H, respectively. The vicinal
a
Reactions were performed with 1.5 mmol 5 and 1.7 mmol 2.
coupling constant between 50-H and 60-H amounts to J¼9.0 Hz.
The exclusive formation of the monosubstituted pyrazolyl cat-
3. Conclusions
echols 9e12, which results from 1,4-addition of 5 to the corre-
sponding o-benzoquinone intermediates
7
is particularly
A simple to execute and efficient method for the synthesis of 4-
substituted 3-tert-butyl-1H-pyrazol-5-ols has been developed.
It relies on the laccase-catalyzed oxidation of a catechol to the
corresponding o-benzoquinone which in turn undergoes an
noteworthy, since the reaction between pyrazolones and catechols
under electrochemical conditions delivers different products or
mixtures of products in considerably lower yields.16

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intermolecular 1,4-addition with the 3-tert-butyl-1H-pyrazol-
5(4H)-one as a nucleophile. The reactions can be performed under
mild reaction conditions with air as the oxidant and the products
are formed with yields ranging between 77 and 99%. Depending on
the substituent on the catechol moiety, different regioisomers are
formed.
1.5 mmol) and 2b (211 mg, 1.7 mmol) according to the general
procedure gave 9b and 10b as a 91:9 regioisomeric mixture
(387 mg, 98%) and as a brown solid; mp 293e295 ꢀC (dec); Rf
~
n
3211, 2963, 2343, 1591,
0.27 (CH2Cl2/MeOH¼8.5:1.5); IR (ATR)
1504, 1314, 1229, 1170, 1078, 1027, 971, 834 cmꢁ1; 9b:17 1H NMR
(300 MHz, DMSO-d6)
d
1.12 (s, 9H, tBu), 2.08 (s, 3H, CH3), 6.34 (d,
J¼1.8 Hz, 1H, 40-H), 6.45 (d, J¼1.8 Hz, 1H, 60-H), 7.99 (br s, 1H,
4. Experimental section
4.1. General
OH), 8.97 (br s, 1H, OH); 13C NMR (75 MHz, DMSO-d6)
d 16.1
(CH3), 30.1 (CH3-tBu), 32.1 (C-tBu), 103.1 (C-4), 116.4 (C-60), 123.4
(C-30), 124.3 (C-50), 124.5 (C-40), 141.8 (C-20), 143.9 (C-10), 147.6
(C-3), 159.3 (C-5); 10b:17 1H NMR (300 MHz, DMSO-d6)
d 1.06 (s,
t
All chemicals and the laccase from A. bisporus (ASA Spezial-
enzyme) were purchased from commercial suppliers. Solvents used
in extraction and purification were distilled prior to use. The pH of
the buffer was adjusted using a pH 330/SET-1 pH-meter. Analytical
thin layer chromatography (TLC) was performed on precoated silica
gel 60 F245 aluminum plates (Merck) with visualization under UV
light and by immersion in ethanolic vanillin solution followed by
heating. Flash chromatography was carried out on silica gel MN 60,
0.04e0.053 mm (Macherey & Nagel). Melting points were de-
termined on a Kofler melting point apparatus and are uncorrected.
IR spectra were measured on a PerkineElmer Spectrum One (FT-IR
spectrometer). 1H and 13C NMR spectra were recorded at 300 (75)
MHz on a Varian Unity Inova instrument using DMSO-d6 as a sol-
vent. The chemical shifts were referenced to the solvent signals at
9H, Bu), 1.84 (s, 3H, CH3), 6.37 (d, J¼8.1 Hz, 1H, 50-H), 6.55 (d,
J¼8.1 Hz, 1H, 60-H); MS (ESI) m/z (%) 263.1 (100) [MþH]þ, 285.1
(9) [MþNa]þ; HRMS (ESI) calculated for C14H18N2O3 262.1317,
found 262.1312.
4.2.3. 50-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)-30-methox-
ybenzene-10,20-diol (9c). Reaction of 5 (210 mg, 1.5 mmol) and 2c
(238 mg, 1.7 mmol) according to the general procedure gave 9c
(334 mg, 80%) as a dark brown solid; mp 283e288 ꢀC (dec); Rf 0.28
~
(CH2Cl2/MeOH¼8.5:1.5); IR (ATR)
n
2959, 2328, 2115, 1734, 1586,
1516, 1423, 1352, 1224, 1099, 818, 734 cmꢁ1 1H NMR (300 MHz,
;
DMSO-d6)
d
1.14 (s, 9H, tBu), 3.69 (s, 3H, OCH3), 6.21 (d, J¼1.5 Hz,1H,
40-H), 6.24 (d, J¼1.5 Hz, 1H, 60-H), 8.06 (s, 1H, OH) 8.73 (s, 1H, OH);
13C NMR (75 MHz, DMSO-d6)
d
30.1 (CH3-tBu), 32.1 (C-tBu), 55.8
d
H/C 2.49/39.50 ppm (DMSO-d6) relative to TMS as internal stan-
(OCH3), 103.2 (C-4), 107.1 (C-40), 112.5 (C-60), 124.3 (C-50), 132.7
(C-20), 144.9 (C-10), 147.5 (C-30), 159.1 (C-5); MS (ESI) m/z (%) 279.1
(100) [MþH]þ, 301.1 (24) [MþNa]þ; HRMS (ESI) calculated for
C14H18N2O4 278.1267, found 278.1259.
dards. Coupling constants J [Hertz] were directly taken from the
spectra and are not averaged. Splitting patterns are designated as s
(singlet), d (doublet), t (triplet) and m (multiplet). Low resolution
electron spray ionisation mass spectra (ESI-LRMS) and exact elec-
tron spray ionisation mass spectra (HRMS) were recorded on
a Bruker Daltonics (micro TOFQ) instrument. The intensities are
reported as percentages relative to the base peak (I¼100%).
4.2.4. 50-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)-30-fluo-
robenzene-10,20-diol (9d) and 40-(3-tert-butyl-5-hydroxy-1H-pyrazol-
4-yl)-30-fluorobenzene-10,20-diol (10d). Reaction of
5 (210 mg,
1.5 mmol) and 2d (218 mg, 1.7 mmol) according to the general
procedure gave 9d and 10d as a 60:40 regioisomeric mixture
(390 mg, 98%) and as a light brown solid; mp >330 ꢀC (dec); Rf 0.25
~
4.2. General procedure for the laccase-catalyzed reaction of
catechols with 3-tert-butyl-1H-pyrazol-5(4H)-one
(CH2Cl2/MeOH¼8.5:1.5); IR (ATR)
n
2964, 1583, 1514, 1480, 1461,
3-tert-Butyl-1H-pyrazol-5(4H)-one (5) (1.5 mmol) and catechol
2 (1.7 mmol) were dissolved in 80 mL 0.2 M phosphate buffer (pH
6.0). Laccase from A. bisporus (50 mg, 6 U/mg) was added and the
mixture was vigorously stirred under air at room temperature until
the substrates had been fully consumed, as judged by TLC. This
mixture was acidified with 2 M HCl to pH w4, saturated with NaCl
and filtered on a Buchner funnel. The filter cake was washed with
15% sodium chloride solution (75 mL) and water (5 mL). The crude
products obtained after drying exhibit a purity of 90e95% (NMR).
Analytically pure products were obtained by recrystallization of the
crude products.
1430, 1348, 1252, 1219, 1026, 998, 835, 796 cmꢁ1; 9d:18 1H NMR
3
(300 MHz, DMSO-d6)
d
1.13 (s, 9H, tBu), 6.39 (dd, J(H,F)¼11.5,
4J(H,H)¼2.0 Hz, 1H, 40-H), 6.46 (dd, 4J(H,H)¼2.0, 5J(H,F)¼2.0 Hz, 1H, 60-
H), 8.83 (br s,1H, OH), 9.38 (br s,1H, OH); 13C NMR (75 MHz, DMSO-
d6)
d
30.1 (CH3-tBu), 32.1 (C-tBu), 102.1 (C-4), 109.5 (d,
4
2J(C,F)¼18.5 Hz, C-40), 114.8 (d, J(C,F)¼1.3 Hz, C-60), 124.6 (d,
2
3J(C,F)¼9.9 Hz, C-50), 131.7 (d, J(C,F)¼14.3 Hz, C-20), 146.6 (d,
3J(C,F)¼6.6 Hz, C-10), 147.9 (C-3),151.3 (d, 1J(C,F)¼236.6 Hz, C-30), 159.1
(C-5); 10d:18 1H NMR (300 MHz, DMSO-d6)
d
1.09 (s, 9H, tBu), 6.43
3
4
3
(dd, J(H,H)¼8.3, J(H,F)¼8.0 Hz, 1H, 50-H), 6.56 (dd, J(H,H)¼8.3,
5J(H,F)¼1.5 Hz, 1H, 60-H), 8.83 (br s, 1H, OH), 9.38 (br s, 1H, OH); 13C
NMR (75 MHz, DMSO-d6)
d
29.7 (CH3-tBu), 31.9 (C-tBu), 95.9 (C-4),
4.2.1. 40-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)benzene-10,20-diol
(6a). Reaction of 5 (210 mg, 1.5 mmol) and 2a (187 mg, 1.7 mmol)
according to the general procedure gave 6a (355 mg, 95%) as
110.3 (d, 5J(C,F)¼2.0 Hz, C-60), 112.9 (d, 2J(C,F)¼15.6 Hz, C-40), 122.4 (d,
2
4J(C,F)¼3.4 Hz, C-50), 133.1 (d, J(C,F)¼15.2 Hz, C-20), 146.5 (d,
3J(C,F)¼5.4 Hz, C-10), 148.8 (C-3), 150.6 (d, J(C,F)¼236.4 Hz, C-30),
1
a
brown solid; mp 298e303 ꢀC (dec); Rf 0.24 (CH2Cl2/
159.6 (C-5); MS (ESI) m/z (%) 267.1 (100) [MþH]þ, 268.1 (14)
[MþNa]þ; HRMS (ESI) calculated for C13H15FN2O3 266.1067, found
266.1060.
~
n
MeOH¼8.5:1.5); IR (ATR)
3236, 2959, 1581, 1515, 1480, 1429, 1364,
1309, 1240, 1114, 812, 788 cmꢁ1 1H NMR (300 MHz, DMSO-d6)
;
d
1.12 (s, 9H, tBu), 6.42 (dd, 3J¼8.1 Hz, 4J¼1.8 Hz, 1H, 50-H), 6.56 (d,
4J¼2.1 Hz, 1H, 30-H), 6.66 (d, 3J¼8.1 Hz, 1H, 60-H), 8.68 (br s, 1H, OH),
4.2.5. 30-Bromo-40-(3-tert-butyl-5-hydroxy-1H-pyrazol-4-yl)ben-
zene-10,20-diol (10e). Reaction of 5 (210 mg, 1.5 mmol) and 2e
(321 mg, 1.7 mmol) according to the general procedure gave 10e
(470 mg, 96%) as a brown solid; mp 240e242 ꢀC (dec); Rf 0.27
~
8.75 (br s, 1H, OH); 13C NMR (75 MHz, DMSO-d6)
d
30.1 (CH3-tBu),
32.1 (C-tBu), 102.9 (C-4), 114.9 (C-60), 119.0 (C-30), 122.5 (C-50), 125.2
(C-40), 143.8 (C-10), 144.3 (C-20), 147.7 (C-3), 159.3 (C-5); MS (ESI) m/
z (%) 249.1 (100) [MþH]þ, 271.1 (3) [MþNa]þ; HRMS (ESI) calculated
for C13H16N2O3 248.1161, found 248.1153.
(CH2Cl2/MeOH¼8.5:1.5); IR (ATR)
n
2965, 2118, 1596, 1476, 1419,
1366, 1300, 1251, 1214, 905, 850, 801 cmꢁ1
;
1H NMR (300 MHz,
t
DMSO-d6)
d
1.07 (s, 9H, Bu), 6.53 (d, J¼8.3 Hz, 1H, 50-H), 6.71 (d,
4.2.2. 50-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)-30-methyl-
J¼8.3 Hz, 1H, 60-H), 8.88 (br s, 1H, OH), 9.60 (br s, 1H, OH); 13C NMR
benzene-10,20-diol (9b) and 40-(3-tert-butyl-5-hydroxy-1H-pyrazol-4-
(75 MHz, DMSO-d6) d
29.7 (CH3-tBu), 31.9 (C-tBu), 102.5 (C-4), 113.2
yl)-30-methylbenzene-10,20-diol (10b). Reaction of
5
(210 mg,
(C-60), 115.2 (C-30), 123.5 (C-50), 126.6 (C-40), 142.7 (C-20), 144.8

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3668
(C-10),147.8 (C-3),159.0 (C-5); MS (ESI) m/z (%) 329.0 (100) [MþH]þ,
359.0 (5) [MþNa]þ; HRMS (ESI) calculated for C13H15BrN2O3
326.0266, found 326.0267.
2. (a) Sugiura, S.; Ohno, S.; Ohtani, O.; Izumi, K.; Kitamikado, T.; Asai, H.; Kato, K. J.
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Demirayak, S.; Capan, G.; Erol, K.; Vural, K. Eur. J. Med. Chem. 2000, 35, 359; (e)
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Lorenz, I.-P.; Mayer, P.; Rozalski, M.; Krajewska, U.; Budzisz, E. J. Enzyme Inhib.
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Nishino, T.; Miyaji, K.; Iwamoto, S.; Mikashima, T.; Saruhashi, K.; Kishikawa, Y.
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4.2.6. 40-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)-50-methyl-
benzene-10,20-diol (11f). Reaction of 5 (210 mg, 1.5 mmol) and 2f
(211 mg, 1.7 mmol) according to the general procedure gave 11f
(389 mg, 99%) as a light brown solid; mp 296e298 ꢀC (dec); Rf 0.22
~
(CH2Cl2/MeOH¼8.5:1.5); IR (ATR)
n
3422, 2965, 2663, 1594, 1512,
1460, 1435, 1367, 1288, 1231, 1165, 882, 821, 775 cmꢁ1
(300 MHz, DMSO-d6)
1.08 (s, 9H, tBu), 1.85 (s, 3H, CH3), 6.46 (s, 1H,
30-H), 6.54 (s, 1H, 60-H), 8.50 (br s, 1H, OH), 8.56 (br s, 1H, OH); 13C
;
1H NMR
d
NMR (75 MHz, DMSO-d6)
d
19.3 (CH3), 29.7 (CH3-tBu), 31.9 (C-tBu),
4. (a) Cheng, F.; Shi, D.-Q. J. Heterocycl. Chem. 2012, 49, 732; (b) Plath, P.; von Deyn, W.;
Engel, S.;Kardoff, U.;Rang, H.; Gerber, M.;Walter, H.; Westphalen, K.-O.; Koenig, H.
Ger. Patent DE 4427997, 1996; (c) Tanaka, N.; Oya, E.; Baba, M. Eur. Patent EP
344775, 1989.
101.5 (C-4), 116.6 (C-60), 119.7 (C-30), 124.1 (C-40), 128.5 (C-50), 142.0
(C-20), 143.9 (C-10), 147.6 (C-3), 159.2 (C-5); MS (ESI) m/z (%) 263.1
(100) [MþH]þ, 285.1 (18) [MþNa]þ; HRMS (ESI) calculated for
C14H18N2O3 262.1317, found 262.1309.
5. (a) Karci, F.; Karci, F. Dyes Pigm. 2008, 76,147; (b) Loewe, I.; Balzer, W. R.; Gerstung,
S. Ger. Patent DE 19619112, 1997; (c) Kornis, G. In Kirk-Othmer Encycl. Chem.
Technol., 3rd ed.; Grayson, M., Eckroth, D., Eds.; Wiley: New York, NY, 1982; Vol.
19, p 436; (d) Schladetsch, H. J.; Deucker, W. UK Patent GB 2024265, 1980; (e)
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6. (a) Hamama, W. S.; El-Gohary, H. G.; Kuhnert, N.; Zoorob, H. H. Curr. Org. Chem.
2012, 16, 373; (b) Varvounis, G. Adv. Heterocycl. Chem. 2009, 98, 143; (c) Mar-
chetti, F.; Pettinari, C.; Pettinari, R. Coord. Chem. Rev. 2005, 249, 2909.
4.2.7. 40-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)-50-ethylbenzene-
10,20-diol (11g). Reaction of 5 (210 mg, 1.5 mmol) and 2g (235 mg,
1.7 mmol) according to the general procedure gave 11g (399 mg,
96%) as a light brown solid; mp 287e292 ꢀC (dec); Rf 0.23 (CH2Cl2/
~
€
7. (a) Backvall, J.-E. Modern Oxidation Methods, 2nd ed.; Wiley-VCH: Weinheim,
n
3350, 2965, 2663, 1596, 1511, 1445, 1367,
Germany, 2011; (b) Sheldon, R. A. Green Oxidation in Water In Anastas, P. T., Ed.;
Handbook of Green Chemistry; Wiley-VCH: Weinheim, Germany, 2010; Vol. 5,
p 75; (c) Thomas, J. M.; Raja, R. Catal. Today 2006, 117, 22.
MeOH¼9:1); IR (ATR)
1291,1256,1222,1130, 1165, 881, 815, 774 cmꢁ1; 1H NMR (300 MHz,
t
DMSO-d6)
d
0.98 (t, 3H, CH3-Et), 1.07 (s, 9H, Bu), 2.21 (q, 2H, CH2-
€
8. (a) Roduner, E.; Kaim, W.; Sarkar, B.; Urlacher, V. B.; Pleiss, J.; Glaser, R.;
Et), 6.44 (s, 1H, 30-H), 6.57 (s, 1H, 60-H), 8.51 (br s, 1H, OH), 8.57 (br s,
Einicke, W.-D.; Sprenger, G. A.; Beifuss, U.; Klemm, E.; Liebner, C.;
Hieronymus, H.; Hsu, S.-F.; Plietker, B.; Laschat, S. ChemCatChem 2013, 5, 82; (b)
Vedernikov, A. Acc. Chem. Res. 2012, 45, 803; (c) Wendlandt, A. E.; Suess, A. M.;
Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062; (d) Lenoir, D. Angew. Chem., Int.
Ed. 2006, 45, 3206.
1H, OH); 13C NMR (75 MHz, DMSO-d6)
d 14.9 (CH3-Et), 25.3 (CH2-
Et), 29.8 (CH3-tBu), 32.0 (C-tBu), 101.2 (C-4), 114.8 (C-60), 119.7 (C-
30), 123.4 (C-40), 134.6 (C-50), 142.0 (C-20), 144.2 (C-10), 147.5 (C-3),
159.4 (C-5); MS (ESI) m/z (%) 277.1 (100) [MþH]þ, 299.1 (26)
[MþNa]þ; HRMS (ESI) calculated for C15H20N2O3 276.1474, found
276.1466.
9. (a) Monti, D.; Ottolina, G.; Carrea, G.; Riva, S. Chem. Rev. 2011, 111, 4111; (b)
€
Hollmann, F.; Arends, I. W. C. E.; Buehler, K.; Schallmey, A.; Buhler, B. Green
Chem. 2011, 13, 226.
10. (a) Witayakran, S.; Ragauskas, A. J. Adv. Synth. Catal. 2009, 351, 1187; (b) Ku-
namneni, A.; Camarero, S.; Garcia-Burgos, C.; Plou, F. J.; Ballesteros, A.; Alcalde,
M. Microb. Cell Fact. 2008, 7, 32; (c) Xu, F.; Damhus, T.; Danielsen, S.; Østergaard,
L. H. In Modern Biooxidations. Enzymes, Reactions and Applications; Schmid, R. D.,
Urlacher, V., Eds.; Wiley-VCH: Weinheim, Germany, 2007; p 43; (d) Riva, S.
Trends Biotechnol. 2006, 24, 219; (e) Burton, S. G. Curr. Org. Chem. 2003, 7, 1317.
11. (a) Giardina, P.; Faraco, V.; Pezzella, C.; Piscitelli, A.; Vanhulle, S.; Sannita, G. Cell.
Mol. Life Sci. 2010, 67, 369; (b) Baldrian, P. FEMS Microbiol. Rev. 2006, 30, 215; (c)
Claus, H. Micron 2004, 35, 93; (d) Mayer, A. M. Phytochemistry 2002, 60, 551; (e)
Thurston, C. F. Microbiology 1994, 140, 19.
12. (a) Constantin, M.-A.; Conrad, J.; Merisor, E.; Koschorreck, K.; Urlacher, V. B.;
Beifuss, U. J. Org. Chem. 2012, 77, 4528; (b) Constantin, M.-A.; Conrad, J.; Beifuss,
U. Tetrahedron Lett. 2012, 53, 3254; (c) Constantin, M.-A.; Conrad, J.; Beifuss, U.
Green Chem. 2012, 14, 2375; (d) Ponzoni, C.; Beneventi, E.; Cramarossa, M. R.;
Raimondi, S.; Travisi, G.; Pagnoni, U. M.; Riva, S.; Forti, L. Adv. Synth. Catal. 2007,
349, 1497; (e) Ncanana, S.; Baratto, L.; Roncaglia, L.; Riva, S.; Burton, S. G. Adv.
Synth. Catal. 2007, 349, 1507; (f) d’Acunzo, F.; Galli, C.; Masci, B. Eur. J. Biochem.
2002, 269, 5330; (g) Shiba, T.; Xiao, L.; Miyakoshi, T.; Chen, C.-L. J. Mol. Catal. B:
Enzym. 2000, 10, 605.
4.2.8. 30-(3-tert-Butyl-5-hydroxy-1H-pyrazol-4-yl)-40-nitrobenzene-
10,20-diol (12h). Reaction of 5 (210 mg, 1.5 mmol) and 2h (264 mg,
1.7 mmol) according to the general procedure gave 12h (340 mg,
77%) as a light yellow solid; mp >330 ꢀC (dec); Rf 0.22 (CH2Cl2/
~
MeOH¼8:2); IR (ATR)
n
3248, 2968, 1600, 1574, 1525, 1494, 1462,
1337, 1308, 1282, 1226, 1148, 1099, 965, 824, 761 cmꢁ1
;
1H NMR
t
(300 MHz, DMSO-d6)
d
1.06 (s, 9H, Bu), 6.84 (d, J¼9 Hz, 1H, 60-H),
7.37 (d, J¼9 Hz,1H, 50-H), 8.73 (br s,1H, OH),10.48 (br s,1H, OH); 13C
NMR (75 MHz, DMSO-d6)
d
29.2 (CH3-tBu), 31.9 (C-tBu), 93.0 (C-4),
113.0 (C-60), 116.0 (C-50), 117.3 (C-30), 143.2 (C-40), 145.2 (C-20), 148þ.5
(C-3),149.7 (C-10),158.7 (C-5); MS (ESI) m/z (%) 294.1 (100) [MþH] ,
316.1 (28) [MþNa]þ; HRMS (ESI) calculated for C13H15N3O5
293.1012, found 293.1004.
13. (a) Abdel-Mohsen, H. T.; Conrad, J.; Beifuss, U. Green Chem. 2012, 14, 2686; (b)
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Lett. 2011, 52, 604; (c) Aksu, S.; Arends, I. W. C. E.; Hollmann, F. Adv. Synth. Catal.
2009, 351, 1211.
Acknowledgements
14. (a) Asta, C.; Conrad, J.; Mika, S.; Beifuss, U. Green Chem. 2011, 13, 3066; (b)
Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Schoemaker, H. E.;
We thank Ms. S. Mika for NMR spectra and Ms. K. Wohlbold
€
€
(Institut fur Organische Chemie, Universitat Stuttgart) for mass
spectra.
€
Schurmann, M.; van Delft, F. L.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2007, 349,
1332; (c) Semenov, A. N.; Lomonosova, I. V.; Brezin, V. I.; Titov, M. I. Biotechnol.
Bioeng. 1993, 42, 1137.
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Med. Chem. 2012, 20, 4472; (d) Wellington, K. W.; Bokako, R.; Raseroka, N.;
Steenkamp, P. Green Chem. 2012, 14, 2567; (e) Hajdok, S.; Conrad, J.; Beifuss, U. J.
Org. Chem. 2012, 77, 445; (f) Hajdok, S.; Conrad, J.; Leutbecher, H.; Strobel, S.;
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S.; Braunberger, C.; Neumann, M.; Mika, S.; Conrad, J.; Beifuss, U. Green Chem.
2009, 11, 676; (h) Hajdok, S.; Leutbecher, H.; Greiner, G.; Conrad, J.; Beifuss, U.
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fuss, U. Synlett 2005, 3126.
Supplementary data
1H NMR and 13C NMR spectra of all compounds. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.03.023.
References and notes
16. (a) Zhad, H. R. L. Z.; Banitaba, M. H.; Roozbahani, M. H. A.; Davarani, S. S. H. ECS
Electrochem. Lett. 2012, 1, G4; (b) Gao, X.-G.; Yang, C.-W.; Zhang, Z.-Z.; Zeng, C.-
C.; Song, X.-Q.; Hu, L.-M.; Zhong, R.-G.; She, Y.-B. Tetrahedron 2010, 66, 9880.
17. The NMR data of 9b and 10b were taken from the NMR spectra of the 91:9
regioisomeric mixture of 9b and 10b.
1. (a) Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, UK, 1984; Vol. 5, p 167; (b) Elguero, J. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, UK, 1996; Vol. 3, p 1; (c) Yet, L. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.;
Elsevier: Oxford, UK, 2008; Vol. 4, p 1.
18. The NMR data of 9d and 10d were taken from the NMR spectra of the 60:40
regioisomeric mixture of 9d and 10d.