Combination of enzyme- and Lewis acid-catalyzed reactions: A new method for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting from 2,5-dimethylfuran and 1,3-cyclohexanediones

Article abstract of DOI:10.1039/c3ob40926k

The Lewis acid-catalyzed domino 1,2-addition/1,4-addition/elimination between (Z)-3-hexene-2,5-dione and 1,3-dicarbonyls delivers 3-methyl-6,7- dihydrobenzofuran-4(5H)-ones exclusively with yields up to 82%. The combination of this new process with the laccase-catalyzed formation of (Z)-3-hexene-2,5- dione by oxidative cleavage of 2,5-dimethylfuran allows for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting directly from 2,5-dimethylfuran.

Full text of DOI:10.1039/c3ob40926k

Organic &
Biomolecular Chemistry
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PAPER
Combination of enzyme- and Lewis acid-catalyzed
reactions: a new method for the synthesis of
6,7-dihydrobenzofuran-4(5H)-ones starting from
2,5-dimethylfuran and 1,3-cyclohexanediones†
Cite this: Org. Biomol. Chem., 2013, 11,
5692
Chimène Asta,a Dietmar Schmidt,a Jürgen Conrad,a Wolfgang Freyb and
Uwe Beifuss*a
The Lewis acid-catalyzed domino 1,2-addition/1,4-addition/elimination between (Z)-3-hexene-2,5-dione
and 1,3-dicarbonyls delivers 3-methyl-6,7-dihydrobenzofuran-4(5H)-ones exclusively with yields up to
82%. The combination of this new process with the laccase-catalyzed formation of (Z)-3-hexene-2,5-
dione by oxidative cleavage of 2,5-dimethylfuran allows for the synthesis of 6,7-dihydrobenzofuran-4-
(5H)-ones starting directly from 2,5-dimethylfuran.
Received 2nd May 2013,
Accepted 4th July 2013
DOI: 10.1039/c3ob40926k
www.rsc.org/obc
with chemical reactions we have developed a number of
processes implementing the laccase-catalyzed generation of
Introduction
One-pot multistep reactions are a powerful tool in organic syn- quinoid systems in chemoenzymatic processes.9
thesis.1 They contribute to the further development of sustain-
Furans and annulated furans are heterocyclic skeletons
able synthetic methods because the required workup and which occur in numerous natural products and exhibit extra-
purification steps, the use of solvents and the production of ordinary biological activities.10 The 6,7-dihydrobenzofuran-4-
waste can be reduced to a minimum.2 The combination of (5H)-one skeleton and derivatives thereof are not only present
different chemical transformations in one-pot reactions has in a number of natural products,11 but also play a role as inter-
been known for a very long time and, accordingly, a multitude mediates in the synthesis of biologically active compounds.12
of examples exist in the literature. Classic examples of this Despite considerable efforts towards their synthesis, there still
type are the Hantzsch dihydropyridine synthesis, the Strecker is a strong demand for more efficient synthetic approaches.13
reaction, the Biginelli reaction and the Ugi reaction.1 There
2,5-Dimethylfuran (1a) is a platform chemical which can be
also exist a great number of examples of the combination of obtained from renewable raw materials and is considered as a
enzymatic transformations.3 On the other hand, the number serious candidate to become a substitute for fossil fuels.14,15
of chemoenzymatic one-pot multistep reactions is only The downstream chemistry of 2,5-dimethylfuran (1a), however,
modest.3,4 However, interest in the combination of enzyme- remains largely unexplored.16 Recently, we have reported that
catalyzed and chemically catalyzed transformations has greatly the laccase-catalyzed ring opening of 2,5-dimethylfuran (1a)
increased over the last few years. Apart from dynamic kinetic using air as an oxidant stereoselectively yields (Z)- or (E)-3-
resolutions, combining a lipase-catalyzed resolution and a hexene-2,5-dione (2a) depending on the mediator employed
metal-catalyzed racemization,5,6 the focus is on the combi- (Scheme 1).17 The combination of (2,2,6,6-tetramethylpiperidin-
nation of oxidoreductases with organocatalysts7 and metal- 1-yl)oxyl (TEMPO) and violuric acid gives (E)-3-hexene-2,5-
based catalysts.8 As part of a synthetic program devoted to the dione (E)-(2a), while in the presence of 4-hydroxy-TEMPO,
development of combinations of enzyme-catalyzed oxidations
aBioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstraße
30, D-70599 Stuttgart, Germany. E-mail: ubeifuss@uni-hohenheim.de;
Fax: (+49)711-459-22951
bInstitut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569
Stuttgart, Germany
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for compounds 5a–h. CCDC 926712 (5b) 926713 (5d). For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3ob40926k
Scheme 1 Laccase-catalyzed ring opening of 2,5-dimethylfuran (1a).
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(Z)-3-hexene-2,5-dione (Z)-(2a) is obtained in 79% yield.
The selective formation of the less stable (Z)-3-hexene-2,5-
dione (Z)-(2a) with 4-hydroxy-TEMPO as the mediator is highly
significant, as the number of methods for the synthesis of
(Z)-2-ene-1,4-diones (Z)-2 is rather limited.18 The (Z)-selective
ring cleavage could be extended to a variety of symmetrical
and unsymmetrical 2,5-dialkylfurans 1.17 With the new
method for the preparation of (Z)-2-ene-1,4-diones in mind,
it was attractive to combine it with suitable chemical
transformations.
Considering the reaction between 2-ene-1,4-diones 2 and
1,3-dicarbonyls 3 it was assumed that either a domino inter-
molecular 1,4-addition/intramolecular 1,2-addition/elimin-
ation (via A, B and C) with formation of furans 4 (type 1
product) (Scheme 2) or a domino intermolecular 1,2-addition/
intramolecular 1,4-addition/elimination (via D, E and F) with
formation of furans 5 (type 2 product) (Scheme 3) could occur.
So far, there has been only a single report from Scettri
et al., who studied a few reactions of (E)-2-ene-1,4-diones 2
with 1,3-dicarbonyls 3 (Scheme 4).19 They found that the two-
step procedure between (E)-pentadec-3-ene-2,5-dione (E)-(2b)
and 1,3-cyclohexanedione (3a) using triethylbenzyl ammonium
Scheme 4 Reaction of (E)-2-ene-1,4-dione (E)-(2b) with 1,3-cyclohexanedione
(3a) according to Scettri et al.19
substituted 6,7-dihydrobenzofuran-4(5H)-one 8 and the 2-decyl-
substituted 6,7-dihydrobenzofuran-4(5H)-one 9 (type 1 pro-
ducts). It is supposed that the transformation starts with an
intermolecular 1,4-addition under basic conditions, which is
followed by an intramolecular 1,2-addition and elimination
under acidic conditions.
chloride (TEBAC) delivered
a mixture of the 2-methyl-
Results and discussion
The reaction between (Z)-3-hexene-2,5-dione (Z)-(2a) and 1,3-
cyclohexanedione (3a) was chosen as a model reaction.
1 equiv. (Z)-2a and 3 equiv. 1,3-cyclohexanedione (3a) were
reacted in the presence of 10 mol% of different Lewis acids20
in CH2Cl2 at r.t. (Table 1, entries 1–12). With 10 mol%
Table 1 Regioselective synthesis of 5a by reaction of 3a with (Z)-2a in the pres-
ence of different Lewis acidsa
Scheme 2 Formation of type
1 products by domino intermolecular 1,4-
addition/intramolecular 1,2-addition/elimination.
Entry Lewis acid Solvent
t (h) Yieldb (%)
1
2
3
4
5
6
7
8
InBr3
ZnBr2
MgBr2
Mg(ClO4)2 CH2Cl2
LiClO4
FeCl3
BF3·OEt2
TiCl4
Yb(OTf)3
Sc(OTf)3
Gd(OTf)3
Cu(OTf)2
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
48
24
24
24
24
48
48
48
48
48
73
71
29c
65
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
H2O
66
41c
10c
9c
9
67
68
74
56
24
49
10
11
12
13
14
15
16
17
0.01 M acetate buffer (pH 4.5) 48
CH3CN
THF
6
24
42
13c
34c
Traces
EtOH
a 1 mmol (Z)-2a was reacted with 3 mmol 3a. b Yields refer to isolated
yields. c Along with (E)-2a as major product.
Scheme 3 Formation of type
2 products by domino intermolecular 1,2-
addition/intramolecular 1,4-addition/elimination.
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Gd(OTf)3 as the catalyst, 3-methyl-2-(2-oxopropyl)-6,7-dihydro-
benzofuran-4(5H)-one (5a) was isolated in 74% yield (Table 1,
entry 11). It is interesting to note that the type 2 product 5a
was formed exclusively. Not even a trace of the corresponding
regioisomer 4a could be isolated. This result implies
that the transformation proceeds as a domino intermolecular
1,2-addition/intramolecular 1,4-addition/elimination. Similar
results, i.e. the exclusive formation of 5a, were obtained
with 10 mol% of InBr3, ZnBr2, Mg(ClO4)2, LiClO4, Yb(OTf)3,
Sc(OTf)3 and Cu(OTf)2 (Table 1). But with all these Lewis acids
the yields of 5a were slightly lower than with Gd(OTf)3. The
transformation could also be catalyzed with MgBr2, FeCl3,
BF3·OEt2 and TiCl4. However, with these catalysts the yields of
5a did not exceed 41% (Table 1, entries 3 and 6–8) and the for-
mation of 5a was accompanied by the isomerization of (Z)-2a
to (E)-2a. In addition to CH2Cl2, the Gd(OTf)3-catalyzed trans-
formation was also run in a number of other solvents, includ-
ing H2O, 0.01 M acetate buffer pH 4.5, CH3CN, THF and EtOH.
However, the yields of 5a were considerably lower than in
CH2Cl2 (Table 1, entries 13–17).
To study the scope of the new transformation, (Z)-3-hexene-
2,5-dione (Z)-(2a) was reacted with different 1,3-dicarbonyls 3
(Fig. 1) in the presence of 10 mol% Gd(OTf)3. The transform-
ations with the substituted 1,3-cyclohexanediones 3b–f deli-
vered the 6,7-dihydrobenzofuran-4(5H)-ones 5b–f with yields
ranging between 51 and 82% (Scheme 5). The new domino
1,2-addition/1,4-addition/elimination is not restricted to 1,3-
cyclohexanediones as substrates. This is substantiated by the
reaction of (Z)-2a with 2,4-pentanedione (3g) which affords the
tetrasubstituted furan 5g in 60% yield.
Scheme 5 Gd(OTf)3-catalyzed reaction of (Z)-3-hexene-2,5-dione (Z)-2a with
1,3-dicarbonyls 3.a,c
It is noteworthy to mention the outcome of a control experi-
ment with (E)-3-hexene-2,5-dione (E)-(2a). When (E)-2a was
reacted with 3a in the presence of 10 mol% Gd(OTf)3 in
CH2Cl2 at r.t. for 48 h, only 9% of 3-methyl-2-(2-oxopropyl)-6,7-
dihydrobenzofuran-4(5H)-one (5a) along with 52% of the sub-
strate (E)-3-hexene-2,5-dione (E)-(2a) were isolated (Scheme 6).
This clearly demonstrates the influence of the double bond
geometry of the enedione on the outcome of the domino
reaction.
The successful development of the new domino process for
the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting
from (Z)-2a and 1,3-dicarbonyls 3 prompted us to consider
whether it is possible to combine it with the laccase-catalyzed
generation of (Z)-3-hexene-2,5-dione (Z)-(2a). This would allow
Scheme 6 Gd(OTf)3-catalyzed reaction of (E)-3-hexene-2,5-dione (E)-(2a) with
3a.
for the preparation of 6,7-dihydrobenzofuran-4(5H)-ones and
related compounds starting from 2,5-dimethylfuran (1) and
1,3-dicarbonyls 3 in a single synthetic step. Initial experiments
revealed that the reaction did not proceed as expected when 1
equiv. 2,5-dimethylfuran (1a) and 3 equiv. 1,3-cyclohexane-
dione (3a) were reacted in the presence of 200 U laccase (Tra-
metes versicolor), 10 mol% TEMPO and 10 mol% Gd(OTf)3 in
acetate buffer (0.1 M) at r.t. for 72 h. Under these conditions
only traces of 5a were formed. However, when 1 equiv. 2,5-
dimethylfuran (1a) and 1 equiv. 1,3-cyclohexanedione (3a)
were reacted under the conditions of the oxidative cleavage of
1a (200 U laccase, 10 mol% 4-hydroxy-TEMPO, air) in acetate
buffer at r.t. for 18 h, i.e. without any additional Lewis acid,
the yield of 5a amounted to 4% (Table 2, entry 1); using 3
equiv. 1,3-cyclohexanedione (3a) the yield was 15% (Table 2,
entry 2). Despite the low yields, these experiments proved that
the one-pot synthesis of 5a is possible even in the absence of
any Lewis acid. The yield of 5a could be increased when the
Fig. 1 1,3-Dicarbonyls
hexene-2,5-dione (Z)-2a.
3 for the Gd(OTf )3-catalyzed reaction with (Z)-3-
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Table 2 Synthesis of 5a in one-pot starting from 1a and 3aa
Entry
Mediator
(mol%)
Catalyst
(mol%)
T (°C)
t (h)
Yield (%)
1
2
3
4
5
6
7
8
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Hydroxy-TEMPO
4-Acetamido-TEMPO
TEMPO
10
10
10
10
10
10
10
25
25
25
25
25
25
25
25
25
25
25
25
25
—
—
—
—
10
10
10
10
10
10
10
10
10
10
10
10
10
20
20
20
20
20
r.t.
r.t.
r.t.
r.t.
70
48
48
48
48
6
4b
15
24c
19c,d
23
19
32
39
42
40
25
22
24
52
51
55
50
39
45
54e
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Gd(OTf)3
Cu(OTf)2
DMAP
Pyridine
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
70
6
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
rt
r.t.
r.t.
r.t.
r.t.
50
48
48
48
48
48
48
48
48
48
48
48
12
12
48
9
10
11
12
13
14
15
16
17
18
19
20
4-Acetamido-TEMPO
TEMPO
4-Acetamido-TEMPO
TEMPO
50
r.t.
4-Acetamido-TEMPO
a 1 mmol of 1a was reacted with 3 equiv. of 3a. b 1 equiv. of 3a was reacted. c 0.1 mmol of DL-alanine was used. d 0.2 mmol of NaOH were used.
e 20 mol% of sodium dodecyl sulfate (SDS) were used.
Lewis acid was added after completion of the oxidative Table 3 Substrate scope of the one-pot synthesis of 6,7-dihydrobenzofuran-4-
(5H)-ones 5
cleavage of 1a, i.e. after 18 h. With 10 mol% of Yb(OTf)3 the
yield could be raised to 32% (Table 2, entry 7). An increase of
the reaction temperature had no positive impact on the
outcome, but when the amount of 4-hydroxy-TEMPO was
raised to 25 mol% the product could be isolated in 39% yield
(Table 2, entry 8). Similar results were observed with Sc(OTf)3
and Gd(OTf)3; with these Lewis acids 5a was formed in 42 and
40%, resp. (Table 2, entries 9, 10). With Cu(OTf)2, however, the
yield of 5a did not exceed 25% (Table 2, entry 11). Then, the
influence of different amounts (10 and 20 mol%) of Gd(OTf)3 Entry
Product
Yield (%)
on the outcome was studied (Table 2, entries 14–17). These
experiments were performed with Gd(OTf)3 since this Lewis
1
2
3
4
5
6
5a
5b
5c
5d
55
40
29
26
27
25
acid is cheaper than Yb(OTf)3 and Sc(OTf)3. With 10 mol%
Gd(OTf)3 in the presence of 25 mol% 4-acetamido-TEMPO or
TEMPO the yield of 5a could be increased to 52 and 51%, resp.
(Table 2, entries 14, 15). Using 20 mol% Gd(OTf)3, the yields
of 5a amounted to 55 and 50% (Table 2, entries 16, 17).
Finally, it was established that raising the reaction temp-
erature of the second step to 50 °C did not pay off (Table 2,
entries 18, 19).
After optimizing the reaction conditions, the scope of the
one-pot synthesis of the 6,7-dihydrobenzofuran-4(5H)-ones 5
with respect to the 1,3-dicarbonyls was studied (Table 3). For
this purpose, the reaction of 1a was performed with the substi-
tuted 1,3-cyclohexanediones 3b–e. In all cases, the one-pot
approach delivered the corresponding 6,7-dihydrobenzofuran-
5e–I + 5e–II
5h
4(5H)-ones 5a–e exclusively. The yields were in the range
between 26 and 55%. The reaction could also be performed
with 3h as the 1,3-dicarbonyl (Table 3, entry 6 and Fig. 2). It
should be noted that the synthesis of 6,7-dihydrobenzofuran-
4(5H)-ones in one pot by the combination of an enzyme-cata-
lyzed with a Lewis acid-catalyzed reaction has been achieved.
However, it was obvious that the yields of 5 required substan-
tial improvement.
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Fig. 2 Structure of 5h.
Fig. 3 Important HSQMBC correlations of 5b.
Considering the finding that the Lewis acid-catalyzed
synthesis of 6,7-dihydrobenzofuran-4(5H)-ones 5 from (Z)-3-
hexene-2,5-dione (Z)-(2a) and 1,3-dicarbonyls 3 could be run
best in CH2Cl2 as the solvent, we speculated that the low yields
of the one-pot approach could be attributed to the aqueous
medium employed. We were wondering whether the yields
could be improved by a solvent change after the oxidative clea-
vage of 1a. Accordingly, a new protocol was developed. After
completion of the laccase-catalyzed oxidative cleavage of 1a
under the best conditions shown in Scheme 1,17 the reaction
product was extracted with CH2Cl2. After drying and concen-
trating, the resulting solution of (Z)-2a in CH2Cl2 was mixed
with 3 equiv. 1,3-cyclohexanedione (3a) and 20 mol% Gd(OTf)3
and the resulting reaction mixture was stirred for 48 h at r.t.
Using this experimental procedure, 3-methyl-2-(2-oxopropyl)-
6,7-dihydrobenzofuran-4(5H)-one (5a) was isolated in 60%
yield (Table 4). After the successful demonstration of the value
of this approach, the reactions of 1a with 3b–g were also
conducted under the new conditions. Gratifyingly, the yields of
the corresponding furans 5b–g were in the range between 45
and 60%. This constitutes a significant improvement over the
one-pot protocol.
Fig. 4 Structure of 3,6-dimethyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4(5H)-
one (5b), derived from X-ray crystal structure analysis.
representing the protons of the methyl groups 3-Me and at
C-3′. Moreover, the 13C NMR spectra confirm the presence of
the methylene signal at δ = 40.8 ppm (C-1′) and the CvO
signals at δ = 195.1 ppm (C-4) and δ = 203.7 ppm (C-2′),
respectively. Additionally, the HSQMBC pulse sequence was
used for the unambiguous determination of the 1H–13C long
range coupling constants. Concerning 5b, the most important
HSQMBC correlations to the aromatic carbons are depicted in
Fig. 3. The large coupling constant 2J(H,C) = 7 Hz between 1′-H
(δ = 3.62 ppm) and C-2 (δ = 144.3 ppm) and the smaller
ones 3J(H,C) = 3 Hz between 1′-H and C-3 (δ = 116.0 ppm)
as well as 4J(H,C) = 5.1 Hz between 1′-H and C-3a (δ =
120.7 ppm) confirm the methylene group to be attached
to C-2. Further, 3-Me shows three important correlations,
namely to C-2 [3J(H,C) = 5.5 Hz], to C-3 [2J(H,C) = 7 Hz] and to
C-3a [3J(H,C) = 2.9 Hz]. Consequently, 3-Me is proved to be
attached to C-3.
The structures of all compounds were confirmed using MS
and NMR methods. The full assignment of all 1H and 13C
chemical shifts was achieved by evaluating their COSY, HSQC
1
and HMBC spectra. The H NMR spectra of 3,6-dimethyl-2-(2-
oxopropyl)-6,7-dihydrobenzofuran-4(5H)-one (5b) shows one
singlet at δ = 3.62 ppm corresponding to the methylene
protons of C-1′ and two singlets at δ = 2.14 and δ = 2.16 ppm
Unequivocal evidence for the structures of 5b and 5d was
provided by X-ray crystal structure analysis. For this purpose,
crystals of 5b and 5d were studied by X-ray crystal structure
analysis. The structure of 5b is depicted in Fig. 4 and reveals
that the methyl group is attached to C-3 and not to C-2.
Table 4 Substrate scope of the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones
5 from 1a and 3 without purification of (Z)-2a
Conclusions
In summary, the Lewis acid-catalyzed domino 1,2-addition/1,4-
addition/elimination between (Z)-3-hexene-2,5-dione and 1,3-
dicarbonyls delivers 3-methyl-6,7-dihydrobenzofuran-4(5H)-
ones exclusively with yields up to 82%. The combination of
this new Lewis acid-catalyzed process with the laccase-cata-
lyzed oxidative cleavage of 2,5-dimethylfuran to (Z)-3-hexene-
2,5-dione allows for the synthesis of 6,7-dihydrobenzofuran-
4(5H)-ones without isolation/purification of the intermediate
(Z)-3-hexene-2,5-dione.
Entry
Product
Yield (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
60
53
45
54
53
53
56
5e–I + 5e–II
5f
5g
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(petroleum ether–EtOAc = 1 : 1) to afford the 6,7-dihydrobenzo-
furan-4(5H)-one 5.
General procedure C for the synthesis of 5a–g starting from
Experimental section
General remarks
All chemicals and the laccase (Trametes versicolor) were pur- 2,5-dimethylfuran (1a) and 1,3-dicarbonyls 3a–g without purifi-
chased from commercial suppliers and were used without cation of (Z)-2a. A 250 mL round-bottomed flask equipped
further purification unless otherwise indicated. Solvents used with a magnetic stir bar was charged with 2,5-dimethylfuran
for extraction and purification were distilled prior to use. The (1a) (96 mg, 1 mmol), n-octane (1 mL), 0.01 M acetate buffer
pH of the buffer was adjusted using a pH 330/SET-1 pH-meter. pH 4.5 (10 mL), 4-hydroxy-TEMPO (17 mg, 0.1 mmol) and 200 U
Analytical thin layer chromatography (TLC) was performed on laccase (Trametes versicolor) and sealed with a septum. The
aluminum-backed plates coated with silica gel with F254 indi- mixture was stirred for 18 h at r.t., then saturated with NaCl
cator (Merck). Compounds were visualized using UV light (1 g) and extracted with CH2Cl2 (4 × 25 mL). The combined
(254 nm) or with vanillin/H2SO4 as a solution in ethanol. Flash organic phases were dried over Na2SO4, filtered and concen-
chromatography was carried out using silica gel 60 M, trated in vacuo to a volume of ca. 10 mL. Then, the 1,3-dicarbo-
230–400 mesh (Macherey & Nagel). Melting points were deter- nyl 3 (3 mmol) and Gd(OTf)3 (120 mg, 0.2 mmol) were added.
mined using a Büchi melting point apparatus B-545 with open After stirring at r.t. for 48 h and concentration the reaction
capillary tubes and are uncorrected. UV/Vis spectra were mixture in vacuo, the crude product was purified by flash
recorded using a Varian Cary 50. IR spectra were measured chromatography on SiO2 (petroleum ether–EtOAc = 1 : 1) to
1
using a Perkin-Elmer Spectrum One FT-IR spectrum. H (13C) afford the 6,7-dihydrobenzofuran-4(5H)-one 5.
NMR spectra were recorded at 300 (75) MHz using a Varian
Determination of laccase activity.21 A 0.1 M solution of
UnityInova spectrometer with CDCl3 (δ = 7.26 ppm in H NMR ABTS (0.3 mL) in 0.01 M acetate buffer (pH = 4.5) was diluted
spectra and δ = 77.0 ppm in 13C NMR spectra) as internal stan- with 0.01 M acetate buffer (2.6 mL, pH = 4.5) and treated with
dards. Coupling constants J [Hz] were directly taken from the a solution of laccase in the same buffer (0.1 mL). The change
spectra and are not averaged. Splitting patterns are designated in absorption was followed using UV/Vis spectroscopy (λ =
as s (singlet), d (doublet), t (triplet), q (quartet), sep (septet) 414 nm). One unit was defined as the amount of laccase
and m (multiplet). HSQC-, HMBC- and COSY-spectra were (Trametes versicolor, Fluka) that converts 1 mmol of ABTS per
recorded using a Varian UnityInova at 300 MHz. Electron minute at pH = 4.5 at r.t.
1
impact low resolution mass spectra (EI) and electron
impact high resolution mass spectra (HRMS) were recorded
at 70 eV using a Finnigan MAT 95 instrument. The intensities
are reported as percentages relative to the base peak (I =
100%).
General procedure A for the Gd(OTf)3-catalyzed synthesis of
6,7-dihydrobenzofuran-4(5H)-ones 5a–g starting from (Z)-3-
hexene-2,5-dione (Z)-(2a) and 1,3-dicarbonyls 3a–g. A 50 mL
round-bottomed flask equipped with a magnetic stir bar was
charged with (Z)-3-hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol),
a 1,3-dicarbonyl 3 (3 mmol), Gd(OTf)3 (60 mg, 0.1 mmol) and
CH2Cl2 (10 mL). The mixture was stirred for 48 h at r.t. After
concentration the reaction mixture in vacuo, the crude product
was purified by flash chromatography on SiO2 (petroleum
ether–EtOAc = 1 : 1) to afford the 6,7-dihydrobenzofuran-4(5H)-
one 5.
General procedure B for the one-pot synthesis of 5a–e,h in
aqueous medium starting from 2,5-dimethylfuran (1a) and 1,3-
dicarbonyls 3a–e,h. A 250 mL round-bottomed flask equipped
with a magnetic stir bar was charged with 2,5-dimethylfuran
(1a) (96 mg, 1 mmol), n-octane (1 mL), 0.01 M acetate buffer
pH 4.5 (10 mL), 4-acetamido-TEMPO (53 mg, 0.25 mmol) and
200 U laccase (Trametes versicolor) and sealed with a septum.
The mixture was stirred for 18 h at r.t. Then, the 1,3-dicarbonyl
3 (3 mmol) and Gd(OTf)3 (120 mg, 0.2 mmol) were added and
Synthesis and analytical data for 5a–5h
3-Methyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4(5H)-one (5a).
According to the general procedure A, a solution of (Z)-3-
hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol) and 1,3-cyclohexa-
nedione (3a) (336 mg, 3 mmol) in CH2Cl2 was reacted in the
presence of Gd(OTf)3 (60 mg, 0.1 mmol) for 48 h. Purification
afforded 5a (152 mg, 0.74 mmol, 74%).
According to the general procedure B, 1,3-cyclohexanedione
(3a) (336 mg, 3 mmol) and Gd(OTf)3 (120 mg, 0.2 mmol) were
added to the reaction mixture of the laccase-catalyzed ring
opening of 2,5-dimethylfuran (1a) (96 mg, 1 mmol) in acetate
buffer and the mixture was reacted for 48 h. Purification
afforded 5a (113 mg, 0.55 mmol, 55%).
According to the general procedure C, the crude product
solution in CH2Cl2 resulting from the laccase-catalyzed ring
opening of 2,5-dimethylfuran (1a) was subjected to 1,3-cyclo-
hexanedione (3a) (336 mg, 3 mmol) and Gd(OTf)3 (120 mg,
0.2 mmol). The reaction mixture was stirred for 48 h. Purifi-
cation furnished 5a (124 mg, 0.6 mmol, 60%).
the mixture was stirred at r.t. for 48 h. The reaction mixture Yellow oil; Rf = 0.53 (PE–EtOAc = 2 : 1); IR (ATR): ˜ν = 2951 (w;
was saturated with NaCl (1 g) and extracted with CH2Cl2 CH2, CH3), 1717 (m; CvO, carbonyl), 1666 (s; CvO, enone),
(4 × 25 mL). The combined organic phases were dried over 1579 (m; CvC), 1357 cm−1; UV/Vis (CH3CN): λmax (log ε) = 210
Na2SO4. After removal of the solvents in vacuo, the crude (4.18), 265 nm (3.61); 1H NMR (300 MHz, CDCl3): δ = 2.12 (2 H,
product was purified by flash chromatography on SiO2 m, 6-H), 2.14 (3 H, s, 3-Me), 2.16 (3 H, s, 3′-H), 2.44 (2 H, t,
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3J (5-H, 6-H) = 6.3 Hz, 5-H), 2.80 (2 H, t, J (7-H, 6-H) = 6.3 Hz,
Organic & Biomolecular Chemistry
3
According to the general procedure B, 5-isopropyl-1,3-
7-H), 3.61 (2 H, s, 1′-H); 13C NMR (75 MHz, CDCl3): δ = 8.9 cyclohexanedione (3c) (462 mg,
3 mmol) and Gd(OTf)3
(3-Me), 22.5 (C-6), 23.4 (C-5), 29.2 (C-3′), 38.1 (C-7), 40.7 (C-1′), (120 mg, 0.2 mmol) were added to the reaction mixture of
116.0 (C-3), 121.0 (C-3a), 144.0 (C-2), 166.2 (C-7a), 195.4 (C-4), the laccase-catalyzed ring opening of 2,5-dimethylfuran
203.6 (C-2′); MS (EI, 70 eV): m/z (%) = 206 (20) [M]+, 163 (100) (1a) (96 mg, 1 mmol) in acetate buffer and the mixture was
[M − CH3CO]+, 43 (48); HRMS (EI, M+) calculated for reacted for 48 h. Purification afforded 5c (72 mg, 0.29 mmol,
C12H14O3: 206.0943; found: 206.0936.
29%).
3,6-Dimethyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4(5H)-one
(5b). According to the general procedure A, a solution of (Z)-3-
hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol) and 5-methyl-1,3-
cyclohexanedione (3b) (378 mg, 3 mmol) in CH2Cl2 was
reacted in the presence of Gd(OTf)3 (60 mg, 0.1 mmol) for
48 h. Purification afforded 5b (180 mg, 0.82 mmol, 82%).
According to the general procedure B, 5-methyl-1,3-cyclo-
hexanedione (3b) (378 mg, 3 mmol) and Gd(OTf)3 (120 mg,
0.2 mmol) were added to the reaction mixture of the laccase-
catalyzed ring opening of 2,5-dimethylfuran (1a) (96 mg,
1 mmol) in acetate buffer and the mixture was reacted for
48 h. Purification afforded 5b (88 mg, 0.4 mmol, 40%).
According to the general procedure C, the crude product
solution in CH2Cl2 resulting from the laccase-catalyzed ring
opening of 2,5-dimethylfuran (1a) was subjected to 5-methyl-
1,3-cyclohexanedione (3b) (378 mg, 3 mmol) and Gd(OTf)3
(120 mg, 0.2 mmol). The reaction mixture was stirred for 48 h.
Purification furnished 5b (117 mg, 0.53 mmol, 53%).
According to the general procedure C, the crude product
solution in CH2Cl2 resulting from the laccase-catalyzed ring
opening of 2,5-dimethylfuran (1a) was subjected to 5-isopro-
pyl-1,3-cyclohexanedione (3c) (462 mg, 3 mmol) and Gd(OTf)3
(120 mg, 0.2 mmol). The reaction mixture was stirred for 48 h.
Purification furnished 5c (112 mg, 0.45 mmol, 45%).
Yellow oil; Rf = 0.65 (PE–EtOAc = 2 : 1); IR (ATR): ˜ν = 2959 (w;
CH2, CH3), 1765 (w), 1717 (m; CvO, carbonyl.), 1670 (s; CvO,
enone), 1582 (m; CvC), 1370 cm−1; UV/Vis (CH3CN): λmax (log
ε) = 209 (4.23), 268 nm (3.42) 1H NMR (300 MHz, CDCl3):
δ = 0.95 (3 H, d, 3J(1′′-H, 2′′-H) = 1.5 Hz, 1′′-H), 0.98 (3 H, d,
3J (3′′-H, 2′′-H) = 1.5 Hz, 3′′-H), 1.65–1.76 (2.14 (1 H, m, 6-H),
1.98–2.11 (1 H, m, 2′′-H), 2.14 (3 H, s, 3-Me), 2.16 (3 H, s, 3′-H),
2.24 (1 H, dd, 3J (5-Hb, 6-H) = 12.5 Hz, 2J (5-Hb, 5-Ha) = 15.7 Hz,
3
2
5-Hb), 2.52 (1 H, dd, J (5-Ha, 6-H) = 0.9 Hz, J (5-Ha, 5-Hb) =
15.8 Hz, 5-Ha), 2.54 (1 H, dd, 3J (7-Hb, 6-H) = 11.2 Hz,
2J (7-Hb, 7-Ha) = 16.9 Hz, 7-Hb), 2.85 (1 H, dd, J (7-Ha, 6-H) =
3
5 Hz, 2J (7-Ha, 7-Hb) = 17 Hz, 7-Ha), 3.62 (2 H, s, 1′-H);
13C NMR (75 MHz, CDCl3): δ = 8.9 (3-Me), 19.46 (C-1′′), 19.68
Yellowish solid; mp 106–108 °C; Rf = 0.62 (PE–EtOAc = 2 : 1); IR (C-3′′), 27.07 (C-3′), 29.2 (C-2′′), 31.6 (C-7), 31.88 (C-6),
(ATR): ˜ν = 2961, 2927 (w; CH2, CH3), 1709 (m; CvO, carbonyl), 40.8 (C-1′), 42.04 (C-5), 115.9 (C-3), 120.8 (C-3a), 144.3 (C-2),
1666 (s; CvO, enone), 1583 cm−1 (m; CvC); UV/Vis (CH3CN): 166.6 (C-7a), 195.1 (C-4), 203.7 (C-2′); MS (EI, 70 eV): m/z
λmax (log ε) = 207 (4.18), 268 nm (3.61); 1H NMR (300 MHz, (%) 248 (92) [M]+, 206 (82) [M − CH3COH]+, 135 (97);
CDCl3): δ = 1.15 (3 H, d, 3J (1′′-H, 6-H) = 6.2 Hz, 1′′-H), 2.14 HRMS (EI, M+) calculated for C15H20O3: 248.1412; found:
(3 H, s, 3-Me), 2.16 (3 H, s, 3′-H), 2.21 (1 H, dd, 3J (5-Hax, 6-H) = 248.1384.
11.2 Hz, 2J (5-Hax, 5-Heq) = 15 Hz, 5-Hax), 2.34–2.45 (1 H, m,
3,6,6-Trimethyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4(5H)-
3
2
one (5d). According to the general procedure A, a solution of
(Z)-3-hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol) and 5,5-
dimethyl-1,3-cyclohexanedione (3d) (420 mg, 3 mmol) in
CH2Cl2 was reacted in the presence of Gd(OTf)3 (60 mg,
0.1 mmol) for 48 h. Purification afforded 5d (154 mg,
0.66 mmol, 66%).
According to the general procedure B, 5,5-dimethyl-1,3-
cyclohexanedione (3d) (420 mg, 3 mmol) and Gd(OTf)3
(120 mg, 0.2 mmol) were added to the reaction mixture
of the laccase-catalyzed ring opening of 2,5-dimethylfuran
(1a) (96 mg, 1 mmol) in acetate buffer and the mixture was
reacted for 48 h. Purification afforded 5d (61 mg, 0.26 mmol,
6-H), 2.48 (1 H, dd, J (7-Hax, 6-H) = 10.5 Hz, J (7-Hax, 7-Heq) =
3
2
17 Hz, 7-Hax), 2.49 (1 H, dd, J (5-Heq, 6-H) = 3 Hz, J (5-Heq
,
3
5-Hax) = 15.8 Hz, 5-Heq), 2.88 (1 H, dd, J (7-Heq, 6-H) = 4.5 Hz,
2J (7-Heq, 7-Hax) = 16.4 Hz, 7-Heq), 3.62 (2 H, s, 1′-H); 13C NMR
(75 MHz, CDCl3): δ = 8.9 (3-Me), 21.1 (6-Me), 29.2 (C-3′), 30.7
(C-6), 31.6 (C-7), 40.8 (C-1′), 46.7 (C-5), 116.0 (C-3), 120.7
(C-3a), 144.3 (C-2), 165.9 (C-7a), 195.1 (C-4), 203.7 (C-2′); MS
(EI, 70 eV): m/z (%) = 220 (4) [M]+, 177 (82) [M − CH3CO]+, 135
(10); HRMS (EI, M+) calculated for C13H16O3: 220.1099; found:
220.1102. Crystals suitable for X-ray diffraction analysis were
grown from EtOAc and cyclohexane.
6-Isopropyl-3-methyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4-
(5H)-one (5c). According to the general procedure A, a solution 26%).
of (Z)-3-hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol) and 5-iso-
According to the general procedure C, the crude product
propyl-1,3-cyclohexanedione (3c) (462 mg, 3 mmol) in CH2Cl2 solution in CH2Cl2 resulting from the laccase-catalyzed ring
was reacted in the presence of Gd(OTf)3 (60 mg, 0.1 mmol) for opening of 2,5-dimethylfuran (1a) was subjected to 5,5-
48 h. Purification afforded 5c (141 mg, 0.57 mmol, 57%).
dimethyl-1,3-cyclohexanedione (3d) (420 mg, 3 mmol) and
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Gd(OTf)3 (120 mg, 0.2 mmol). The reaction mixture was stirred ov.,6-H) (II), 2.114 (3 H, s, 3-Me) (II), 2.119 (3 H, s, 3-Me) (I),
for 48 h. Purification furnished 5d (126 mg, 0.54 mmol, 54%).
2.13 (3 H, s, 3′-H), 2.16 (3 H, s, 3′-H), 2.45–2.48 (2 H, m, 5-H)
(II), 2.79–2.84 (2 H, m, 7-H) (I), 3.62 (4 H, s, 2 × 1′-H); 13C NMR
(75 MHz, CDCl3): δ = 8.86 (3-Me) (II), 8.93 (3-Me) (I), 20.9 (C-7)
(I), 24.1 (5-Me) (I), 25.9 (7-Me) (II), 29.1 (C-3′) (II), 29.2 (C-3′) (I),
32.7 (C-7) (II), 35.9 (C-5) (II), 36.4 (C-6) (I), 37.8 (C-6) (II), 40.9
(2 × C-1′), 42.1 (C-5) (I), 115.9 (C-3) (II), 116.6 (C-3) (I), 118.8
(C-3a) (II), 119.2 (C-3a) (I), 144.0 (C-2), 144.3 (C-2), 164.4 (C-7a)
(I), 172.0 (C-7a) (II), 195.4 (C-4) (II), 200.7 (C-4) (I), 203.7
(2 × C-2′); MS (EI, 70 eV): m/z (%) 234 (28) [M]+, 191 (100)
[M − CH3CO]+, 28 (82); HRMS (EI, M+) calculated for
C14H18O3: 234.1256; found: 234.1249.
3-Methyl-6-phenyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4(5H)-
one (5f). According to the general procedure A, a solution of
(Z)-3-hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol) and 5-phenyl-
1,3-cyclohexanedione (3f) (564 mg, 3 mmol) in CH2Cl2 was
reacted in the presence of Gd(OTf)3 (60 mg, 0.1 mmol) for
48 h. Purification afforded 5f (144 mg, 0.51 mmol, 51%).
According to the general procedure C, the crude product
solution in CH2Cl2 resulting from the laccase-catalyzed ring
opening of 2,5-dimethylfuran (1a) was subjected to 5-phenyl-
1,3-cyclohexanedione (3f) (564 mg, 3 mmol) and Gd(OTf)3
(120 mg, 0.2 mmol). The reaction mixture was stirred for 48 h.
Purification furnished 5f (150 mg, 0.53 mmol, 53%).
Yellowish solid; mp 74–76 °C; Rf = 0.64 (PE–EtOAc = 2 : 1); IR
(ATR): ˜ν = 2959 (w; CH2, CH3), 1765 (w), 1714 (m; CvO, carbo-
nyl), 1667 (s; CvO, enone), 1594 (m), 1372 cm−1 (m); UV/Vis
(CH3CN): λmax (log ε) = 209 (4.20), 258 nm (4.08); 1H NMR
(300 MHz, CDCl3): δ = 1.11 (6 H, s, 6-Me), 2.14 (3 H, s, 3-Me),
2.16 (3 H, s, 3′-H), 2.32 (2 H, s, 5-H), 2.67 (2 H, s, 7-H), 3.62
(2 H, s, 1′-H); 13C NMR (75 MHz, CDCl3): δ = 8.9 (3-Me), 28.6
(6-Me), 29.2 (C-3′), 35.0 (C-6), 37.4 C-7), 40.9 (C-1′), 52.5 (C-5),
115.9 (C-3), 119.9 (C-3a), 144.4 (C-2), 165.4 (C-7a), 194.8 (C-4),
203.7 (C-2′); MS (EI, 70 eV): m/z (%) = 234 (68) [M]+, 191 (100)
[M
−
CH3CO]+, 135 (100); HRMS (EI, M+) calculated
for C14H18O3: 234.1256; found: 234.1249. Crystals suitable
for X-ray diffraction analysis were grown from EtOAc and
cyclohexane.
3,5,5-Trimethyl-2-(2-oxopropyl)-6,7-dihydrobenzofuran-4(5H)-
one (5e–I) and 3,7,7-trimethyl-2-(2-oxopropyl)-6,7-dihydrobenzo-
furan-4(5H)-one (5e–II). According to the general procedure A,
a solution of (Z)-3-hexene-2,5-dione (Z)-(2a) (112 mg, 1 mmol)
and 4,4-dimethyl-1,3-cyclohexanedione (3e) (420 mg, 3 mmol)
in CH2Cl2 was reacted in the presence of Gd(OTf)3 (60 mg,
0.1 mmol) for 48 h. Purification afforded a mixture of regio-
isomers 5e–I and 5e–II (124 mg, 0.53 mmol, 53%).
According to the general procedure B, 4,4-dimethyl-1,3-
Yellow oil; Rf = 0.67 (PE–EtOAc = 2 : 1); IR (ATR): ˜ν = 2929 (w;
CH2, CH3), 1766 (w), 1732 (s; CvO, carbonyl), 1671(s; CvO,
enone), 1580 (m; CvC), 1372 (m), 1239 (s), 1043 cm−1 (s); UV/
cyclohexanedione (3e) (420 mg,
3 mmol) and Gd(OTf)3
(120 mg, 0.2 mmol) were added to the reaction mixture of the
laccase-catalyzed ring opening of 2,5-dimethylfuran (1a)
(96 mg, 1 mmol) in acetate buffer and the mixture was reacted
for 48 h. Purification afforded a mixture of regioisomers 5e–I
and 5e–II (63 mg, 0.27 mmol, 27%).
1
Vis (CH3CN): λmax (log ε) = 209 (4.38), 268 nm (3.5); H NMR
(300 MHz, CDCl3): δ = 2.18 (3 H, s, 3-Me), 2.20 (3 H, s, 3′-H),
2.68–2.81 (2 H, m, spectra higher order, 5-H), 3.00 (1 H, dd,
3
2J (7-Ha, 7-Hb) = 17.2 Hz, J (7-Ha, 6-H) = 10.9 Hz, 7-Ha), 3.10
(1 H, dd, 2J (7-Hb, 7-Ha) = 17.1 Hz, 3J (7-Hb, 6-H) = 5.2 Hz,
7-Hb), 3.44–3.56 (1 H, m, 6-H), 3.66 (2 H, s, 1′-H), 7.26–7.31
(2 H, m, 2′′-H, 6′′-H), 7.33–7.40 (3 H, m, 3′′-H, 4′′-H, 5′′-H);
13C NMR (75 MHz, CDCl3): δ = 9 (3-Me), 29.3 (C-3′), 31.3 (C-7),
40.8 (C-6), 41.2 (C-1′), 45.5 (C-5), 116.1 (C-3), 121.0 (C-3a),
126.7 (C-2′′, C-6′′), 127.2 (C-4′′), 128.8 (C-3′′, C-5′′), 142.5 (C-1′′),
144.7 (C-2), 165.4 (C-7a), 194.0 (C-4), 203.5 (C-2′); MS (EI, 70
eV): m/z (%) = 282 (32) [M]+, 239 (100) [M − CH3CO]+, 135 (93);
HRMS (EI, M+) calculated for C18H18O3: 282.1256; found:
220.1237.
According to the general procedure C, the crude product
solution in CH2Cl2 resulting from the laccase-catalyzed ring
opening of 2,5-dimethylfuran (1a) was subjected to 4,4-
dimethyl-1,3-cyclohexanedione (3e) (420 mg, 3 mmol) and
Gd(OTf)3 (120 mg, 0.2 mmol). The reaction mixture was stirred
for 48 h. Purification furnished a mixture of regioisomers 5e–I
and 5e–II (124 mg, 0.53 mmol, 53%).
1-(4-Acetyl-3,5-dimethylfuran-2-yl)propan-2-one (5g). Accord-
ing to the general procedure A, a solution of (Z)-3-hexene-2,5-
dione (Z)-(2a) (112 mg, 1 mmol) and acetylacetone (3g)
Yellow oil; Rf = 0.67 (PE–EtOAc = 2 : 1); IR (ATR): ˜ν = 2965, 2930 (300 mg, 3 mmol) in CH2Cl2 was reacted in the presence of Gd
(w; CH2, CH3), 1719 (m; CvO, carbonyl), 1668 (s; CvO, (OTf)3 (60 mg, 0.1 mmol) for 48 h. Purification afforded 5g
enone), 1585 (m; CvC), 1357 cm−1; UV/Vis (CH3CN): λmax (116 mg, 0.6 mmol, 60%).
1
(log ε) = 207 (4.00), 266 nm (3.50); H NMR (300 MHz, CDCl3):
According to the general procedure C, the crude product
δ = 1.15 (6 H, s, 2 × 5-Me) (I), 1.32 (6 H, s, 2 × 7-Me) (II), 1.94 solution in CH2Cl2 resulting from the laccase-catalyzed
(2 H, t, 3J (6H, 7-H) = 6.4 Hz, 6-H) (I), 1.95 (2 H, m, part. ring opening of 2,5-dimethylfuran (1a) was subjected to
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Organic & Biomolecular Chemistry
acetylacetone (3g) (300 mg, 3 mmol) and Gd(OTf)3 (120 mg,
0.2 mmol). The reaction mixture was stirred for 48 h. Purifi-
cation furnished 5g (109 mg, 0.56 mmol, 56%).
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Yellow oil; Rf = 0.53 (PE–EtOAc = 2 : 1); IR (ATR): ˜ν = 2973, 2931
(w; CH2, CH3), 1711 (m; CvO, carbonyl), 1655 (s; CvO,
enone), 1559 (m; CvC), 1354 cm−1 (m); UV/Vis (CH3CN): λmax
(log ε) = 207 (4.2), 273 nm (3.7); 1H NMR (300 MHz, CDCl3): δ =
2.10 (3 H, s, 3-Me), 2.15 (3 H, s, 3′-H), 2.41 (3 H, s, 2′′-H), 2.52
(3 H, s, 5-Me), 3.60 (2 H, s, 1′-H); 13C NMR (75 MHz, CDCl3): δ
= 10.6 (3-Me), 15.2 (5-Me), 29.1 (C-3′), 30.8 (C-2′′), 40.9 (C-1′),
117.5 (C-3), 123.2 (C-4), 142.6 (C-2), 157.6 (C-5), 194.7 (C-1′′),
203.9 (C-2′); MS (EI, 70 eV): m/z (%) 194 (7) [M]+, 151 (31) [M −
CH3CO]+, 43 (100), 28 (86); HRMS (EI, M+) calculated for
C11H14O3: 194.0943; found: 194.0927.
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3,6-Dimethyl-2-(2-oxopropyl)-4H-furo[3,2c]pyran-4-one
According to the general procedure B, 4-hydroxy-6-methyl-2-
pyron (3h) (378 mg, mmol) and Gd(OTf)3 (120 mg,
(5h).
3
0.2 mmol) were added to the reaction mixture of the laccase-
catalyzed ring opening of 2,5-dimethylfuran (1a) (96 mg,
1 mmol) in acetate buffer and the mixture was reacted for
48 h. Purification afforded 5h (56 mg, 0.25 mmol, 25%).
6 For selected examples of dynamic kinetic resolutions, see:
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Yellow oil; Rf = 0.52 (PE–EtOAc = 2 : 1); IR (ATR): ˜ν = 2926 (w;
CH2, CH3), 1712 (s; CvO), 1616 (m), 1575 (m; CvC), 1358 (m),
1158 (m), 947 cm−1 (m); UV/Vis (CH3CN): λmax (log ε) = 248
(3.9), 298 nm (3.3); 1H NMR (300 MHz, CDCl3): δ = 2.19 (3 H, s,
3′-H), 2.23 (3 H, s, 3-Me), 2.30 (3 H, s, 1′′-H), 3.7 (2 H, s, 1′-H),
6.3 (1 H, s, 7-H); 13C NMR (75 MHz, CDCl3): δ = 8.5 (3-Me),
20.2 (C-1′′), 29.3 (C-3′), 41.0 (C-1′), 52.5 (C-5), 115.9 (C-3), 95.7
(C-7), 109.2 (C-3a), 116.1 (C-3), 145.3 (C-2), 159.5.4 (C-6), 160.2
(C-7a), 161.0 (C-4), 202.8 (C-2′); MS (EI, 70 eV): m/z (%) 220 (86)
[M]+, 177 (100) [M − CH3CO]+, 137 (77); HRMS (EI, M+) calcu-
lated for C12H12O4: 220.0892; found: 220.0722.
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Acknowledgements
We thank Ms S. Mika and Ms E. Rubalevska for recording
the NMR spectra as well as Dr A. Baskakova and Dipl.-Chem.
H.-G. Imrich for recording the mass spectra.
Notes and references
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