Laccase-catalyzed domino reactions between hydroquinones and cyclic 1,3-dicarbonyls for the regioselective synthesis of substituted p -benzoquinones

Article abstract of DOI:10.1021/jo202082v

Highly substituted p-benzoquinones were obtained in yields ranging from 39% to 98% by laccase-catalyzed domino reactions between hydroquinones and cyclic 1,3-dicarbonyls using aerial oxygen as the oxidant. In almost all reactions bis-adducts with two adjacent 1,3-dicarbonyl substituents on the quinone moiety were formed selectively. The transformations can be regarded as domino oxidation/1,4-addition/oxidation/1,4-addition/oxidation processes. With unsubstituted hydroquinone as the substrate 2,3-disubstituted p-benzoquinones were isolated. Bis-adducts were also formed exclusively upon reaction with monosubstituted hydroquinones. In almost all cases the 2,3,5-trisubstituted p-benzoquinones were obtained. When 2,3-disubstituted hydroquinones were employed as starting materials the 2,3,5,6-tetrasubstitutedp-benzoquinones were isolated. The unambiguous structure elucidation of all products has been achieved by NMR spectroscopic methods including spin pattern analysis of the long-range coupled C=O carbons and ¹³C satellites analysis in ¹H NMR spectra.

Full text of DOI:10.1021/jo202082v

Article
pubs.acs.org/joc
Laccase-Catalyzed Domino Reactions between Hydroquinones and
Cyclic 1,3-Dicarbonyls for the Regioselective Synthesis of Substituted
p-Benzoquinones
Szilvia Hajdok, Jurgen Conrad, and Uwe Beifuss*
̈
Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstrasse 30, D-70599 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Highly substituted p-benzoquinones were obtained in
yields ranging from 39% to 98% by laccase-catalyzed domino reactions
between hydroquinones and cyclic 1,3-dicarbonyls using aerial oxygen as
the oxidant. In almost all reactions bis-adducts with two adjacent 1,3-
dicarbonyl substituents on the quinone moiety were formed selectively.
The transformations can be regarded as domino oxidation/1,4-addition/
oxidation/1,4-addition/oxidation processes. With unsubstituted hydro-
quinone as the substrate 2,3-disubstituted p-benzoquinones were isolated.
Bis-adducts were also formed exclusively upon reaction with mono-
substituted hydroquinones. In almost all cases the 2,3,5-trisubstituted
p-benzoquinones were obtained. When 2,3-disubstituted hydroquinones
were employed as starting materials the 2,3,5,6-tetrasubstituted
p-benzoquinones were isolated. The unambiguous structure elucidation
of all products has been achieved by NMR spectroscopic methods
1
including spin pattern analysis of the long-range coupled CO carbons and 13C satellites analysis in H NMR spectra.
and cross-linking.7k−m Laccases are capable of oxidizing a variety
INTRODUCTION
■
of compounds.8 With redox mediators the redox potential of
laccases can be extended, allowing for the oxidation of
substrates with higher redox potentials.9 The substrates for
laccase-catalyzed oxidations include phenolic compounds;5a,10
aromatic methyl groups;11 benzylic, allylic, and aliphatic
alcohols;12 ethers;13 and benzyl amines and hydroxylamines.14
The attractiveness of enzyme-catalyzed transformations can be
considerably increased when combining them with one or
more chemical transformations to new domino processes.15 In
this respect, laccase-catalyzed oxidations are very promising
since combinations with a number of chemical transformations
such as 1,4-additions and Diels−Alder reactions have already
been successful. Examples of laccase-catalyzed domino pro-
cesses include the synthesis of phenoxazinones by reaction of
two o-aminophenols16 and the preparation of 2,3-diaminophe-
nazine by reaction of two molecules of o-phenylenediamine.17
When the laccase-catalyzed oxidation of o-phenylenediamine
was performed in the presence of aromatic aldehydes, the selec-
tive formation of 2-aryl-1H-benzimidazoles occurred.17 As was
demonstrated, the laccase-catalyzed oxidation of catechols
to o-benzoquinone can also be combined with intermolecular
Diels−Alder reactions18 or 1,4-additions of several nucleo-
philes.19,20 Using 1,3-dicarbonyls as nucleophiles, several
heterocycles are accessible in highly selective and efficient one-
pot reactions, including 1H-pyrano[4,3-b]benzofuran-1-ones,20g
Today, enzyme-catalyzed transformations occupy a prominent
position in organic synthesis as they allow a multitude of
transformations to be performed in a selective and efficient
manner.1 Currently, the development of enzyme-catalyzed
oxidations is a topic of growing interest to many chemists.2
Enzymatic oxidative transformations are highly attractive as
they can supplement and expand the repertoire of standard
methods used for oxidations, replace toxic oxidants, and avoid
the formation of toxic byproducts. Furthermore, most enzy-
matic oxidations can be performed under mild reaction con-
ditions, and very often they do not require organic solvents.2b
There are several groups of enzymes, including dehydro-
genases, oxidases, oxygenases, and peroxidases, that are capable
of catalyzing oxidations. Oxidases catalyze the oxidation of a
substrate with simultaneous reduction of O2 to either hydrogen
peroxide or to water without incorporation of oxygen into
the oxidation product.3 Among the most interesting oxidases
are laccases.4 Laccases (benzenediol: O2 oxidoreductase E.C.
1.10.3.2.) mainly occur in fungi but also in plants, insects, and
bacteria. They can easily be isolated, and some of them are
commercially available. Laccases belong to the blue-copper
oxidases and are able to catalyze the oxidation of a substrate
with simultaneous reduction of O2 to give H2O.4c They can be
used in aqueous buffer solutions, in biphasic water/organic
solvent systems,5a−d mixtures of organic solvents and water,5e
as well as ionic liquid/water systems.6 Also, they can be im-
mobilized using different techniques such as binding to a
carrier,7a−g inclusion/entrapment or encapsulation in polymer,7h−j
Received: October 7, 2011
Published: November 25, 2011
© 2011 American Chemical Society
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Figure 1. Hydroquinones 1−7 and 1,3-dicarbonyls 8−11 for the laccase-catalyzed domino reactions.
3,4-dihydro-dibenzofuran-1(2H)-ones,20e benzofuro[3,2-c]-
pyridin-1(2H)-ones,20b benzofuro[3,2-c]quinolin-6(5H)-ones,20b
corresponding p-benzoquinones with the 1,4-addition of
β-diketones.31 In most cases the initially formed 1,4-adducts
were transformed into the corresponding benzofuran deriva-
tives under reaction conditions. However, the combination of
the laccase-catalyzed oxidation of hydroquinones and related
compounds with the 1,4-addition of 1,3-dicarbonyls to the
resulting p-quinoid systems has not yet been studied.
5-thiocoumestans,20b and polycyclic dispiropyrimidinones.20b
The objective of the present study was to find out whether
the laccase-catalyzed oxidation of hydroquinones to p-benzo-
quinones and the 1,4-addition of 1,3-dicarbonyls to p-benzoqui-
nones can be linked to provide a new reaction sequence for the
functionalization of hydroquinones. This approach appeared
quite promising because it is well-known that p-benzoquinones
can be reacted with numerous N-,21,22 O-,21,23 S-,21,22a,24 and
C-nucleophiles,21,25,26 though not necessarily selectively. With
respect to the results presented here the available studies on
transformations of p-benzoquinones and related compounds
with 1,3-dicarbonyls are most interesting. Makosza et al.
have reported on the reaction of 2-chloromalonates with 1,4-
naphthoquinones to yield 2-substituted naphthoquinones,26a
and Xu et al. have observed that the reaction of a 1,3-dicarbonyl
with 2,3-dichloronaphthoquinone under basic conditions pro-
ceeds with formation of a naphtho[2,3-b]furan-4,9-dione as
the result of a domino 1,4-addition/elimination process.26b An
efficient procedure for the synthesis of 2,3-dihydronaphtho-
[1,2-b]furans and related compounds has been developed by
De Kimpe et al.26c The Yb(OTf)3-catalyzed reaction starts with
the conjugate addition of a β-ketoester to an activated naph-
thoquinone followed by intramolecular hemiacetal formation.
A similar reaction was found by Chan et al., who reported on
the Cu(OTf)2-catalyzed cyclocondensation of 1,4-benzoqui-
nones with several 1,3-diketones to give a variety of substituted
3-acyl-benzofurans.26d Direct reaction between hydroquinones
and nucleophiles is also feasible when the in situ oxidation
of the hydroquinone to the corresponding quinone can be
performed in the presence of the corresponding nucleophile.
A number of reagents, including potassium ferricyanide,27a
copper(II) sulfate,27b Fenton's reagent,27c copper(II) acetate,
silver(I) oxide,28b and sodium iodate,27a,28b have been used for
the in situ generation of p-benzoquinone.
RESULTS AND DISCUSSION
■
Here we report on laccase-catalyzed reactions of hydroquinones
with cyclic 1,3-dicarbonyls using aerial oxygen as the oxidant. A
number of differently substituted hydroquinones, namely, the
unsubstituted hydroquinone (1), the monosubstituted com-
pounds methylhydroquinone (2), methoxyhydroquinone (3),
phenylhydroquinone (4), and chlorohydroquinone (5), as well
as the disubstituted compounds 2,3-dimethylhydroquinone (6)
and 1,4-dihydroxynaphthalene (7), were chosen as substrates
(Figure 1). They were reacted with the following cyclic 1,3-
dicarbonyls: 5,5-dimethyl-1,3-cyclohexanedione (8), 5-methyl-
1,3-cyclohexanedione (9), 4-hydroxy-6-methyl-2H-pyran-2-one
(10), and 4-hydroxycoumarin (11).
All reactions were performed in acetate buffer (pH 4.37,
0.2 M) at room temperature employing 180 U (15 U/mg, 12 mg,
2.25 U/mL) of a commercially available laccase from Trametes
versicolor32 as the catalyst and air as the oxidant. The hydro-
quinone and the 1,3-dicarbonyl were used in a 1:2 ratio. We
started with reacting hydroquinone (1) and 5,5-dimethyl-1,
3-cyclohexanedione (8), which gave the 2,3-disubstituted
p-benzoquinone 12 in 66% yield (Table 1). Apart from this
bis-adduct no other product was isolated. When the reaction of
1 and 8 was run at 50 °C, the yield of 12 decreased to 40%.
When the Trametes versicolor laccase was replaced by an
Agaricus bisporus laccase (250 U, 5 U/mg, 50 mg, 3.13 U/mL)
(phosphate buffer, 0.2 M, pH 6.00, rt, 20 h) 12 was obtained in
only 20% yield after recrystallization. When the reaction of
1 equiv 1 and 2 equiv 8 was conducted in the absence of any
laccase, not even a trace of the product 12 was formed. The
reaction of hydroquinone (1) with 4-hydroxycoumarin (11)
follows much the same course as the transformation of 1 with
8. Here, the bis-adduct 13 was isolated in almost quantitative
yield (98%) (Table 1). The structures of products 12 and 13
were unambiguously elucidated by NMR spectroscopic methods
(see below).
Furthermore, it has been demonstrated that the laccase-
catalyzed oxidation of hydroquinones to p-benzoquinones
can be combined with the 1,4-addition of N-,28 O-,29 and
S-nucleophiles.30 An interesting example comes from Bhalerao
et al., who showed that the preparation of 1,2,4-triazolo-
(4,3-b)(4,1,2)benzothiadiazine-8-ones can be achieved by
reacting 4-amino-3-mercapto-1,2,4-triazoles with p-benzoqui-
none generated in situ by laccase-catalyzed oxidation of
hydroquinone.30a The oxidation of hydroquinones can also
be accomplished electrochemically. Nematollahi et al. have
linked the electrochemical oxidation of hydroquinones to the
It is assumed that the reaction sequence starts with
the laccase-catalyzed oxidation of hydroquinone (1) to
p-benzoquinone (14) and is then followed by 1,4-addition of
the 1,3-dicarbonyl (8, 11) to 14 (Scheme 1). Subsequent
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Table 1. Laccase-Catalyzed Domino Reactions of Hydroquinone (1) with 5,5-Dimethyl-1,3-cyclohexanedione (8) and
4-Hydroxycoumarin (11) for the Synthesis of 12 and 13
entry
p-hydroquinone
1,3-dicarbonyl
time (h)
product
yield (%)
1
2
1
1
8
8
12
13
66
98
11
18
Scheme 1. Possible Reaction Mechanism for the Reaction of Hydroquinone (1) with 1,3-Dicarbonyls 8, 11
oxidation of the resulting 2-substituted hydroquinone 15 deli-
vers the benzoquinone 16, which is attacked by a second mole-
cule 8 or 11 to give 17. The final step is an oxidation result-
ing in the formation of the 2,3-disubstituted p-benzoquinone
12, 13.
Notably, none of the two possible benzofuran derivatives 18
Figure 2. Benzofuran derivatives 18, 19 as possible products of the
reaction between 1 and 8.
or 19 is formed (Figure 2). Instead, the exclusive formation of
the noncyclized bis-adducts 12 and 13 takes place. This fact is
all the more astonishing given that in most other reactions
between 1,3-dicarbonyls and unsubstituted p-benzoquinones
that have been reported products with a benzofuran skeleton
are formed.26d,31b It is also remarkable that the reactions
proceed with excellent regioselectivity: the 2,3-disubstituted
bis-adducts I are the only products, while none of the 2,5- and
the 2,6-disubstituted products II and III are formed (Figure 3).
The exclusive formation of the 2,3-disubstituted products I
can be attributed to the fact that the 3-position of the
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difference: we never observed the formation of benzofuran-
type products under the conditions of the laccase-catalyzed
reaction.
The results of the reactions of monosubstituted hydro-
quinones with 1,3-dicarbonyls are summarized in Table 2.
Methylhydroquinone (2), methoxyhydroquinone (3), phenyl-
hydroquinone (4), and chlorohydroquinone (5) were chosen
as monosubstituted hydroquinones and reacted with 5,5-
dimethyl-1,3-cyclohexanedione (8), 5-methyl-1,3-cyclohexane-
dione (9), 4-hydroxy-6-methyl-2H-pyran-2-one (10), and
4-hydroxycoumarin (11) as the cyclic 1,3-dicarbonyls. When
methylhydroquinone (2) was treated with 5,5-dimethyl-1,3-
cyclohexandione (8) the 2,3,5-trisubstituted quinone 20 was
formed exclusively in 75% yield (Table 2, entry 1). Obviously,
the reaction proceeds with high regioselectivity, as only one out
of the three possible regioisomeric bis-adducts IV, V, and VI
is formed (Figure 4). This is in accordance to the results
Figure 3. Possible regioisomeric products from the reaction of
hydroquinone (1) with 1,3-dicarbonyls.
monosubstituted quinone 16 is more electron-deficient than
positions 5 and 6.
As already mentioned, the bis-adducts 12 and 13 formed
exclusively when the reactions of the 1,3-dicarbonyls 8, 11 with
the hydroquinone 1 were conducted in a 2:1 ratio. When the
ratio of 8 and 1 was changed to 1:1, again the bis-adduct 12 was
formed exclusively. However, the yield of 12 decreased from
66% to 29%.
With respect to products and product distributions, the
results published so far on 1,4-additions of nucleophiles to
hydroquinone/p-benzoquinone differ greatly.21−31 In a number
of examples, such as the reactions of p-benzoquinone with
aniline or thiophenol, the monosubstituted p-benzoquinones
were isolated exclusively and in very good yields.22a,b,24a On the
other hand, there are also reactions between hydroquinone or
p-benzoquinone, which have been reported to result in the
formation of mixtures of the monoadduct and the bis-adduct. A
typical example is the reaction between p-benzoquinone and
imidazoles (1:1) leading to the formation of mixtures of the
monosubstituted, the 2,3-disubstituted, and the 2,5-disubsti-
tuted product.22d Similar findings are known from the trans-
formations between p-benzoquinone and pyrazoles.22e With
respect to the domino processes presented here the reaction
between p-benzoquinone electrochemically generated from hy-
droquinone and 2 equiv of a cyclic 1,3-dicarbonyl (3-hydroxy-
1H-phenalen-1-one) are particular noteworthy. Under the
specific reaction conditions the formation of a 2,5-disubstituted
bis-adduct took place, which however could not be isolated
but underwent cyclization to the corresponding benzofuran
derivative.31b The reaction conditions seem to make a big
Figure 4. Possible regioisomeric products from the reaction of
monosubstituted hydroquinones 2−4 with 1,3-dicarbonyls.
obtained with the unsubstituted hydroquinone (8). Again, only
the regioisomer with both 1,3-dicarbonyl groups occupying
positions next to each other is formed.
The reactions of methylhydroquinone (2) with 5-methyl-1,3-
cyclohexanedione (9), 4-hydroxy-6-methyl-2H-pyran-2-one (10)
and 4-hydroxycoumarin (11) also proceeded with exclusive
formation of the corresponding 2,3,5-trisubstituted bis-adducts
21-23 (Table 2, entries 2−4). Similar results were obtained when
methoxyhydroquinone (3) and phenylhydroquinone (4) were
reacted with the 1,3-dicarbonyls 8, 9, and 11 (Table 2, entries 5−10).
In all cases the selective formation of bis-adducts of type IV
Table 2. Laccase-Catalyzed Domino Reactions of Monosubstituted Hydroquinones 2−4 with 1,3-Dicarbonyls 8−11 for the
Synthesis of 20−29
entry
p-hydroquinone
1,3-dicarbonyl
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
9
10
2
2
2
2
3
3
3
4
4
4
8
9
19
19
19
20
18
19
19
19
19
20
20
21
22
23
24
25
26
27
28
29
75
83
41
98
55
73
44
90
63
85
10
11
8
9
11
8
9
11
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Scheme 2. Possible Reaction Mechanism for the Reaction of Monosubstituted Hydroquinones 2−4 with 1,3-Dicarbonyls 8−11
Scheme 3. Laccase-Catalyzed Domino Reaction of Chlorohydroquinone (5) with 4-Hydroxycoumarin (11) for the Synthesis of 36
took place with yields ranging from 41% to 98%. The structures
of the products 20−29 were unambiguously determined by
NMR spectroscopic methods (see below). Control reactions
were conducted with each of the hydroquinones 2−4 (1 equiv)
and 8 (2 equiv) without the laccase under standard conditions.
In no case could the formation of an addition product be
detected. We assume that the initial attack of the nucleophilic
1,3-dicarbonyls 8−11 takes place on C-5 of the monosubstituted
quinones 30−32 (Scheme 2). The reason for its regioselectivity
is that C-5 is the most electrophilic carbon atom suitable for
a 1,4-addition. Subsequently, the resulting hydroquinone 33
undergoes oxidation to the corresponding 1,4-benzoquinone 34.
Next, the second 1,4-addition of a 1,3-dicarbonyl takes places with
the attack occurring at C-6, which is the most electrophilic site of
34 suitable for 1,4-addition. The final oxidation delivers the
2,3,5-trisubstituted bis-adducts 20−29.
Several studies on reactions of monosubstituted hydro-
quinones/quinones with nucleophiles have been published
investigating, among other things, the influence of the first
substituent on the course of the reaction. Furukawa et al.,
for example, observed that the reactions of methylquinone
(2 equiv) with anilines (1 equiv) deliver mixtures of 2,5- and
2,6-disubstituted products in a 2:1 ratio.22f Similar results have
been obtained by Lalk et al. when they studied the reactions
of monosubstituted hydroquinones with p-aminobenzoic acid
derivatives.28a,c From the work of Wilgus et al. who investigated
reactions with 1-phenyl-5-mercaptotetrazole as the nucleophile
we may conclude that the 1,4-additions of mercaptans to mono-
substituted p-benzoquinones also proceed with low regioselecti-
vity.24b The 1,4-additions of monosubstituted p-benzoquinones
with indoles are remarkable exceptions since the 2,5-disub-
stituted p-benzoquinones are the only products being
isolated.25b,f,g Only little is known of transformations with
1,3-dicarbonyls. It has been reported that in the reaction
between electrochemically generated formyl-p-benzoquinone
and 3-hydroxy-1H-phenalen-1-one starts with the formation of
a 2,5-disubstituted bis-adduct, which then undergoes cyclization
to the corresponding benzofuran derivative.31b Reactions
between methylquinone and malononitrile that have been run
under the conditions of a electrochemical oxidation proceed
with the exclusive formation of benzofurans, too.31c Consider-
ing the results that have been reported on 1,4-additions of
different nucleophiles to monosubstituted p-benzoquinones,
our findings are quite notable for the selective formation of type
IV bis-adducts.
The outcome of the reaction between 1 equiv of
chlorohydroquinone (5) and 2 equiv of 4-hydroxycoumarin
(11) came as a surprise (Scheme 3). Instead of the expected
1:2 adduct of type IV the formation of the 1:3 adduct 36
was detected. Another surprise was the exclusive formation of a
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substituted hydroquinone instead of the corresponding
p-benzoquinone. The 1:3 adduct 36 was also formed exclusively
when the substrates 5 and 11 were reacted in 1:3 ratio. In
this case 36 could be isolated with 30% yield. In the absence
of laccase no reaction between chlorohydroquinone (5) and
4-hydroxycoumarin (11) was observed. Concerning the mech-
anism we assume that in the first step the addition of a 1,3-
dicarbonyl occurs at C-3 of 37, which is the most electron-
deficient position available for a 1,4-addition (Scheme 4). In the
Figure 5. Possible products from the reaction of disubstituted
hydroquinones 6, 7 with 1,3-dicarbonyls.
Scheme 4. Possible Reaction Mechanism for the Reaction of
Chlorohydroquinone (5) with a 1,3-Dicarbonyl (11)
isolated, meaning that the structure of the products from
disubstituted hydroquinones resembles that of the products
obtained from the reactions with unsubstituted and mono-
substituted hydroquinones. Control reactions in the absence of
laccase were conducted between 6 and 8 as well as 7 and 8.
While no product was formed when 6 and 8 were reacted, the
reaction between 7 and 8 yielded product 44. Obviously, air
oxidation of 1,4-dihydroxynaphthalene (7) to 1,4-naphthoqui-
none also occurs in the absence of laccase. This is corroborated
by the finding that the yields of the 1:2 adduct 44 are compa-
rable under both reaction conditions. Although 40−47 display
mirror image symmetry, most of the compounds produced
a double set of NMR signals. This is probably due to the
occurrence of rotamers (for details see Structure Elucidation by
NMR).
Certainly the addition of a number of nucleophiles to 2,3-
disubstituted hydroquinone/quinones and 1,4-naphthochinone,
respectively, has been reported, but results vary a lot. For exam-
ple, in the reactions between naphthoquinones and indoles,
monoadducts are formed selectively,25f,g while the reactions
of naphthoquinone with imidazole and benzimidazole, res-
pectively, yield bis-adducts.22d In connection with the results
presented here it is worth mentioning that the laccase-catalyzed
reaction of 2,3-dimethylhydroquinone (6) with L-phenylalanine
has been reported to deliver the monoadduct28d and that
the electrochemical oxidation of 2,3-dimethylhydroquinone in
the presence of 1,3-dicarbonyl compounds has been found to
give monoadducts, which partly cyclize to give benzofurans.31a
Structure Elucidation by NMR. The preliminary analysis
of the NMR and the mass spectra revealed that the laccase-
catalyzed reactions between p-hydroquinones and 1,3-dicar-
bonyls exclusively produce bis-adducts made up of 1 equiv
of the p-benzoquinone and 2 equiv of the 1,3-dicarbonyl
(Tables 1−3), except for the tris-adduct 36, which was obtained
from reaction of chlorohydroquinone (5) with 11. The
reactions of differently substituted hydroquinones with 1,3-
dicarbonyls lead to the formation of different types of
regioisomeric bis-adducts. In the reactions of 2,3-disubstituted
hydroquinones 6, 7 only bis-adducts of type VIII (40−47) can
be formed (Figure 6), and therefore the structure elucidation
proved to be unproblematic. Although the reactions of the
monosubstituted hydroquinones can give rise to three types of
regioisomers, only the 2,3,5-trisubstituted products of type IV
were formed (Figure 6). The structural assignment of the
products 20−29 was straightforward. The HMBC NMR
course of the domino process two more 1,3-dicarbonyls 11
undergo 1,4-additions to the remaining positions C-5 and C-6
of 39.
A number of studies concerning the 1,4-addition of
nucleophiles to hydroquinones/quinones carrying electron-
withdrawing substituents has been reported. When the laccase-
catalyzed reaction of equimolar amounts of 2-chlorohydroqui-
none (5) and p-aminobenzoic acid was performed, the amination
took place at both C-3 and C-5, and the corresponding two
monoaminated quinones were formed in yields of 38% and
15%, respectively.28c With hydroquinones carrying a carbonyl
substituent at C-2, the laccase-catalyzed amination with
p-aminobenzoic acid preferentially takes place at C-3.28c When
the hydroquinone carries a carboxyl substituent at C-2, the
laccase-catalyzed reaction with equimolar amounts of a
p-aminobenzoic acid derivative occurs with double amination.28a
Apart from the 3,6-diaminated quinone a small amount of a
3-monoaminated quinone formed. An excess of the amine can be
used to suppress the formation of the monoaminated quinone.
In the light of the results reported on the addition of nucleo-
philes to hydroquinones/quinones carrying electron-withdrawing
substituents, the formation of a 1:3 adduct like 36 is quite
unusual.
3
spectra of 20−29 show a strong JH,C correlation between the
Finally, the reactions of 2,3-disubstituted hydroquinones
were studied. When 2,3-dimethylhydroquinone (6) and 1,4-
dihydroxynaphthalene (7) were reacted with the 1,3-
dicarbonyls 8−11 the exclusive formation of bis-adducts of
type VIII (Figure 5) with yields ranging from 39% to 92% was
observed (Table 3). In no case could type VII monoadducts be
olefinic proton and the respective carbon of the R′-substituent
of the quinone, confirming the general substitution pattern of
the products. Also in the reactions of the unsubstituted
hydroquinone (1) three regioisomeric bis-adducts, namely, the
2,3-, the 2,5-, and the 2,6-disubstituted products, can be formed
(Figure 3). The proof of structure for the selectively formed
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Table 3. Laccase-Catalyzed Domino Reactions of Disubstituted Hydroquinones 6, 7 with 1,3-Dicarbonyls 8−11 for the
Synthesis of 40−47
entry
p-hydroquinone
1,3-dicarbonyl
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
6
6
6
6
7
7
7
7
8
9
19
19
19
19
18
17
17
18
40
41
42
43
44
45
46
47
82
83
44
92
72
70
39
80
10
11
8
9
10
11
method was applied in the case of the model compound to
have conditions similar to all investigated compounds, which
usually possess only a quaternary carbon at that position. The
possibility of a 2,6-isomer could easily be ruled out, because
in contrast to 2,5-dimethylquinone (49) and 2,3-dimethyl-
quinone (50), in the proton broadband decoupled 13C NMR
spectrum of 2,6-dimethylquinone (48) two different signals
for the CO carbons could be observed. The proton
broadband decoupled 13C NMR spectra of 2,5-dimethylqui-
none (49) and 2,3-dimethylquinone (50) as well as the
spectra of the products 12 and 13 display only one signal for
the chemically equivalent CO groups of the quinone
substructure. Further arguments for the exclusion of the 2,6-
isomer are the appearance of a triplet pattern (3JH,C = 9.9 Hz)
for one CO resonance and the appearance of a broad
Figure 6. Possible product structures from the reaction of (a) 2,3-
disubstituted hydroquinones and (b) monosubstituted hydroquinones.
products 12 and 13 by standard NMR methods turned out to
be difficult as the three possible regioisomeric structures I−III
are symmetrical.
1
singlet for the other CO resonance in the H coupled 13C
The structure elucidation of most of the bis-adducts was
also impeded by some additional difficulties. First of all, the
13C NMR spectra of products 12, 20, 21, 24, 25, 27, 28, 40,
41, 44 and 45 do not exhibit all of the expected signals. In
particular, signals for the CO carbons of the 1,3-dicarbonyl
substituents are missing. This is probably due to oxo-enol
tautomerism and complicated the signal assignment consid-
erably. The chemical shifts of the missing CO carbons
could not even be determined indirectly in the HMBC spectra
because the adjacent methylene groups appear as broad
humps displaying no HMBC correlation at all. Moreover, the
13C NMR spectra of the symmetrical (12, 13, 40−47) as well
as the nonsymmetrical (20−29) reaction products exhibit a
second set of NMR signals that can be attributed to the
presence of at least two conformers/rotamers in solution at
room temperature.
NMR spectrum (Me groups selectively decoupled). The
triplet pattern can be explained by the 3JH,C coupling between
one CO group and the magnetically equivalent olefinic
protons with a coupling constant of 9.9 Hz, and the broad
2
singlet can be attributed to a JH,C coupling with a small
coupling constant between the latter and the other CO
group (Figure 7).
Figure 7. Observed H,C couplings in the 1H coupled 13C NMR
spectrum (Me groups selectively decoupled) of 2,6-dimethylquinone
(48).
In order to establish an NMR-based assignment procedure,
three model compounds, namely, 2,6-dimethylquinone (48),
2,5-dimethylquinone (49), and 2,3-dimethylquinone (50),
were selected for comparing (a) the evaluation of the splitt-
1
ing pattern of the 13C satellites in the H NMR spectra of
The 1H coupled 13C NMR spectra of the other two isomers,
the 2,5-dimethylquinone (49) and the 2,3-dimethylquinone
(50), (with selectively decoupled methyl groups) displayed a
doublet-like signal for the CO carbon in 2,5-dimethylqui-
none (49) and a quintet-like signal for 2,3-dimethylquinone
(50) (Figures 8 and 9; see also Figures A and B in Supporting
Information, lower parts of spectra). Replacement of one
the different isomers and (b) the spin pattern analysis of
the long-range coupled CO carbons in each molecule.
Different 13C NMR spectra including the proton broadband
1
decoupled 13C NMR spectra, the fully H coupled 13C NMR
spectra, and the methyl group protons selectively decoupled
13C NMR spectra of the model compounds 48−50 were
measured in acetone-d6 at 75 and at 125 MHz. The latter
451
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The Journal of Organic Chemistry
Article
1
13C satellite signals of the olefinic protons in the H NMR
spectra of the compounds in question. In the case of a
compound with a 2,3-substitution pattern [12, 13, 2,3-
dimethylquinone (50), and the maleic acid derivatives 51−
3
53], a doublet with a typical vicinal JH,H of 10 Hz was
observed, whereas only small long-range coupling constants
were detected in the case of 2,6-disubstituted compounds [e.g.,
1
Figure 8. CO multiplets in the H coupled 13C NMR spectra of
4
2,6-dimethylquinone (48), JH,H = 0.4 Hz] or 2,5-disubstituted
2,5-dimethylquinone (49) and 2,3-dimethylquinone (50) (Me groups
5
compounds [e.g., 2,5-dimetylquinone (49), JH,H = 0.1 Hz]
selectively decoupled).
(Figures 10 and 11; see also Figures D−F in Supporting
1
Figure 9. CO multiplets in the H coupled 13C NMR spectra of
Figure 10. Splitting of the outer 13C satellite signals of the olefinic
protons in the 1H NMR spectrum of 2,6-dimethylquinone (48),
2,5-dimethylquinone (49), and 2,3-dimethylquinone (50).
compound 12 and 13.
12CO by 13CO (approximately 1% natural abundance)
abolishes the symmetry in both compounds resulting in an
ABX spin system, where the chemical shift difference between
the protons A and B corresponds to the difference between the
two bond and three bond isotope shifts from the 13CO.33 In
2
3
order to extract the JH,C and JH,C coupling constants of the
13CO multiplets, the NUMMRIT approach34 implemented
in SpinWorks35 was applied for the analysis of the 13C NMR
spectra of the respective isotopomers (Figures 8 and 9; see also
Figures A and B in Supporting Information, upper parts of
spectra).
Figure 11. Splitting of the outer 13C satellite signals of the olefinic
1
Computational analysis of the H coupled 13C NMR spectra
protons in the H NMR spectrum of compound 12.
1
of compounds 12 and 13 reveals coupling constants of JHA,HB
≈
Information). Summarizing all of these observations, the
structures of 12 and 13 are unambiguously assigned as the
2,3-isomer.
10 Hz, JHA,CO ≈ 0.2 Hz, and JHB,CO ≈ 11 Hz for the ABX system
indicating a 2,3-substitution pattern similar to the results
obtained for 2,3-dimethylquinone (50)36 (Table 4). As a proof
of concept the NMR spectra of maleic acid (51), maleic acid
dimethylester (52), and maleic anhydride (53) were included
as additional reference compounds (see Figure C in Supporting
Information), because these compounds exhibit the same
substructure as 2,3-dimethylquinone (50) and compounds 12
and 13.
In order to address the occurrence of a second set of carbon
resonances in the 13C NMR spectra of the analytes, high
temperature measurements in different NMR solvents were
performed. As an example, the vinylic proton of the 1,3-dicarbonyl
moiety of 42 gives rise to two singlets in the 1H NMR
spectra recorded in DMSO-d6 (ratio of the two singlets ∼1:1)
and acetone-d6 (ratio of the two singlets ∼2:1). This suggests an
equilibrium mixture of at least two conformers/rotamers in
solution at room temperature. Therefore, compound 42 was
The JH,C coupling constants of the 13CO multiplets from
1
the H coupled 13C NMR spectra of the reference compounds
maleic acid (51), maleic acid dimethyl ester (52) and maleic
anhydride (53), and the products 12 and 13 obtained by
iteration are also summarized in Table 4.
A fast and rapid method to confirm the 2,3-substitution
pattern is based on the multiplet pattern analysis of the outer
1
heated stepwise from 25 to 120 °C, and H NMR spectra were
measured in DMSO-d6 at defined intervals. At the coalescence
point of ∼120 °C both singlets coalesce into a single signal. This
demonstrates that the molecules in question form equilibrium
Table 4. Coupling Constants for ABX Spin System by SpinWorks Analysis
coupling constants
[Hz]
2,5-dimethylquinone
2,3-dimethylquinone
maleic acid
(51)
maleic acid dimethyl ester
maleic anhydride
(49)
(50)
12
13
(52)
(53)
HA, HB
HA, CO
HB, CO
0.1
0.2
9.8
9.9
0.1
9.9
0.3
10.4
0.2
12.0
2.4
11.9
2.6
5.7
7.7
11.1
11.1
11.4
13.0
13.3
14.6
452
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Article
2,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)cyclohexa-
2,5-diene-1,4-dione (12).
mixtures of isomers at room temperature (Figure G in Supporting
Information).
CONCLUSIONS
■
The laccase-catalyzed transformations between differently
substituted hydroquinones and 1,3-dicarbonyls offer a new
and highly selective access to quinones with two adjacent
1,3-dicarbonyl substituents. The new method makes use of
aerial oxygen as the oxidant and proceeds under mild reaction
conditions. It can be interpreted as a domino oxidation/
1,4-addition/oxidation/1,4-addition/oxidation process. The
substitution pattern of the resulting quinones strongly
depends on the structure of the hydroquinones employed as
substrates. With the unsubstituted hydroquinone as starting
material the 2,3-disubstituted p-benzoquinones were formed
exclusively with yields ranging from 66% to 98%. Also with
monosubstituted hydroquinones such as 2-methylhydroqui-
none, 2-methoxyhydroquinone, and 2-phenylhydroquinone
as the substrates only the bis-adducts with two adjacent
1,3-dicarbonyl substituents were formed. The 2,3,5-trisub-
stituted p-benzoquinones were obtained with yields ranging
from 41% to 98%. The only exception is the reaction of
2-chlorohydroquinone with 4-hydroxycoumarin, which deliv-
ers the 2,3,5,6-tetrasubstituted hydroquinone as the sole product.
When 2,3-disubstituted hydroquinones were employed as
substrates the 2,3,5,6-tetrasubstituted bis-adducts were the only
products. They were isolated in yields ranging from 39% to 92%.
The selective transformation of hydroquinones into quinones
presented here is a new example for a highly selective laccase-
catalyzed oxidative domino process. Another remarkable feature is
that the products of the laccase-catalyzed reactions between
hydroquinones and 1,3-dicarbonyls differ from the products
obtained under electrochemical conditions. In this respect, the
present study emphasizes the growing importance of laccases as
catalysts in organic transformations in a particular manner.
Reaction of 1 (110 mg, 1 mmol) and 8 (280 mg, 2 mmol)
according to the general procedure for 8 h gave 12 as an orange
solid in 66% yield (253 mg, 0.7 mmol): mp 199−202 °C
̃
(CH2Cl2); Rf = 0.36 (MeOH/CH2Cl2 = 1:9); IR (ATR)ν 2870,
2550, 1651, 1566 1388, 1343, 1309, 1255, 1154, 1031, 838
cm−1; UV (MeOH) λmax (log ε) 243 nm (4.62); 1H NMR (300
MHz, DMSO-d6) δ 0.98 (s, 6H, CH3), 1.05 (s, 6H, CH3),
2.00−2.23 (m, 8H, CH2), 6.84 ppm (s, 2H, 5-H and 6-H); 13
C
NMR (75 MHz, DMSO-d6) δ 28.4 (CH3), 29.1 (CH3), 32.2
(C-4′ and C-4″), 47.4 (CH2), 110.0 (C-1′ and C-1″), 137.4 (C-5
and C-6), 142.9 (C-2 and C-3), 186.2 ppm (C-1 and C-4); MS
(ESI) m/z (%) 769.3 (100) [2M + H]+, 523.2 (16), 385.2 (37)
[M + H]+; HRMS calcd for C22H24O6 (384.1573), found
384.1570.
2,3-Bis(4-hydroxy-2-oxo-2H-chromen-3-yl)cyclohexa-2,5-diene-
1,4-dione (13).
Reaction of 1 (110 mg, 1 mmol) and 11 (324 mg, 2 mmol)
according to the general procedure for 18 h gave 13 as an
orange solid in 98% yield (419 mg, 1 mmol): mp >340 °C
EXPERIMENTAL SECTION
■
General Experimental Section. Chemicals, solvents, and the
laccase from Trametes versicolor are commercially available. Melting
points are uncorrected. Analytical thin layer chromatography was
performed on precoated silica gel F245 aluminum plates with
visualization under UV light and by staining using vanillin reagent.
IR spectra were recorded using an ATR instrument. Mass spectra and
high resolution mass spectra were recorded using the ESI method. NMR
̃
(CH2Cl2); Rf 0.07 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2972,
1663, 1599, 1553, 1515, 1298, 1216, 1103, 825, 754 cm−1; UV
1
(MeOH) λmax (log ε) 213 (4.59), 304 nm (4.13); H NMR
(300 MHz, DMSO-d6) δ 7.05 (s, 2H, 5-H and 6-H), 7.27 (t,
J = 8.1 Hz, 4H, arom), 7.55 (dt, J = 7.5 Hz, 1.5 Hz, 2H, 7′-H
and 7″-H), 7.86 ppm (dd, J = 8.1 Hz, 1.5 Hz, 2H, 5′-H and 5″-
H); 13C NMR (75 MHz, DMSO-d6) δ 98.5 (C-3′ and C-3″),
116.6 (arom), 119.9 (C-4a′ and C-4a″), 124.1 (arom), 125.2
(C-5′ and C-5″), 132.6 (C-7′ and C-7″), 137.9 (C-5 and C-6),
143.0 (C-2 and C-3), 153.6 (C-8a′ and C-8a″), 161.9 (C-2′
and C-2″), 169.0 (C-4′ and C-4″), 186.5 ppm (C-1 and C-4);
MS (ESI) m/z (%) 451.0 (100) [M + Na]+, 301.1 (20), 284.1
(19), 139.0 (62); HRMS calcd for C24H12O8 (428.0532),
spectra were recorded on a 300 or 500 MHz instrument. The 1H and 13
C
chemical shifts were referenced to residual solvent signal at δH/C 2.52/
40.23 ppm (DMSO-d6) or 2.05/29.8 ppm (acetone-d6) relative to TMS.
All 1D NMR (1H,13C) and 2D NMR (COSY, HSQC, HMBC) measure-
ments were performed using standard pulse sequences. LSPD: 13C NMR
modified for selective long-range proton decoupling during acquisition
with low power decoupling corresponding to γB2 ≈ 30 Hz. * means
ambiguous assignment of NMR Data.
General Procedure for the Laccase-Catalyzed Domino
Reaction. A solution of hydroquinone (1 mmol) and 1,3-dicarbonyl
(2 mmol) in 0.2 M acetate buffer (80 mL) (pH 4.37) was placed in a
250 mL Erlenmeyer flask. Laccase from Trametes versicolor (12 mg)
(15 U/mg)32 was added, and the mixture was vigorously stirred in air at
room temperature overnight (17−20 h). The reaction mixture was
found 428.0524.
2,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-5-methyl-
cyclohexa-2,5-diene-1,4-dione (20).
saturated with solid NaCl and filtered with suction using a Buchner
̈
funnel. The filter cake obtained was washed with aq NaCl (15%,
20 mL) and H2O (5 mL). When no solid product was formed, the reac-
tion mixture was extracted with CH2Cl2 (3 × 30 mL), and the combined
organic layers were dried over MgSO4, filtered, and evaporated in vacuo.
The crude products obtained exhibit a purity of at least 90% (NMR).
Analytically pure products were obtained by recrystallization.
453
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Reaction of 2 (124 mg, 1 mmol) and 8 (280 mg, 2 mmol)
according to the general procedure for 19 h gave 20 as a yellow
solid in 75% yield (293 mg, 0.7 mmol): mp 218−219 °C
140.9 (C-2 and C-3), 146.4 (C-5), 161.7, 161.8, 162.3, 162.9,
163.0, 163.03 (C-4′, C-4″, C-6′ and C-6″), 167.05, 167.1,
167.3, 167.4 (C-2′ and C-2″), 185.4, 185.6, 185.7 ppm (C-1
and C-4); MS (ESI) m/z (%) 393.1 (100) [M + Na]+, 371.1
(15) [M + H]+; HRMS calcd for C19H14O8 (370.0689),
found 370.0685.
̃
(CH2Cl2); Rf 0.31 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2959,
2555, 1652, 1567, 1386, 1342, 1309, 1256, 1149, 1028, 883,
1
793, 708 cm−1; UV (MeOH) λmax (log ε) 253 nm (4.50); H
2,3-Bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-methylcyclohexa-
2,5-diene-1,4-dione (23).
NMR (300 MHz, DMSO-d6) δ 0.98 (s, 6H, CH3), 1.06
(s, 6H, CH3), 1.99 (s, 3H, CH3 on C-5), 2.06−2.28 (m, 8H,
CH2), 6.71 ppm (s, 1H, 6-H); 13C NMR (75 MHz, DMSO-
d6) δ 15.4 (CH3 on C-5), 27.6, 27.7, 28.2, 28.4 (CH3), 31.4,
31.5 (C-4′ and C-4″), 47.0 (CH2), 109.3, 109.6 (C-1′ and
C-1″), 133.2 (C-6), 142.0 (C-2 and C-3), 145.1 (C-5), 185.4,
185.5 ppm (C-1 and C-4); MS (ESI) m/z (%) 421.2 (100)
[M + Na]+, 399.2 (61) [M + H]+; HRMS calcd for C23H26O6
(398.1729), found 398.1726.
2,3-Bis(2-hydroxy-4-methyl-6-oxocyclohex-1-enyl)-5-methylcy-
clohexa-2,5-diene-1,4-dione (21).
Reaction of 2 (124 mg, 1 mmol) and 11 (324 mg, 2 mmol)
according to the general procedure for 20 h gave 23 as an
orange solid in 98% yield (432 mg, 1 mmol): mp 277−
278 °C (MeOH); Rf 0.08 (MeOH/CH2Cl2 = 1:9) IR (ATR)
̃
ν 3076, 1657, 1599, 1556, 1259, 1241, 1215, 1162, 1096,
783, 765 cm−1; UV (MeOH) λmax (log ε) 205 (4.31), 264 nm
1
(3.89); H NMR (300 MHz, DMSO-d6) δ 2.11 (s, 3H, CH3
on C-5), 6.95 (bs, 1H, 6-H), 7.29 (d, J = 8.4 Hz, 2H, 8′-H
and 8″-H), 7.36 (t, J = 7.5 Hz, 2H, 6′-H and 6″-H), 7.64 (t,
J = 7.7 Hz, 2H, 7′-H and 7″-H), 7.88 ppm (d, J = 7.8 Hz, 2H,
5′-H and 5″-H); 13C NMR (75 MHz, DMSO-d6) δ 16.4
(CH3), 98.3, 98.6 (C-3′ and C-3″), 116.6 (C-8′ and C-8″),
116.9 (C-4a′ and C-4a″), 124.6 (C-5′ and C-5″), 124.9 (C-6′
and C-6″), 133.7 (C-7′ and C-7″), 133.8 (C-6), 141.2, 141.5
(C-2 and C-3), 146.5 (C-5), 153.2 (C-8a′ and C-8a″), 160.6
(C-2′ and C-2″), 163.46, 163.5 (C-4′ and C-4″), 185.2, 185.5
ppm (C-1 and C-4); MS (ESI) m/z (%) 465.1 (100) [M +
Na]+; HRMS calcd for C25H14O8 (442.0689), found
Reaction of 2 (124 mg, 1 mmol) and 9 (252 mg, 2 mmol)
according to the general procedure for 19 h gave 21 as an
orange solid in 83% yield (306 mg, 0.8 mmol): mp 198−
199 °C (CH2Cl2); Rf 0.29 (MeOH/CH2Cl2 = 1:9); IR
̃
(ATR) ν 2879, 2569, 1652, 1570, 1397, 1327, 1254, 1024
1
cm−1; UV (MeOH) λmax (log ε) 255 nm (4.52); H NMR
(300 MHz, DMSO-d6) δ 0.98 (d, 3H, CH3), 1.02 (d, 3H,
CH3), 1.98 (s, 3H, CH3 on C-5), 2.04−2.43 (m, 10H, CH2,
CH), 6.70 ppm (s, 1H, 6-H); 13C NMR (75 MHz, DMSO-
d6) δ 16.2 (CH3 on C-5), 20.8, 21.2 (CH3 on C-4′ and C-4″),
27.8, 28.0, 28.6, 28.7 (CH, CH2), 110.9 (C-1′ and C-1″),
133.9 (C-6), 142.6, 142.7, 142.8, 142.9 (C-2 and C-3),
145.8, 145.9 (C-5), 186.0, 186.2 ppm (C-1 and C-4); MS
(ESI) m/z (%) 393.1 (100) [M + Na]+, 371.2 (14) [M +
H]+; HRMS calcd for C21H22O6 (370.1416), found
442.0683.
2,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-5-methoxy-
cyclohexa-2,5-diene-1,4-dione (24).
370.1411.
2,3-Bis(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-5-methylcyclo-
hexa-2,5-diene-1,4-dione (22).
Reaction of 3 (140 mg, 1 mmol) and 8 (280 mg, 2 mmol)
according to the general procedure for 18 h gave 24 as a
yellow solid in 55% yield (229 mg, 0.6 mmol): mp 237−
240 °C (CH2Cl2); Rf 0.23 (MeOH/CH2Cl2 = 1:9); IR
Reaction of 2 (124 mg, 1 mmol) and 10 (252 mg, 2 mmol)
according to the general procedure for 19 h gave 22 as a
yellow solid in 17% yield after recrystallization (63 mg,
0.2 mmol): mp 236−238 °C (CH2Cl2); Rf 0.1 (MeOH/
̃
(ATR) ν 2958, 2571, 1674, 1639, 1598, 1565, 1386, 1336,
1310, 1258, 1216, 1153, 1030, 1001, 845, 734 cm−1; UV
1
(MeOH) λmax (log ε) 202 (4.17), 256 nm (4.46); H NMR
(300 MHz, DMSO-d6) δ 0.97 (s, 3H, CH3), 1.05 (s, 3H,
CH3), 2.05−2.29 (m, 8H, CH2), 3.80 (s, 3H, OCH3), 6.07
ppm (s, 1H, 6-H); 13C NMR (75 MHz, DMSO-d6) δ 28.4,
29.3 (CH3), 32.25, 32.3 (C-4′ and C-4″), 47.3 (CH2), 57.0
(OCH3), 108.3 (C-6), 109.9, 110.3 (C-1′ and C-1″), 140.8
(C-2), 143.4 (C-3), 159.4 (C-5), 180.8 (C-1), 186.1 ppm
(C-4); MS (ESI) m/z (%) 437.2 (38) [M + Na]+, 415.2
(100) [M + H]+; HRMS calcd for C23H26O7 (414.1679),
found 414.1675.
̃
CH2Cl2 = 1:9); IR (ATR) ν 3082, 2681, 1652, 1579, 1447,
1415, 1354, 1258, 1225, 1170, 1087, 994, 806 cm−1; UV
(MeOH) λmax (log ε) 202 (4.53), 262 (4.20), 287 nm (4.17);
1H NMR (300 MHz, DMSO-d6) δ 2.04 (s, 3H, CH3 on C-5),
2.17 (s, 6H, CH3), 5.96, 5.98 (s, 2H, 5′-H and 5″-H), 6.84
ppm (s, 1H, 6-H); 13C NMR (75 MHz, DMSO-d6) δ 16.2
(CH3 on C-5), 20.1 (CH3), 96.7, 96.8, 96.9, 97.0 (C-3′ and
C-3″), 100.6, 100.7 (C-5′ and C-5″), 134.0 (C-6), 140.8,
454
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Article
2,3-Bis(2-hydroxy-4-methyl-6-oxocyclohex-1-enyl)-5-methoxycy-
clohexa-2,5-diene-1,4-dione (25).
Reaction of 4 (186 mg, 1 mmol) and 8 (280 mg, 2 mmol)
according to the general procedure for 19 h gave 27 as a
yellow solid in 90% yield (414 mg, 0.9 mmol): mp 157−
159 °C (CH2Cl2); Rf 0.44 (MeOH/CH2Cl2 = 1:9) IR
̃
(ATR) ν 3187, 2960, 1657, 1597, 1399, 1368, 1337, 1275,
1241, 1210, 1117, 732, 712, 695 cm−1; UV (MeOH) λmax
1
(log ε) 243 nm (4.59); H NMR (300 MHz, DMSO-d6) δ
1.00 (s, 6H, CH3), 1.07 (s, 6H, CH3), 2.10−2.40 (m, 8H,
CH2), 6.93 (s, 1H, 6-H), 7.45−7.53 ppm (m, 5H, Ph); 13C
NMR (75 MHz, DMSO-d6) δ 28.3, 28.4, 29.1, 29.2 (CH3),
32.2, 32.25 (C-4′ and C-4″), 47.5 (CH2), 110.0, 110.6 (C-1′
and C-1″), 129.0, 129.9, 130.2 (Ph), 133.1 (C-6), 134.3 (Ph C to
C-5), 142.3 (C-3), 143.4, 146.3 (C-2 and C-5), 185.5 (C-4),
186.0 ppm (C-1); MS (ESI) m/z (%) 483.2 (96) [M + Na]+,
461.2 (100) [M + H]+; HRMS calcd for C28H28O6 (460.1886),
found 460.1882.
Reaction of 3 (140 mg, 1 mmol) and 9 (232 mg, 2 mmol)
according to the general procedure for 19 h gave 25 as an orange
solid in 73% yield (282 mg, 0.7 mmol): mp 198−199 °C
̃
(CH2Cl2); Rf 0.20 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2959,
1676, 1643, 1590, 1332, 1254, 1221, 1144, 1026, 987, 841 cm−1;
1
UV (MeOH) λmax (log ε) 242 nm (4.62); H NMR (300 MHz,
DMSO-d6) δ 0.95 (d, J = 6.6 Hz, 3H, CH3), 0.98 (d, J = 6.6 Hz,
3H, CH3), 1.89−2.49 (m, 10H, CH, CH2), 3.77 (s, 3H, OCH3),
6.03 ppm(s, 1H, 6-H); 13C NMR (75 MHz, DMSO-d6) δ 20.8,
21.2, 21.3, 21.8 (CH3), 27.8, 28.0, 28.6, 28.7 (CH2), 41.7 (C-4′
and C-4″), 56.8 (OCH3), 108.2 (C-6), 110.6 (C-1′ and C-1″),
140.6, 140.8, 140.9 (C-2), 143.2, 143.3, 143.4, 143.5 (C-3), 159.2,
159.24 (C-5), 180.5, 180.54 (C-1), 185.87, 185.9, 186.0 ppm
(C-4); MS (ESI) m/z (%) 409.1 (100) [M + Na]+, 387.1 (32),
231.0 (15); HRMS calcd for C21H22O7 (386.1366), found 386.1358.
2,3-Bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-methoxycyclohexa-
2,5-diene-1,4-dione (26).
2,3-Bis(2-hydroxy-4-methyl-6-oxocyclohex-1-enyl)-5-phenylcy-
clohexa-2,5-diene-1,4-dione (28).
Reaction of 4 (186 mg, 1 mmol) and 9 (252 mg, 2 mmol)
according to the general procedure for 19 h gave 28 as a green
solid in 63% yield (271 mg, 0.6 mmol): mp 189−191 °C
̃
(TBME); Rf 0.39 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2959,
2660, 2342, 1646, 1584, 1360, 1257, 1225, 1031 cm−1; UV
1
(MeOH) λmax (log ε) 242 nm (4.60); H NMR (300 MHz,
DMSO-d6) δ 1.00 (d, 3H, CH3), 1.03 (d, 3H, CH3), 1.90−2.50
(m, 10H, CH, CH2), 6.92 (s, 1H, 6-H), 7.46−7.50 ppm
(m, 5H, Ph); 13C NMR (75 MHz, DMSO-d6) δ 20.5*, 20.6*
(CH3), 27.2*, 28.0* (CH2), 128.2, 129.2, 129.4 (Ph), 132.4
(C-6), 133.6 (Ph C to C-5), 141.8* (C-3), 142.7* (C-2), 145.5
(C-5), 184.6*, 185.15* ppm (C-1 and C-4); MS (ESI) m/z
(%) 455.2 (100) [M + Na]+, 433.2 (11) [M + H]+; HRMS
calcd for C26H24O6 (432.1573), found 432.1567.
Reaction of 3 (140 mg, 1 mmol) and 11 (324 mg, 2 mmol)
according to the general procedure for 19 h gave 26 as a brown
solid in 44% yield (202 mg, 0.4 mmol): mp 281−284 °C (CH2Cl2);
̃
Rf 0.06 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 3357, 1678, 1645,
1600, 1556, 1513, 1456, 1425, 1232, 1203, 1171, 1106, 1006, 760
1
cm−1; UV (MeOH) λmax (log ε) 208 (4.57), 272 nm (4.21); H
2,3-Bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-phenylcyclohexa-
2,5-diene-1,4-dione (29).
NMR (300 MHz, DMSO-d6) δ 3.87 (s, 3H, OCH3), 6.29 (s, 1H,
6-H), 7.26 (m, 4H, 8′-H, 6′-H, 8″-H and 6″-H), 7.54 (t, J = 7.8 Hz,
2H, 7′-H and 7″-H), 7.86 ppm (d, J = 7.8 Hz, 2H, 5′-H and 5″-H);
13C NMR (75 MHz, DMSO-d6) δ 57.2 (OCH3), 98.1, 99.0 (C-3′
and C-3″), 108.9 (C-6), 116.6 (C8′ and C-8″), 119.8, 120.0 (C-4a′
and C-4a″), 124.10, 124.14 (C-6′ and C-6″), 125.17, 125.25 (C-5′
and C-5″), 132.6 (C-7′ and C-7″), 141.1 (C-2), 143.1 (C-3), 153.59,
153.62 (C-8a′ and C-8a″), 159.5 (C-5), 161.8, 161.9 (C-2′ and
C-2″), 168.5, 169.3 (C-4′ and C-4″), 181.2 (C-1), 186.1 ppm (C-4);
MS (EI, 70 eV) m/z (%) 458.1 (100) [M]+, 373.0 (33), 310.0
(23); HRMS calcd for C25H14O9 (458.0638), found 458.0638.
2,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-5-phenyl-
cyclohexa-2,5-diene-1,4-dione (27).
Reaction of 4 (186 mg, 1 mmol) and 11 (324 mg, 2 mmol)
according to the general procedure for 20 h gave 29 as a yellow
solid in 85% yield (429 mg, 0.9 mmol): mp 290−292 °C
̃
(MeOH); Rf 0.17 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 3050,
1669, 1654, 1600, 1563, 1499, 1272, 1203, 1168, 1101, 898,
771, 753, 703, 687, 671 cm−1; UV (MeOH) λmax (log ε) 202
(4.36), 281 nm (3.77); 1H NMR (300 MHz, DMSO-d6) δ 7.19
(s, 1H, 6-H), 7.30 (dd, J = 1.8 Hz, 5.1 Hz, 2H, 8′-H and 8″-H),
7.37 (t, J = 4.8 Hz, 2H, 6′-H and 6″-H), 7.51−7.53, 7.62−7.66
(m, 5H, Ph), 7.65* (t?, 2H, 7′-H and 7″-H), 7.92 ppm (dt?, 2H,
5′-H and 5″-H); 13C NMR (75 MHz, DMSO-d6) δ 98.1, 98.7
(C-3′ and C-3″), 116.6 (C-4a′ and C-4a″), 116.9 (C-8′ and
455
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C-8″), 124.7 (C-5′ and C-5″), 125.0 (C-6′ and C-6″), 129.06,
129.14, 130.0, 130.1, 130.4 (Ph), 133.1 (C-6), 133.8 (C-7′ and
C-7″), 134.2 (Ph C to C-5), 141.3 (C-3), 141.8 (C-2), 146.7
(C-5), 153.2 (C-8a′ and C-8a″), 160.7 (C-2′ and C-2″), 163.7
(C-4′ and C-4″), 184.3, 185.1 ppm (C-1 and C-4); (MS (ESI)
m/z (%) 527.1 (100) [M + Na]+; HRMS calcd for C30H16O8
(504.0845), found 504.0839.
solid in 82% yield (339 mg, 0.8 mmol): mp 200−205 °C (CH2-
̃
Cl2); Rf 0.44 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 3532, 2960,
1632, 1616, 1591, 1391, 1352, 1326, 1278, 1220, 1148, 1066, 1031,
1
833, 735 cm−1; UV (MeOH) λmax (log ε) 254 nm (4.43); H
NMR (300 MHz, DMSO-d6) δ 0.98 (s, 6H, CH3), 1.06 (s, 6H,
CH3), 1.97 (s, 6H, CH3 on C-5 and C-6), 2.10 (m, 4H, CH2), 2.22
ppm (m, 4H, CH2); 13C NMR (75 MHz, DMSO-d6) δ 12.9 (CH3
on C-5 and C-6), 28.4, 29.1 (CH3 on C-4′ and C-4″), 32.2 (C-4′
and C-4″), 47.5 (C-5′ and C-5″), 110.4 (C-1′ and C-1″), 140.7 (C-5
and C-6), 142.3 (C-2 and C-3), 185.6 ppm (C-1 and C-4); MS
(ESI) m/z (%) 825.4 (100) [2M + H]+, 413.2 (51) [M + H]+;
2,3,5-Tris(4-hydroxy-2-oxo-2H-chromen-3-yl)-6-chloro-1,4-dihy-
droxybenzene (36).
HRMS calcd for C24H28O6 (412.1886), found 412.1880.
2,3-Bis(2-hydroxy-4-methyl-6-oxocyclohex-1-enyl)-5,6-dimethyl-
cyclo-hexa-2,5-diene-1,4-dione (41).
A solution of chlorohydroquinone (5) (144 mg, 1 mmol) and
4-hydroxycoumarin (11) (486 mg, 3 mmol) in 0.2 M acetate
buffer (80 mL) (pH 4.37) was placed in a 250 mL flask. Laccase
from Trametes versicolor (12 mg) (15 U/mg)32 was added, and the
mixture was vigorously stirred under air at room temperature for
20 h. The reaction mixture was saturated with NaCl and filtered
Reaction of 6 (138 mg, 1 mmol) and 9 (252 mg, 2 mmol)
according to the general procedure for 19 h gave 41 as a yellow
solid in 83% yield (318 mg, 0.8 mmol): mp 220−222 °C (TBME);
with suction on a Buchner funnel. The filter cake was washed with
̈
aq NaCl (15%, 20 mL) and H2O (5 mL). An analytically pure
sample of 36 was obtained by recrystallization from MeOH
(187 mg, 30%, white solid): mp 317−318 °C; Rf 0.06 (MeOH/
̃
Rf 0.36 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2934, 1650, 1589,
1282, 1251, 1158, 1140, 1021, 827, 734, 711 cm−1; UV (MeOH)
1
λmax (log ε) 209 nm (4.16); H NMR (300 MHz, DMSO-d6) δ
̃
CH2Cl2 = 1:9); IR (ATR) ν 3225, 1682, 1651, 1612, 1570, 1547,
0.98 (d, J = 6.3 Hz, 3H, CH3), 1.02 (d, J = 6.3 Hz, 3H, CH3), 1.96
(s, 6H, CH3 on C-5 and C-6), 2.00−2.51 ppm (m, 10H, CH,
CH2,); 13C NMR (75 MHz, DMSO-d6) δ 12.9 (CH3 on C-5 and
C-6), 20.8, 21.1, 21.2 (CH3), 27.8, 28.0, 28.6, 28.7 (CH2), 110.9,
111.0, 111.2, 111.3 (C-1′ and C-1″), 140.6, 140.63 (C-5 and C-6),
142.2, 142.3, 142.4, 142.5 (C-2 and C-3), 185.5 ppm (C-1 and
C-4); (MS (ESI) m/z (%) 822.2 (22), 769.3 (100) [2M + H]+,
385.2 (50), 367.2 (10), [M + H]+; Anal. calcd for C22H24O6
1497, 1426, 1260, 1219, 1192, 1165, 1147, 1107, 1059, 753 cm−1;
UV (MeOH) λmax (log ε) 216 (4.77), 284 (4.38), 310 nm (4.46);
1H NMR (500 MHz, DMSO-d6) δ 7.21 (s, 1H, 8′-H or 8″-H), 7.23
(s, 1H, 8′-H or 8″-H), 7.31 (t, J = 7.5 Hz, 1H, 6′-H or 6″-H), 7.33 (t,
J = 8.0 Hz, 1H, 6′-H or 6″-H), 7.40 (t, J = 7.5 Hz, 1H, 6‴-H), 7.43
(d, J = 8.0 Hz, 1H, 8‴-H), 7.56 (dt, J = 8.0 Hz, J = 1.5 Hz, 1H, 7′-H
or 7″-H), 7.57 (dt, J = 8.0 Hz, J = 1.5 Hz, 1H, 7′-H or 7″-H), 7.69
(dt, J = 7.5 Hz, J = 1.5 Hz, 1H, 7‴-H), 7.82 (dd, J = 8.0 Hz, J = 1.5
Hz, 1H, 5′-H or 5″-H), 7.927 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, 5′-H
or 5″-H), 7.934 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, 5‴-H), 8.37 (s, 1H,
OH on C-4‴), 8.62 (bs, 1H, OH on C-1 or C-4), 10.20 (s, 1H, OH
on C-4′ or C-4″), 10.95 (s, 1H, OH on C-4′ or C-4″), 12.0 ppm (bs,
1H, OH on C-1 or C-4); 13C NMR (125 MHz, DMSO-d6) δ 99.8
(C-3‴), 100.1, 100.5 (C-3′ and C-3″), 115.9, 116.0, 116.1, 116.2
(C-8′, C-8″, C-8‴, C-4a′, C-4a″ and C-4a‴), 116.8, 118.8, 119.4
(C-2, C-3 and C-5), 123.5, 123.6, 123.67, 123.72, 123.75, 123.9,
124.0 (C-5′, C-5″, C-5‴, C-6′, C-6″, C-6‴ and C-6), 132.1 (C-7′ and
C-7″), 132.5 (C-7‴), 146.0, 148.5 (C-1 and C-4), 152.5, 152.6 (C-
8a′ and C-8a″), 152.9 (C-8a‴), 160.7, 161.0, 161.3, 161.6, 161.7,
162.5 ppm (C-2′, C-2″, C-2‴, C-4′, C-4″ and C-4‴); MS (ESI) m/z
(%) 647.1 (100) [M + Na]+, 625.1 (31) [M + H]+; HRMS calcd
for C33H17O11Cl (624.0459), found 624.0455.
(384.42): C, 68.74; H, 6.29; found C, 68.49; H, 6.34.
2,3-Bis(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-5,6-dimethyl-
cyclohexa-2,5-diene-1,4-dione (42).
Reaction of 6 (138 mg, 1 mmol) and 10 (252 mg, 2 mmol)
according to the general procedure for 19 h gave 42 as an orange
solid in 44% yield (168 mg, 0.4 mmol): mp 238−240 °C
̃
(CH2Cl2); Rf 0.15 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2927,
2,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-5,6-di-
methylcyclo-hexa-2,5-diene-1,4-dione (40).
1645, 1556, 1417, 1367, 1279, 1211, 1171, 1067, 997, 848, 751,
1
724 cm−1; UV (MeOH) λmax (log ε) 241 nm (4.65); H NMR
(300 MHz, DMSO-d6) δ 2.00 (s, 3H, CH3 on C-5 or C-6), 2.02
(s, 3H, CH3 on C-5 or C-6), 2.13 (s, 3H, CH3) 2.16 (s, 3H, CH3),
5.87, 5.93 ppm (5′-H and 5″-H); 13C NMR (75 MHz, DMSO-d6)
δ 13.1 (CH3 on C-5 and C-6), 20.0, 20.1 (CH3), 97.2, 97.23 (C-3′
and C-3″), 101.0, 102.8 (C-5′ and C-5″), 140.6, 141.2, 141.3, 141.5
(C-2, C-3, C-5 and C-6), 162.0, 162.6, 162.7, 162.8 (C-4′, C-6′, C-
4″ and C-6″), 167.2, 170.1 (C-2′ and C-2″), 185.2, 185.6 ppm (C-1
and C-4); MS (ESI) m/z (%) 407.1 (100) [M + Na]+, 385.1 (12)
[M + H]+; HRMS calcd for C20H16O8 (384.0845), found
384.0843.
Reaction of 6 (138 mg, 1 mmol) and 8 (280 mg, 2 mmol)
according to the general procedure for 19 h gave 40 as a yellow
456
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2,3-Bis(4-hydroxy-2-oxo-2H-chromen-3-yl)-5,6-dimethylcyclo-
hexa-2,5-diene-1,4-dione (43).
Reaction of 7 (160 mg, 1 mmol) and 9 (252 mg, 2 mmol)
according to the general procedure for 17 h gave 45 as a
brown solid in 70% yield (283 mg, 0.7 mmol): mp 237−239 °C
(CH2Cl2); Rf 0.39 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν
̃
2931, 1664, 1615, 1584, 1375, 1315, 1280, 1252, 1008, 710
1
cm−1; UV (MeOH) λmax (log ε) 252 nm, (4.58); H NMR
(300 MHz, DMSO-d6) δ 1.00 (d, J = 6.3 Hz, 3H, CH3), 1.04
(d, J = 6.3 Hz, 3H, CH3), 1.88−2.52 (m, 10H, CH, CH2), 7.85
(m, 2H, arom), 7.99 ppm (m, 2H, arom) 13C NMR (75 MHz,
DMSO-d6) δ 20.9, 21.2 (CH3), 27.9, 28.1, 28.6, 28.7 (CH2),
111.0, 111.1, 111.3, 111.5 (C-1′ and C-1″), 126.5 (C-5 and
C-8), 133.0 (C-4a and C-8a), 134.2 (C-6 and C-7), 145.1, 145.2,
145.3, 145.4 (C-2 and C-3), 183.2 ppm (C-1 and C-4); MS
(ESI) m/z (%) 429.1 (100) [M + Na]+, 407.2 (37) [M + H]+,
389.1 (19); HRMS calcd for C24H22O6 (406.1416), found
406.1412.
Reaction of 6 (138 mg, 1 mmol) and 11 (324 mg, 2 mmol)
according to the general procedure for 19 h gave 43 as a yellow
solid in 92% yield (420 mg, 0.9 mmol): mp 307−310 °C
̃
(MeOH); Rf 0.20 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 3076,
1650, 1598, 1555, 1499, 1285, 1295, 1236, 1170, 1117, 1107,
1050, 771, 723 cm−1; UV (MeOH) λmax (log ε) 206 (4.65), 268
nm (4.24); 1H NMR (300 MHz, DMSO-d6) δ 2.10 (s, 6H, CH3),
7.29 (d, J = 8.1 Hz, 2H, 8′-H and 8″-H), 7.36 (t, J = 7.5 Hz, 2H, 6′-
H and 6″-H), 7.64 (dt, J = 7.5 Hz, 1.2 Hz, 2H, 7′-H and 7″-H),
7.88 ppm (dd, J = 8.1 Hz, 1.2 Hz, 2H, 5′-H and 5″-H); 13C NMR
(75 MHz, DMSO-d6) δ 13.2 (CH3), 98.7 (C-3′ and C-3″), 116.5
(C-8′ and C-8″), 116.9 (C-4a′ and C-4a″), 124.6 (C-5′ and C-5″),
124.9 (C-6′ and C-6″), 133.6 (C-7′ and C-7″), 140.9, 141.0 (C-2,
C-3, C-5 and C-6), 153.2 (C-8a′ and C-8a″), 160.6 (C-2′ and C-
2″), 163.3 (C-4′ and C-4″), 184.8 ppm (C-1 and C-4) MS (ESI)
m/z (%) 501.0 (18), 479.0 (100) [M + Na]+, 457.0 (19) [M +
H]+; HRMS calcd for C26H16O8 (456.0845), found 456.0837.
2,3-Bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-
naphthalene-1,4-dione (44).
2,3-Bis(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)naphthalene-
1,4-dione (46).
Reaction of 7 (160 mg, 1 mmol) and 10 (252 mg, 2 mmol)
according to the general procedure for 17 h gave 46 as a
yellow solid in 39% yield (158 mg, 0.4 mmol): mp 295−298 °C,
dec (acetone); Rf 0.18 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν
̃
2858 2641, 1661, 1612, 1578, 1557, 1444, 1413, 1383, 1353,
1284, 1230, 795, 718 cm−1; UV (MeOH) λmax (log ε) 240 nm
1
(4.65); H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 6H, CH3),
6.00 (s, 2H, 5′-H and 5″-H), 7.91 (m, 2H, arom), 8.06 ppm
(m, 2H, arom); 13C NMR (75 MHz, DMSO-d6) δ 97.1, 97.2
(C-3′ and C-3″), 100.9, 101.0 (C-5′ and C-5″), 126.8 (C-5 and
C-8), 132.6, 132.7 (C-4a and C-8a), 134.8 (C-6 and C-7),
143.2, 143.4 (C-2 and C-3), 161.9, 162.3 (C-4′ and C-4″),
162.9, 163.0 (C-6′ and C-6″), 167.2, 167.7 (C-2′ and C-2″),
182.8, 182.9 ppm (C-1 and C-4); MS (ESI) m/z (%) 1219.2
(28) [3M + H]+, 866.1 (11), 813.2 (100) [2M + H]+, 407.2 (22)
[M + H]+; HRMS calcd for C22H14O8 (406.0689), found
406.0684.
Reaction of 7 (160 mg, 1 mmol) and 8 (280 mg, 2 mmol)
according to the general procedure for 18 h gave 44 as a brown
solid in 72% yield (313 mg, 0.7 mmol): mp 240−242 °C
̃
(CH2Cl2); Rf 0.44 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν 2956,
1667, 1608, 1574, 1327, 1279, 1234, 1145, 1028, 1013, 717
cm−1; UV (MeOH) λmax (log ε) 252 nm (4.55); 1H NMR (300
MHz, DMSO-d6) δ 1.01 (s, 6H, CH3), 1.10 (s, 6H, CH3),
2.04−2.32 (m, 8H, CH2), 7.86 (m, 2H, arom), 7.99 ppm (m,
2H, arom); 13C NMR (75 MHz, DMSO-d6) δ 28.6 (CH3), 28.9
(CH3), 32.3 (C-4′ and C-4″), 47.5 (CH2), 110.5 (C-1′ and
C-1″), 126.5 (C-5 and C-8), 133.0 (C-4a and C-8a), 134.2 (C-6
and C-7), 145.4 (C-2 and C-3), 183.4 (C-1 and C-4); MS
(ESI) m/z (%) 869.4 (100) [2M + H]+, 591.2 (16), 435.2 (40)
[M + H]+, 417.2 (13); HRMS calcd for C26H26O6 (434.1729),
found 434.1721.
2,3-Bis(4-hydroxy-2-oxo-2H-chromen-3-yl)naphthalene-1,4-
dione (47).
2,3-Bis(2-hydroxy-4-methyl-6-oxocyclohex-1-enyl)naphthalene-
1,4-dione (45).
Reaction of 7 (160 mg, 1 mmol) and 11 (324 mg, 2 mmol)
according to the general procedure for 18 h gave 47 as an
orange solid in 80% yield (381 mg, 0.8 mmol): mp 308−
310 °C (MeOH); Rf 0.18 (MeOH/CH2Cl2 = 1:9); IR (ATR) ν
̃
3072, 1676, 1652, 1603, 1566, 1499, 1363, 1283, 762, 718
cm−1; UV (MeOH) λmax (log ε) 203 (4.64), 270 nm (4.13); 1H
NMR (300 MHz, DMSO-d6) δ 7.31 (d, J = 8.4 Hz, 2H, 8′-H
and 8″-H), 7.38 (t, J = 7.5 Hz, 2H, 6′-H and 6″-H), 7.66 (dt, J =
7.9 Hz, 1.5 Hz, 2H, 7′-H and 7″-H), 7.91 (dd, J = 7.9 Hz, 1.5
Hz, 2H, 5′-H and 5″-H), 7.97 (m, 2H, 6-H and 7-H), 8.15 ppm
457
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(m, 2H, 5-H and 8-H); 13C NMR (75 MHz, DMSO-d6) δ 98.7
(C-3′ and C-3″), 116.5 (C-8′ and C-8″), 116.9 (C-4a′ and
C-4a″), 124.6 (C-5′ and C-5″), 125.0 (C-6′ and C-6″), 126.9
(C-5 and C-8), 132.9 (C-4a and C-8a), 133.7 (C-7′ and C-7″),
134.6 (C-6 and C-7), 143.4 (C-2 and C-3), 153.2 (C-8a′ and
C-8a″), 160.6 (C-2′ and C-2″), 163.4 (C-4′ and C-4″), 182.7 ppm
(C-1 and C-4); MS (ESI) m/z (%) 501.1 (100) [M + Na]+, 479.1
(9) [M + H]+; HRMS calcd for C28H14O8 (478.0689), found
478.0682.
2008, 53, 13. (c) Berrio, J.; Plou, F. J.; Ballesteros, A.; Martinez, A. T.;
Martinez, M. J. Biocatal. Biotransform. 2007, 25, 130. (d) Kunamneni,
A.; Ghazi, I.; Camarero, S.; Ballesteros, A.; Plou, F. J.; Alcalde, M.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ubeifuss@uni-hohenheim.de.
■
ACKNOWLEDGMENTS
We thank Ms. Sabine Mika for recording of NMR spectra and
Ms. Katrin Wohlbold (Institut fur Organische Chemie der
■
̈
(9) Morozova, O. V.; Shumakovich, G. P.; Shleev, S. V.; Yaropolov,
A. I. Appl. Biochem. Microbiol. 2007, 43, 523.
Universitat Stuttgart) and Ms. Iris Klaiber (Biosensorik,
̈
Zentrale Serviceeinheit des Life Science Center der Universitat
̈
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Hohenheim) for recording of mass spectra. We thank Dr. Kirk
Marat (University of Manitoba, Winnipeg Canada) for fruitful
discussions on SpinWorks.
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