Synthesis of 4-substituted pyrano[4,3-b]pyran-2,5-diones in an ionic liquid

Article abstract of DOI:10.1016/j.tet.2012.05.113

The mildly basic ionic liquid N,N,N,N-tetramethylguanidinium triflate (TMGTf) was found to be a very effective solvent for the reaction between 4-hydroxy-6-methyl-2H-pyran-2-one, Meldrum's acid, and aldehydes to afford some novel pyrano[4,3-b]pyran-2,5-diones in high yields at room temperature. The stages, through which these reactions might proceed, depend largely on the nature of the aldehyde substrates. The reaction of aliphatic aldehydes has given access to some novel carboxylated products.

Full text of DOI:10.1016/j.tet.2012.05.113

Tetrahedron 68 (2012) 6472e6476
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 4-substituted pyrano[4,3-b]pyran-2,5-diones in an ionic liquid
*
Kurosh Rad-Moghadam , Masoumeh Sharifi-Kiasaraie, Seyyedeh Cobra Azimi
Chemistry Department, University of Guilan, 41335-19141 Rasht, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The mildly basic ionic liquid N,N,N,N-tetramethylguanidinium triflate (TMGTf) was found to be a very
effective solvent for the reaction between 4-hydroxy-6-methyl-2H-pyran-2-one, Meldrum’s acid, and
aldehydes to afford some novel pyrano[4,3-b]pyran-2,5-diones in high yields at room temperature. The
stages, through which these reactions might proceed, depend largely on the nature of the aldehyde
substrates. The reaction of aliphatic aldehydes has given access to some novel carboxylated products.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 January 2012
Received in revised form 12 May 2012
Accepted 28 May 2012
Available online 5 June 2012
Keywords:
3,4-Dihydo-pyrano[4,3-b]pyran-2,5-dione
Meldrum’s acid
Ionic liquid
Multicomponent reaction
1. Introduction
paid to the synthesis of 3,4-dihydro-pyrano[4,3-b]pyran-2,5-dione
derivatives.20e22
Pyran derivatives represent the key building blocks of many
natural products,1e3 and constitute the core of valuable compounds
exhibiting a broad spectrum of biological activities.4e8 Certain
pyran-based motifs are often found as recurring structures in a va-
riety of natural and biologically relevant products. Arisugacins,
davallialactone, clavilactone, pyripyropenes, philigridrins, and ter-
ritrems are representatives of natural and secondary metabolites
being characterized by the presence of pyrano[4,3-b]pyran-5H-one
nucleus in their structures. Pyripyropenes9 are the most potent
naturally occurring biologically available inhibitors of
acyleCoA:cholesterol acyltransferase (ACAT). The inhibition of
ACAT represents a promising new approach to prevention of ath-
erosclerosis. Arisugacins, and territrems are inhibitors of acetyl-
cholinesterase, making them potential drugs for treatment of
dementia diseases, such as Alzheimer’s disease.10,11 Davallia-
lactone12 downregulates LPS-induced macrophage inflammatory
responses, and clavilactone13 was identified as an antifungal, and
antibacterial agent, as well as being a potent inhibitor of tyrosine
kinases. These interesting features have projected the pyrano[4,3-
b]pyran-5H-one framework as a valuable lead pharmacophore and
inspired much efforts toward the synthesis of its derivatives.14e16
This interest is further intensified by the fact that the
2H-pyranone ring is prone to conversion to carbocyclic or even to
other heterocyclic systems.17e19 However, little efforts have been
With this background in mind and in line with our interest in
the synthesis of pyranopyranone compounds, and also in per-
forming reactions with the aid of ionic liquids,23e25 herein we re-
port an efficient one-pot synthesis of 4-aryl-3,4-dihydro-7-methyl-
pyrano[4,3-b]pyran-2,5-diones 4 in ionic liquid medium. Recently,
ionic liquids (ILs) have received recognition as a new generation of
solvents having unique chemical and physical properties, such as
nonvolatility, nonflammability, and thermal stability. Their dual
organic and ionic nature allows them to establish ioneion and
ionedipole as well as van der Waals interactions with reacting
species, including transition states; hence they sometimes give rise
to improved yields and rate enhancements. Structural variation of
ILs gives more flexibility to their applications and provides fine
tunning of their miscibility, promoting phase-separation of prod-
ucts. Moreover, functionalized ILs offer task-specific types for ca-
talysis applications, or serve as solution phase supports for elegant
combinatorial syntheses.26
2. Result and discussion
To approach the synthesis, we first focused our studies on two
model reactions, involving 4-hydroxy-6-methylpyran-2H-one 1,
Meldrum’s
acid
2,
and
4-methylbenzaldehyde
3d/2-
chlorobenzaldehyde 3b, with the expected production of the de-
sired pyrano[4,3-b]pyran-2,5-diones 4d and 4b, respectively. In this
regard, we attempted to determine the optimum conditions by
examining the influence of IL (Table 1), temperature, and solvent
(Table 2) variations on the progress of the trial reactions. It can be
* Corresponding
author.
E-mail
address:
radmm880@gmail.com
(K. Rad-Moghadam).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.113

K. Rad-Moghadam et al. / Tetrahedron 68 (2012) 6472e6476
6473
Table 1
Evaluation of three ionic liquids, having different acid-base characteristics, on progress of the reaction at room temperature
O
O
H
OH
O
O
O
TMGTf
rt
+
+
O
O
O
O
O
O
X
X
2
X= 4-Me /2-Cl
1
3
4
Entry
X
Ionic liquids
Reaction time
Yield(%) of 4
1
2
3
4
5
6
7
8
2-Cl
4-Me
2-Cl
4-Me
2-Cl
4-Me
2-Cl
d
24 h
24 h
24 h
24 h
24 h
24 h
30 min
50 min
d
d
d
[BMIm]BF4
[BMIm]BF4
[BMIm]BF4eLiCl
[BMIm]BF4eLiCl
TMGTf
d
d
Trace
Trace
95
4-Me
TMGTf
83
Table 2
Effect of solvent on synthesis of 4-aryl-3,4-dihydro-pyrano[4,3-b]pyran-2,5-diones 4a and 4b
O
O
H
OH
O
O
O
TMGTf
rt
+
+
O
O
O
O
O
O
X
X
2
X= 4-OMe /2-Cl
1
3
4
Entry
X
Conditions
Reaction time
Yield (%) of 4a
1
2
3
4
5
6
7
8
4-Me
2-Cl
4-Me
2-Cl
4-Me
2-Cl
4-Me
4-Me
2-Cl
H2O-rt
H2O-rt
H2O-reflux
H2O-reflux
H2OeEtOH-rt
H2OeEtOH-rt
H2OeEtOH-reflux
EtOH-rt
EtOH-rt
EtOH-reflux
EtOHeTMGTf-rt
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
d
d
d-
d
Trace
Trace
Trace
<30
<30
<30
<20
9
10
11
4-Me
2-Cl
a
Isolated yields.
seen that the best yields of the expected products were obtained in
N,N,N,N-tetramethylguanidinium triflate (TMGTf) at room tem-
perature (Table 1, entries 7 and 8).
The mechanism of the reaction has not been determined. A
possible pathway is proposed in Scheme 1. The synthesis is likely
initiated by TMGTf, which upon removing a proton from Meldrum’s
acid 2 promotes a Knoevenagel condensation with the aldehyde 3,
resulting in formation of the intermediate 5. This intermediate
subsequently undergoes a Michael type addition with 4-hydroxy-
6-methyl-2H-pyran-2-one 1 to produce the adduct 6. Cyclization of
6 via a translactonization reaction leads to liberation of an acetone
molecule leaving the initial product 7 bearing a carboxyl group at
the 3-position. Spontaneous decarboxylation of the product 7 af-
fords the 4-aryl-product 4. The initial condensation during the
three-component reaction appears to be influenced by the different
pKa values of the two dicarbonyl substrates, such that the Knoe-
venagel condensation of Meldrum’s acid predominates, due to its
stronger acidity. This consideration was in fact confirmed by iso-
lation of intermediate 5 from the reaction media.
The ionic liquid, TMGTf, could be recovered from the aqueous
extracts of the reaction mixtures by evaporation of water under
reduced pressure. It retains almost all the initial activity after re-
covery, when reused in the next successive cycles. For instance
running the model reaction of 4-hydroxy-6-methylpyran-2H-one 1,
Meldrum’s acid 2, and 2-chlorobenzaldehyde 3 in 1 mL of fresh,
first recycled, and second recycled TMGTf at ambient temperature
has given, respectively, 95%, 94%, and 92% of the product 4b.
Interestingly, no by-products formed via condensation of
2 equiv of either carbon acids (1 or 2) with an aldehyde substrate.
After optimization of the conditions for the model reactions,
a range of different aldehydes were screened to explore the scope of
this protocol. As shown in Table 3, the reaction is compatible with
an array of arylaldehydes bearing either electron-withdrawing or
electron-donating substituents. It also proceeds well with sterically
hindered 2-chlorobenzaldehyde and enolizable aliphatic aldehydes
to afford fairly high yields of the corresponding products.
The activity of TMGTf is better conceived by considering its acid-
base bifunctional nature, providing both proton donating and
accepting functions during the catalysis process. Under this hy-
drogen bonding network and the mildly basic conditions, the

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K. Rad-Moghadam et al. / Tetrahedron 68 (2012) 6472e6476
Table 3
Reaction of 4-hydroxy-6-methyl-2H-pyran-2-one 1 with Meldrum’s acid 2 and various aldehydes 3 in the presence of (TMGTf)
O
O
O
CO2H
R
O
O
O
OH
CO2
R
R
TMGTf
rt
O
O
R-CHO
or
O
O
O
O
O
O
O
O
O
O
1
2
3
7
4a-e
4f
Product
R
Reaction time
Yield (%)
4a
4b
4c
4d
4e
4f
7a
7b
7c
7d
4-MeO$C6H4
2-Cl$C6H4
3-Br$C6H4
4-Me$C6H4
4-NO2$C6H4
Thiophene-2-yl
Methyl
Ethyl
n-Propyl
n-Butyl
55
30
35
50
35
45
40
45
45
50
85
95
92
83
79
90
82
80
84
85
N
O
R
O
H
TMGTf
N
5
CF3SO3
H
H
N
H
O
O
O
O
H
N
H
CF3SO3
O
O
N
O
N
H
H
R
O
1
2
3
O
O
N(CH3)2
N(CH3)2
H
δ
N
O
O
R
O
O
CO2H
H
O
O
δ
CO2
O
O
H
O
R
O
O
O
O
Acetone
G
O
O
6
7
4
Scheme 1. A plausible sequence of events resulting in production of compounds 4 and 7.
employed arylaldehydes proceeded entirely through de-
carboxylation of the intermediates 7 to give the products 4aef,
while the reaction of aliphatic aldehydes stopped at this stage to
give the corresponding 3-carboxylic acid products 7aed. Pre-
sumably, decarboxylation of the intermediates 7 are facilitated by
the presence of an aryl group at the 4-position. In the case of 4f, the
sequence of reactions is followed by an aerobic dehydrogenation to
give the corresponding dehydrogenated product 4f.
The NMR spectra and the mass spectrometric data as well as el-
emental analyses of all the products are consistent with their
structures. For example, the 1H NMR spectrum of 4a displayed an
AMX spin system for the CH2CH protons (at dH 3.11, 3.47, and
4.67 ppm). A relatively large coupling between a vicinal pair of
protons of this system (3J¼9.6 Hz) can be attributed to their axial
orientation in the molecule and consequently to restricted inversion
of the dihydropyranone ring bearing the aryl substituent at the
equatorial position. Compounds 7aed exhibited a precise pattern of
1H-resonances embedding an AX spin system in the aliphatic region
along with a singlet signal at low field, which are best interpreted as
arising from the ReCHeCHeCO2H congestion. Here also, the alkyl
substituents (R) occupy the pseudo-equatorial position, as the two
methine protons gain nearly anti-orientation and establish the
coupling of about 8.9 Hz. Presumably, the diastereoselective for-
mation of 7aed arises from a biased conformation that adducts 5
adopt, as in Fig. 1, during cyclization transition. This likely confor-
mation is the requirement of repulsive steric interactions between
the bulky aryl or pyranyl substituents and the axial methyl group
rendering the two vicinal protons to achieve an anti arrangement.
O
Ar
H
O
O
CH3
CH3
O
O
H
O
O
5
H
Fig. 1. The prescribed conformation of adduct 5 during cyclization.

K. Rad-Moghadam et al. / Tetrahedron 68 (2012) 6472e6476
6475
3. Conclusion
NMR (125.7 MHz, DMSO-d6): dC 22.6, 35.5, 37.8, 101.8, 104.0, 130.3,
131.1,132.6,133.3,135.5,140.1,164.8,166.0,167.1,167.9. MS (EI, 70 eV)
m/z: 291 (Mþþ1, 35Cl, 0.8), 255 (MþꢁCl, 95), 227 (MþꢁCleHCO, 25),
213 (MþꢁCleCO2, 100), 173 (58), 136 (28), 101 (26). Anal. Calcd for
C15H11ClO4 (290.70): C, 61.98; H, 3.81%. Found: C, 62.11; H, 3.77%.
In summary, a one-pot three-component reaction for synthesis
of
4-aryl-7-methyl-3,4-dihydro-pyrano[4,3-b]pyran-2,5-diones
using the reaction of arylaldehydes with 4-hydroxy-2H-pyranone
1 and Meldrum’s acid in the ionic liquid N,N,N,N-tetramethylgua-
nidinium triflate was introduced. Aliphatic aldehydes go through
a similar reaction, however in TMGTf their products resist toward
decarboxylation process, leading to production of 4-alkyl-7-
methyl-2,5-dioxo-2,3,4,5-tetrahydro-pyrano[4,3-b]pyran-3-
carboxylic acids. The ionic liquid acts as a catalyst in these reactions,
enabling for the first time to control the progress of reaction of
aliphatic aldehydes, and can be recovered for reuse several times.
Another advantage of the present method is that it requires no
metal catalysts or additional solvent.
4.2.3. 4-(3-Bromophenyl)-7-methyl-3,4-dihydro-pyrano[4,3-b]py-
ran-2,5-dione 4c. White powder (0.308 g, 92%). Mp 216e218 oC. IR
(KBr): 3070, 1670 (C]O), 1560, 1440, 1408 (C]C), 1280 cmꢁ1 1H
NMR (500.1 MHz, DMSO-d6): dH 1.93 (s, 3H, 7-CH3), 2.88 (br s,1H, 3-
HB), 3.04 (br s, 1H, 3-HA), 4.58 (br s, 1H, 4-H), 5.72 (s, 1H, 8-H), 7.14
(t, 1H, 3J 7.7 Hz, 50-H), 7.27 (d, 2H, 3J 7.7 Hz, Ar), 7.50 (s, 1H, 20-H). 13C
NMR (125.7 MHz, DMSO-d6): dC 20.1, 36.2, 36.8, 100.8, 102.9, 122.1,
127.4, 129.8, 129.9, 130.8, 131.1, 164.5, 164.6, 166.6, 166.8. MS (EI,
70 eV) m/z: 336 (Mþþ2, 81Br, 9), 334 (Mþ, 79Br, 8) 308 (336ꢁCO, 36),
306 (334eCO, 35), 227 (15), 202 (29), 200 (32), 185 (32), 183 (32),
157 (C6H4e81Br, 23), 155 (C6H4e79Br, 23), 149 (62), 115 (27), 43
(100). Anal. Calcd for C15H11BrO4 (335.15): C, 53.76; H, 3.31%. Found:
C, 53.71; H, 3.42%.
4. Experimental section
4.1. General
All of the solvents and reagents were purchased from Fluka or
Merck chemical companies. Melting points were measured on an
electrothermal apparatus. IR spectra were obtained in KBr disks on
a Shimadzu IR-470 spectrometer. 1H and 13C NMR spectra were
measured with Brucker DRX-400 AVANCE spectrometers. Chemical
shifts of 1H and 13C NMR spectra were expressed in parts per mil-
lion downfield from tetramethylsilane. Mass spectra were recorded
on a Shimadzu QP1100EX mass spectrometer operating at an ion-
ization potential of 70 eV. Elemental analyses for C, H, and N were
performed using a Foss Heraus CHN-O-rapid analyzer.
4.2.4. 4-(4-Methylphenyl)-7-methyl-3,4-dihydro-pyrano[4,3-b]py-
ran-2,5-dione (4d). White powder (0.224 g, 83%). Mp 183e185 C. IR
(KBr): 3080, 2955, 2920, 1724 (C]O), 1668 (C]O), 1277 cmꢁ1 1H
NMR (500.1 MHz, DMSO-d6): dH 2.05 (s, 3H, 7-CH3), 2.31 (s, 3H, 40-
CH3), 3.16 (dd,1H, 3J 4.9 and 2J 16.6 Hz, 3-HB), 3.43 (dd,1H, 3J 9.3 and
2J 16.6 Hz, 3-HA), 4.73 (dd, 1H, J 9.3 and 4.9 Hz, 4-H), 5.83 (s, 1H, 8-
H), 7.08 (d, 2H, J 7.6 Hz, Ar), 7.29 (d, 2H, J 7.6 Hz, Ar). 13C NMR
(125.7 MHz, DMSO-d6): dC 19.9, 21.4, 30.0, 35.4, 102.5, 106.1, 127.3,
128.3, 128.9, 134.1, 159.2, 159.3, 167.9, 174.2. MS (EI, 70 eV) m/z: 270
(Mþ, 9), 242 (MþꢁCO, 12), 227 (MþeCH3CO, 35), 213 (94), 185 (19),
149 (23), 115 (70), 98 (39), 91 (36), 43 (100). Anal. Calcd for
C16H14O4 (270.28): C, 71.10; H, 5.22%. Found: C, 71.14; H, 5.33%.
4.2. Typical experimental procedure
A mixture of the 4-hydroxy-6-methyl-2H-pyran-2-one (0.126 g,
4.2.5. 4-(4-Nitrophenyl)-7-methyl-3,4-dihydro-pyrano[4,3-b]pyran-
2,5-dione (4e). Pale yellow powder (0.237 g, 79%). Mp 193e195 C.
IR (KBr): 3080, 2925, 1704 (C]O), 1667 (C]O), 1518, 1340,
842 cmꢁ1 1H NMR (500.1 MHz, DMSO-d6): dH 2.07 (s, 3H, 7-CH3),
2.89 (br s, 3-HB), 3.13 (br s, 3-HA), 4.75 (br s, 1H, 4-H), 5.65 (s, 1H, 8-
H), 7.53 (d, 2H, J 7.7 Hz, Ar), 8.05 (d, 2H, J 7.7 Hz, Ar). 13C NMR
(125.7 MHz, DMSO-d6): dC 19.9, 34.1, 36.5, 101.6, 105.8, 123.8, 128.6,
146.0, 153.3, 159.6, 166.3, 167.2, 174.1. MS (EI, 70 eV) m/z: 301 (Mþ,
24), 273 (MþꢁCO, 76), 256 (8), 230 (12), 189 (9), 115 (17), 101 (18),
85 (52), 43 (100). Anal. Calcd for C15H11NO6 (301.25): C, 59.80; H,
3.68; N, 4.65%. Found: C, 59.85; H, 3.73% N, 4.59%.
1
mmol), Meldrum’s acid (0.144 g,
1
mmol) and 4-
methoxybenzaldehyde (0.121 mL, 1 mmol) was added to a vial
containing a magnetic stirring bar and the ionic liquid (TMGTf,
1 mL). The reaction mixture was sealed and stirred at room tem-
perature until disappearance of the starting materials (55 min as
monitored by TLC). After completion of the reaction, the residue
was washed with 4ꢀ7 mL of cold water to extract the ionic liquid.
The solid residue was recrystallized from ethanol (95.5%) to obtain
pure product 4a (0.24 g, 85%). The ionic liquid was recovered from
the aqueous extracts by evaporating of water under reduced pres-
sure and reused in the next cycles.
4.2.6. 4-(Thiophene-2-yl)-7-methyl-pyrano[4,3-b]pyran-2,5-dione
(4f). Pale yellow powder (0.234 g, 90%). Mp 188e189 ꢂC. IR (KBr):
3097, 1716 (C]O), 1558, 1397, 1190 cmꢁ1 1H NMR (500.1 MHz,
DMSO-d6): dH 2.08 (s, 3H, 7-CH3), 5.64 (s, 1H, 8-H), 6.00 (s, 1H, 3-H),
6.45 (br s, 1H, Thiophenyl 3-H), 6.75 (t, 1H, J 3.7 Hz, Thiophenyl 4-
H), 7.08 (d, 1H, J 4.9 Hz, Thiophenyl 5-H). 13C NMR (125.7 MHz,
DMSO-d6): dC 19.9, 102.6, 105.9, 106.0, 123.1, 123.4, 126.7, 150.0,
159.2, 165.8, 166.9, 172.7, 173.9. MS (EI, 70 eV) m/z: 260 (Mþ, 3), 239
(10), 220 (100),191 (15),177 (43),136 (78),108 (70), 98 (59), 85 (35),
69 (95), 43 (86). Anal. Calcd for C13H8O4S (260.27): C, 59.99H, 3.10%.
Found: C, 60.14; H, 3.15%.
4.2.1. 4-(4-Methoxyphenyl)-7-methyl-3,4-dihydro-pyrano[4,3-b]py-
ran-2,5-dione (4a). White powder (0.243 g, 85%). Mp 194e196 C. IR
(KBr): 3000, 1724 (C]O), 1667 (C]O), 1580, 1510, 1410, 1245 cmꢁ1
1H NMR (500.1 MHz, CDCl3): dH 2.16 (s, 3H, 7-CH3), 3.11 (dd, 1H, 2J
17.0 and 3J 4.6 Hz), 3.47 (dd, 1H, 2J 17.0 and 3J 9.6 Hz), 3.79 (s, 3H,
OMe), 4.67 (dd,1H, 3J 9.6 and 4.6 Hz), 5.88 (s,1H, 8-H), 6.83 (d, 2H, 3J
8.7 Hz, Ar), 7.29 (d, 2H, 3J 8.7 Hz, Ar). 13C NMR (125.7 MHz, CDCl3):
dC 20.1, 35.5, 36.6, 55.6, 101.8, 105.1, 114.0, 129.2, 133.2, 158.6, 161.3,
165.3, 166.3, 175.6. MS (EI, 70 eV) m/z: 286 (Mþ, 12), 279 (14), 258
(100), 243 (30), 207 (44), 165 (46), 149 (79), 134 (54), 43 (94). Anal.
Calcd for C16H14O5 (286.28): C, 67.13; H, 4.93%. Found: C, 67.20; H,
5.06%.
4.2.7. 2,3,4,5-Tetrahydro-4,7-dimethyl-2,5-dioxopyrano[4,3-b]pyran-
3-carboxylic acid (7a). White powder (0.195 g, 82%). Mp 130e132 C.
IR (KBr): mp 126e128 C. IR (KBr): 3100, 2995, 2600 (broad and
strong), 1720 (C]O), 1635, 1580, 1540, 1300, 1250 cmꢁ1 1H NMR
(500.1 MHz, DMSO-d6): dH 0.82 (t, 3H, 3J 7.2 Hz,10-CH3), 2.14 (s, 3H, 7-
CH3), 3.52 (dt,1H, 3J 8.9 and 3J 5.7 Hz, 4-H), 4.14 (d,1H, 3J 8.9 Hz, 3-H),
5.96 (s,1H, 8-H),11.46 (s,1H, CO2H).13C NMR (125.7 MHz, DMSO-d6):
dC 14.7, 20.0, 29.0, 48.0, 100.7, 105.7, 161.6, 164.6, 165.1, 165.9, 166.9.
MS (EI, 70 eV) m/z: 238 (Mþ, 40), 230 (20), 222 (22), 179 (85), 153
4.2.2. 4-(2-Chlorophenyl)-7-methyl-3,4-dihydro-pyrano[4,3-b]py-
ran-2,5-dione (4b). White powder (0.275 g, 95%). Mp 228e230 oC. IR
(KBr): 3010, 1700 (C]O), 1590, 1100 cmꢁ1 1H NMR (500.1 MHz,
DMSO-d6): dH 2.29 (s, 3H, 7-CH3), 2.76 (dd,1H, J 16.0,1.8 Hz), 3.53 (dd,
1H, 2J 16.0 and 3J 8.2 Hz), 4.58 (br d,1H, J 6.8 Hz), 6.47 (s,1H, 8-H), 6.96
(dd,1H, 3J 7.6 and 4J 1.7 Hz, Ar), 7.27 (dt,1H, 3J 7.5 and 4J 1.3 Hz, Ar), 7.32
(dt,1H, 3J 7.5 and 4J 1.7 Hz, Ar), 7.52 (dd,1H, 3J 7.8 and 4J 1.3 Hz, Ar).13
C

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K. Rad-Moghadam et al. / Tetrahedron 68 (2012) 6472e6476
(31), 121 (68), 95 (50), 69 (67), 43 (100). Anal. Calcd for C11H10O6
(238.19): C, 55.47; H, 4.23%. Found: C, 55.35; H, 4.39%.
(39), 69 (60), 53 (34), 43 (100). Anal. Calcd for C14H16O6 (280.27): C,
59.99; H, 5.75%. Found: C, 60.12; H, 5.63%.
4.2.8. 4-Ethyl-2,3,4,5-tetrahydro-7-methyl-2,5-dioxo-pyrano[4,3-b]
pyran-3-carboxylic acid (7b). White powder (0.201 g, 80%). Mp
128e130 ꢂC. IR (KBr): 3000, 2980, 2600 (broad and strong), 1790,
1740 (C]O), 1620, 1540, 1400, 1350 cmꢁ1 1H NMR (500.1 MHz,
DMSO-d6): dH 0.82 (t, 3H, 3J 7.2 Hz, 20-CH3), 1.75e1.81 (m, 1H, 10-HB),
1.88e1.91 (m, 1H, 10-HA), 2.14 (s, 3H, 7-CH3), 3.48 (dt, 1H, 3J 8.9 and
5.7 Hz, 4-H), 4.14 (d,1H, 3J 8.9 Hz, 3-H), 5.96 (s, 1H, 8-H), 11.46 (s,1H,
CO2H). 13C NMR (125.7 MHz, DMSO-d6): dC 14.7, 20.0, 22.8, 36.0,
48.0,100.8,105.7,161.6,164.6,165.0,166.0,166.8. MS (EI, 70 eV) m/z:
252 (Mþ, 50), 237 (22), 222 (23), 205 (43), 179 (84), 154 (29),
123(59), 94 (50), 69 (43), 43 (100). Anal. Calcd for C12H12O6
(252.22): C, 57.14; H, 4.80%. Found: C, 57.28; H, 4.93%.
Acknowledgements
We gratefully acknowledge the financial support from the Re-
search Council of University of Guilan.
References and notes
1. Ciblat, S.; Kim, J.; Stewart, C. A.; Wang, J.; Forgione, P.; Clyne, D.; Paquette, L. A.
Org. Lett. 2007, 9, 719.
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Savage, R. E.; Chan, T. C. K.; Ashwell, M. A. Bioorg. Med. Chem. 2008, 16, 5635.
3. Tietze, L. F. Angew. Chem., Int. Ed. Engl. 1983, 22, 828.
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dutta, A. K. J. Med. Chem. 2006, 49, 4239.
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8. Perez-Sacau, E.; Diaz-penate, R. G.; Estevez-Braun, A.; Ravelo, A. G.; Garcia-
Castellano, J. M.; Pardo, L.; Campillo, M. J. Med. Chem. 2007, 50, 696.
9. Obata, R.; Sunazuka, T.; Zhuorong, L.; Tomoda, H.; Omura, S. J. Antibiot.1995, 48, 749.
10. Tomoda, H.; Kim, Y. K.; Nishida, H.; Masuma, R.; Omura, S. J. Antibiot. 1994, 47, 148.
11. Handa, M.; Sunazuka, T.; Nagai, K.; Kimura, R.; Shirahata, T.; Tian, Z.-M.; Oto-
guro, K.; Harigaya, Y.; Omura, S. J. Antibiot. 2001, 54, 382.
12. Lee, Y. G.; Lee, W. M.; Kim, J. Y.; Lee, J. Y.; Lee, I. K.; Yun, B.-S.; Rhee, M. H.; Cho, J.
Y. Br. J. Pharmacol. 2008, 154, 852.
4.2.9. 4-Propyl-2,3,4,5-tetrahydro-7-methyl-2,5-dioxo-pyrano[4,3-b]
pyran-3-carboxylic acid (7c). White powder (0.223 g, 84%). Mp
130e132 ꢂC. IR (KBr): 3097, 2940, 2600 (broad and strong), 1780.
1740 (C]O), 1656 (C]O), 1545, 1403, 1336 cmꢁ1 1H NMR
(500.1 MHz, DMSO-d6): dH 0.82 (t, 3H, 3J 7.2 Hz, 30-CH3),
1.12e1.21 (m, 2H, 20-H), 1.67e1.75 (m, 1H, 10-HB), 1.87e1.90 (m,
1H, 10-HA), 2.14 (s, 3H, 7-CH3), 3.51 (dt, 1H, 3J 8.9 and 5.7 Hz, 4-
H), 4.14 (d, 1H, 3J 8.9 Hz, 3-H), 5.96 (s, 1H, 8-H), 11.46 (s, 1H,
CO2H). 13C NMR (125.7 MHz, DMSO-d6): dC 14.7, 20.0, 28.4, 29.0,
35.7, 48.1, 100.7, 105.7, 161.6, 164.6, 165.1, 166.0, 166.9. MS (EI,
70 eV) m/z: 263 (Mþꢁ3, 13), 240 (4), 222 (22), 205 (13), 179
(80), 165 (8), 152 (27), 122 (74), 94 (36), 68 (43), 43 (100). Anal.
Calcd for C13H14O6 (266.25): C, 58.64; H, 5.30%. Found: C, 58.75;
H, 5.23%.
13. Merlini, L.; Nasini, G.; Scaglioni, L.; Cassinelli, G.; Lanzi, C. Phytochemistry 2000,
53, 1039.
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Kuwajima, I.; Ohmura, S. Org. Lett. 2002, 4, 367.
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4.2.10. 4-Butyl-2,3,4,5-tetrahydro-7-methyl-2,5-dioxo-pyrano[4,3-b]
pyran-3-carboxylic acid (7d). White powder (0.238 g, 85%). Mp
128e130 ꢂC. IR (KBr): 3100, 2992, 2610 (broad and strong), 1782,
1741 (C]O), 1660 (C]O), 1610, 1542, 1410, 1328 cmꢁ1 1H NMR
3
(500.1 MHz, DMSO-d6): dH 0.81 (t, 3H, J 7.0 Hz, 30-CH3), 1.13e1.30
(m, 4H, 2CH2), 1.75e1.81 (m, 1H, 10-HB), 1.87e1.95 (m, 1H, 10-HA),
2.14 (s, 3H, 7-CH3), 3.49 (dt, 1H, 3J 9.0 and 5.7 Hz, 4-H), 4.14 (d, 1H, 3J
9.0 Hz, 3-H), 5.95 (s, 1H, Ar), 11.46 (s, 1H, CO2H). 13C NMR
(125.7 MHz, DMSO-d6): dC 14.7, 20.0, 28.4, 29.0, 30.0, 35.9, 48.1,
100.7, 105.7, 161.6, 164.6, 165.0, 166.0, 166.9. MS (EI, 70 eV) m/z: 280
(Mþ, 2), 237 (18), 223 (57), 205 (43), 179 (91), 137 (57), 108 (41), 98