A One-Pot Diastereoselective Synthesis of 2-[Aryl(hydroxy)methyl]-6-methyl-2 H -furo[3,2- c ]pyran-3,4-diones: Crystallographic Evidence for the Furanone Ring Closure

Article abstract of DOI:10.1055/s-0034-1380214

Novel furopyran-3,4-dione-fused heterocycles have been obtained by a one-pot reaction of α-brominated dehydroacetic acid and benzaldehydes under organobase conditions. The prepared 2-[aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-diones were fully

Full text of DOI:10.1055/s-0034-1380214

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1749–1754
letter
1749
Y. Abdi et al.
Letter
Synlett
A One-Pot Diastereoselective Synthesis of 2-[Aryl(hydroxy)-
methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-diones: Crystallo-
graphic Evidence for the Furanone Ring Closure
Yamina Abdia,b
Baya Boutemeur-Kheddis*a
Maamar Hamdia
Oualid Talhic,d
Filipe A. Almeida Paze
Gilbert Kirschf
Artur M. S. Silva*c
a Laboratoire de Chimie Organique Appliquée (Groupe Hétérocycles),
Faculté de Chimie, Université des Sciences et de la Technologie
Houari Boumediène BP 32, El-Alia Bab-Ezzouar, 16111, Alger,
Algeria
kheddis.2012@gmail.com
b Ecole Préparatoire Sciences et Techniques (EPST), BP 474, Place des Martyres, 16000, Alger, Algeria
c QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
artur.silva@ua.pt
d Centre de Recherche Scientifique et Technique en Analyses Physico-Chimiques CRAPC, BP 384, Bou-Ismail, 42004, Tipaza, Algeria
e CICECO Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
f
Laboratoire Structure et Réactivité des Systèmes Moléculaires Complexes, UMR 7565, Université de Lorraine, Avenue du Général Delestraint, 57070 Metz, France
Received: 14.03.3015
Accepted after revision: 21.04.2015
Published online: 21.05.2015
DOI: 10.1055/s-0034-1380214; Art ID: st-2015-d0185-l
R2
O
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Abstract Novel furopyran-3,4-dione-fused heterocycles have been
obtained by a one-pot reaction of α-brominated dehydroacetic acid
and benzaldehydes under organobase conditions. The prepared 2-
[aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-diones were
fully characterized by 2D NMR spectroscopy and supported by single-
crystal X-ray analysis to unequivocally prove the furan-3-one five-mem-
bered ring-closure mechanism instead of the dihydroflavanon-3-ol six-
membered cyclization which has recently been proposed in the litera-
ture.
O
Figure 1 Aurone general structure
Pyran-2-ones, six-membered lactones, constitute a
large family of biologically active natural products mainly
encountered in animals, insects, plants, and microbial sys-
tems.2 Simple chemical modification of the substitution
pattern in the pyran-2-one ring has often led to diverse bio-
logical properties, for instance, 4-hydroxypyran-2-ones
constitute an important class of anti-HIV agents and also
exhibit antifungal, phytotoxic, antimicrobial, cytotoxic, and
neurotoxic activities.6
Aiming at the preparation of aurone mimics, we recent-
ly reported the covalent combination of furan-3-one and
pyran-2-one into a fused dyad. The route relies on the treat-
ment of 3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-
one with aliphatic primary amines in ethanol, leading to
the formation of a single product 6-methyl-2H-furo[3,2-
c]pyran-3,4-dione. Under acidic conditions, this compound
undergoes classical Knoevenagel condensation of the furan-
3-one ring (through its active methylene group) with benz-
aldehydes to yield 2-arylidene-6-methyl-2H-furo[3,2-
c]pyran-3,4-diones.7a,b The synthesis of these aurone-type
compounds has also been initiated by heating dehydroace-
tic acid (DHA = 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-
one) in the presence of several aliphatic and aromatic
Keywords furan-3-ones, pyran-2-ones, dehydroacetic acid, synthesis,
organobase, 2D NMRspectroscopy, single-crystal X-ray diffraction
Furan-3-ones and pyran-2-ones are important oxygen
heterocycles which are mostly present in the structure of a
variety of biologically active natural compounds.1,2 Such
substances sharing five- or six-membered ring systems
have deserved considerable attention in organic chemistry
due to their structural simplicity and low-molecular weight
advantages, being readily accessible by several synthetic
routes.3,4 The furan-3-one ring system is found in aurones
[2-benzylidenebenzofuran-3(2H)-ones, Figure 1] which are
abundant colored natural flavonoids with outstanding
therapeutic potential.5a Furan-3-one-containing molecules
continue to attract interest, and we have recently reported
some valuable anticancer and photosensitive templates,
namely the [benzopyran-(2 or 4)-one/benzofuran-3-one]5b
and [benzofuran-3-one/hydantoin]5c,d conjugate dyads.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1749–1754

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amines.7g DHA and its brominated derivatives have shown a
wide synthetic potential, being readily converted into inter-
esting heterocyclic systems (e.g., pyrazoles, 1,2-benzothia-
zepines, benzodiazepines, and pyrimidines) through their
condensation with a variety of bisnucleophiles.8
Following our interest in the use of DHA (1) as a syn-
thetic precursor of pyran-2-ones, we focused our efforts on
its selective α-monobromination to afford 3-(bromoace-
tyl)-4-hydroxy-6-methyl-2H-pyran-2-one (2, acetyl methy-
lene group: δH = 4.71 ppm, δC = 35.2 ppm) in good yield (up
to 61%), by refluxing 1 with one equivalent of bromine in
glacial acetic acid (Scheme 1).9 α-Haloketones are general
and versatile synthons used for the preparation of various
heterocyclic compounds due to their high reactivity and se-
lective chemical transformations.7 Finally, in the context of
this communication, the development of practical and effi-
cient methodologies for the synthesis of substituted fu-
ro[3,2-c]pyran-4-ones is still gaining interest.
Herein we report the diastereoselective synthesis of 2-
[aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-
diones 3 by the condensation of α-brominated DHA 2 with
various benzaldehydes in ethanol at ambient temperature
using an equimolar amount of triethylamine (Scheme 1).
This procedure leads to furo[3,2-c]pyran-3,4-diones 3 in
high yields (87–97%), in short reaction time (15 min).10 Ste-
reochemically, two adjacent asymmetric carbons have been
created in a fused furopyran-3,4-dione heterocyclic scaffold
3 with the potential to generate a pair of diastereomers.
ford 2-[aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]py-
ran-3,4-diones 3 (Scheme 2, pathway a). An alternative
deprotonation can occur at the active methylene of the α-
bromo-DHA 2 creating a carbanion that directly condenses
with the benzaldehyde leading to the intermediates 5. As-
suming a subsequent deprotonation of the 4-OH in the in-
termediates 5, the furan-3-one cyclization can occur by nu-
cleophilic attack on the bromomethyl group, thus affording
3 (Scheme 2, pathway b). Recent reports have shown that
the condensation between similar α-halocarbonyl com-
pounds 2 and carbonyl compounds (such as benzaldehydes)
in basic medium is a useful synthetic route to access α,β-
epoxycarbonyl derivatives.11 In this way, the formation of
the epoxides 6 is expected through deprotonation of β-OH
in 5 and subsequent nucleophilic substitution of the α-bro-
mo substituent. Such epoxide derivatives 6 are known to be
versatile synthetic intermediates that can be converted into
a wide range of multifunctional heterocyclic scaffolds.
Thus, the presence of a free 4-hydroxyl group on the pyran-
2-one makes α,β-epoxycarbonyl 6 capable of undergoing
intramolecular heterocyclization to give, either the five-
membered furan-3-one ring 3 via nucleophilic attack on
the α-carbon (Scheme 2, pathway c), or six-membered di-
hydroflavanon-3-ols 7 through ring closure at the β-carbon
(Scheme 2, pathway d). Recent literature data disclose that
dihydroflavanon-3-ols are preferably formed following
condensation reaction of α-halocarbonyl compounds with
benzaldehydes under basic conditions.12 The Wheeler reac-
tion, usually employed for the synthesis of aurones, has also
been adapted to access dihydroflavanon-3-ols via opening
of 2′-hydroxychalcone α,β-epoxides at the β-carbon.12a Sev-
eral authors have provided evidence that dihydroflavonols
are selectively obtained from 2′-hydroxychalcone α,β-epox-
ides using different catalysts rather than 2-[aryl(hy-
droxy)methyl] benzofuran-3-ones, but this conclusion was
R
3"
OH
O
OH
O
Br
2"
(ii)
1'
(i)
O
2
O
O
O
O
CHO
O
H
8
O
1
2 (61%)
3
1
only supported by H NMR and 13C NMR data.12b,c The dif-
R
6
O
O
4
ferentiation between a dihydroflavanon-3-ol 7 and a 2-
[aryl(hydroxy)methyl]benzofuran-3-one 3 using 1H NMR
and 13C NMR assignments is not trivial because other stud-
ies suggest that both α- or β-cyclizations of α,β-epoxycar-
bonyl substrates may take place in the presence of a free
hydroxyl group (such as in 2′-hydroxychalcone α,β-epox-
ides). Moreover, this is strongly dependent on the nature of
the catalyst.12d
a R = H; b R = 3"-NO2; c R = 2"-OH
d R = 3"-OH; e R = 4"-Cl; f R = 2"-Me
g R = 4"-OMe; h R = 3"-Br; i R = 4"-Br
j R = 4"-F
3a–j (87–97%)
Scheme 1 Synthesis of 2-[aryl(hydroxy)methyl)-6-methyl-2H-fu-
ro[3,2-c]pyran-3,4-diones 3a–j. Reagents and conditions: (i) Br2, glacial
acetic acid, reflux 60 °C; (ii) Et3N (1 equiv), EtOH, r.t.
A detailed analysis of proton acidity of the α-bromo-
DHA 2 in basic medium (such as Et3N) suggests two possi-
ble deprotonation sites leading to quiet different intermedi-
ates that could be involved in the reaction with the benzal-
dehyde (Scheme 2). A plausible reaction mechanism for the
synthesis of compounds 3 can be drawn via initial depro-
tonation at the 4-hydroxyl group which may drive the α-
bromo-DHA 2 to a furan-3-one ring closure via nucleophilic
attack on the bromomethyl group, affording 4 as previously
noted.7a,b Compound 4 can undergo in situ condensation
with the benzaldehyde under organobase conditions to af-
To overcome the potential for structural ambiguity be-
tween such five- and six-membered heterocycles, we stud-
ied the structure of products 3 in detail based on their 2D
NMR spectra (HSQC, HMBC, and NOESY). In the 1H NMR
spectra H-2 and H-1′ appear at δH = 5.07–5.38 ppm as dou-
blets (J = 0.5–1.6 Hz) and doublets of doublets; these as-
signments being confirmed by their HSQC correlations with
two different carbons at δC = ca. 70 and ca. 90 ppm, respec-
tively. The doublet assigned to 1′-OH (δH = 5.76–6.68 ppm,
J = 3.7–6.4 Hz) does not show any HSQC connectivity. Be-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1749–1754

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a
base
O
R
strong
weak
R
O
b
1'
H
O
H
1'
O
2
a
O
H
O
a
OH
O
O
Br
H
O
3
Br
b
H
H
b
2
H
O
8a
8
b
H
H
O
R
3
4
O
O
a
OH
base
R
2
O
H3C
O
O
H3C
O
O
a
5
Figure 2 Comparison between the experimental HMBC correlations
observed in the synthesized furopyrandiones 3 and the predicted
HMBC connectivities which would be present in the proposed dihydro-
flavanon-3-ols 7
base
H
d
O
c
a
O
OH
O
O
O
H
b
R
R
O
O
O
R
2''
R
2'
O
d
4
6
H
a
H
O
H
O
H
O
1'
c
H
O
2
H
H
3
2
R
H
O
O
R
O
H3C
O
O
H3C
O
O
O
O
H
O
H
Figure 3 Comparison between the experimental NOE effects ob-
served in the synthesized furopyrandiones 3 and the predicted NOE
cross-couplings that could be present in the proposed dihydroflavanon-
3-ols 7
O
O
3
O
O
7
O
O
Scheme 2 Possible mechanistic pathways for the formation of furopy-
ran-3,4-diones 3 and/or dihydroflavanon-3-ols 7
Single-crystal X-ray diffraction was performed in order
to describe the 3D structure of the furopyran-3,4-diones 3
unambiguously. Good-quality crystals of compound 3a
were isolated from a 5:2 mixture of hexane–ethanol by a
slow evaporation at 6 °C. X-ray diffraction studies revealed
structure 3a, which is in a complete agreement with the 2D
NMR studies (Figure 4). Two asymmetric carbon atoms (C8
and C9 crystallographic numbering, Figure 4) are clearly
observed in the crystal structure. Because 3a crystallizes in
centrosymmetric P1 triclinic space groups, the unit cell
contains the mirror image of the organic molecule depicted
in Figure 3, leading to a solid-state racemic mixture of two
possible enantiomers [(2R,1′S) and (2S,1′R)]. In this context,
we can conclude that this protocol represents a diastereose-
lective synthetic approach towards furopyran-3,4-diones 3.
In conclusion, we have described a simple and efficient
diastereoselective route towards 2-[aryl(hydroxy)methyl]-
6-methyl-2H-furo[3,2-c]pyran-3,4-diones via condensation
of α-bromo-DHA with a variety of benzaldehydes using or-
ganobase catalysis. This reaction could follow different
mechanistic pathways where the most likely one is the for-
mation of an α,β-epoxycarbonyl intermediate that under-
goes preferential α-cyclization to afford a fused furo[3,2-
c]pyran-3,4-dione. 2D NMR spectroscopic studies were
used for tentative differentiation between the furan-3-one
and the largely reported dihydroflavanon-3-ol ring closure.
However, due to the high structural similarity between
sides the exact determination of the C2–C1′ bond, the key
13C NMR resonances of 3a–j present characteristic signals
assigned by HMBC experiments (Figure 2 and Figures S16,
S17 in Supporting Information for compound 3g), namely
C-1′′ (δC = 127.4–143.7 ppm), C-8 (δC = 188.2–188.4 ppm),
and C-3 (δC = 192.2–193.3 ppm), respectively. We also ob-
served weak HMBC connectivities between the 1′-OH and
C-1′′, making us less confident of such structural interpre-
tation because the expected HMBC correlations of the dihy-
droflavanon-3-ols 7 are similar to those observed in furo-
pyrandiones 3 (Figure 2). For this reason, the 2D NMR study
of compounds 3 was extended to NOESY experiments that
were helpful in suggesting the stereochemical arrangement
of the whole scaffold 3. Notable NOE enhancements were
observed between H-2 and H-1′; H-1′ and 1′-OH; 1′-OH and
H-2′′ and of H-1′ with H-2′′,6′′ (Figure 3 and Figure S18 in
Supporting Information for compound 3g). Likewise, the
expected NOE effects in the dihydroflavanon-3-ols 7 have
led us to the same conclusions as summarized in Figure 3.
The 2D NMR spectral determination is important and ex-
tremely useful in most of the cases, particularly for compli-
cated structural elucidation procedures. However, a rare
similarity was found between the isomeric compounds fu-
ropyrandiones 3 and dihydroflavanon-3-ols 7, ultimately
leading to inconclusive results.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1749–1754

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PT2020 Partnership Agreement, for funding the purchase of the sin-
gle-crystal X-ray diffractometer.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380214.
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References and Notes
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Figure 4 Schematic representation of the molecular unit present in
the asymmetric unit of compound 3a. Atoms C8 and C9 correspond to
stereocenters. Nonhydrogen atoms are represented as thermal ellip-
soids drawn at the 50% probability level and hydrogen atoms as small
spheres with arbitrary radii. The half-occupied water molecule present
in the asymmetric unit of 3a and the second position for the hydrogen
atom bound to O5 have been omitted for clarity.
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these scaffolds, results were not wholly conclusive. Howev-
er, single-crystal X-ray diffraction study was decisive in the
elucidation of the diastereoselective synthetic pathway to-
ward 2-[aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]py-
ran-3,4-diones. We believe that this result may lead to the
revision of many previously reported β-hydroxyfuran-3-
one and 3-hydroxypyran-4-one structures synthesized
from α,β-epoxycarbonyls, for which only 2D NMR spectro-
scopic analysis was used.
(6) (a) Singh, K.; Sharma, P. K. Int. J. Pharm. Pharm. Sci. 2014, 6, 345.
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Acknowledgment
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R. Russian J. Gen. Chem. 2012, 82, 1464. (e) Penta, S.; Gadidasu,
K. K.; Basavoju, S.; Rao, V. R. Tetrahedron Lett. 2013, 54, 5663.
(f) Penta, S.; Rao, V. R. J. Sulfur Chem. 2011, 32, 327. (g) Stephen,
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Abbassi, M.; Essassi, E. M.; Fifani, J. Tetrahedron Lett. 1987, 28,
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Thanks are due to the University of Aveiro, Fundação para a Ciência e
a Tecnologia (FCT, Portugal), EU, QREN, FEDER, COMPETE, for funding
the
Organic
Chemistry
Research
Unit
(project
PEst-
C/QUI/UI0062/2013), and the Portuguese National NMR Network
(RNRMN). We would like to thank the General Directorate for Scien-
tific Research and Technological Development-DGRSDT of Algeria for
the financial support. O. Talhi also thanks the project New Strategies
Applied to Neuropathological Disorders (CENTRO-07-ST24-FEDER-
002034), co-funded by QREN, ‘Mais Centro-Programa Operacional
Regional do Centro’ and EU, FEDER for his postdoctoral position. We
further wish to thank CICECO Aveiro Institute of Materials (Ref. FCT
UID /CTM /50011/2013), financed by national funds through the
FCT/MEC, and when applicable co-financed by FEDER under the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1749–1754

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Pecher, J. Synth. Commun. 1990, 20, 1579. (f) Rachedi, Y.; Hamdi,
M.; Sakellariou, R.; Speziale, V. Synth. Commun. 1991, 21, 1189.
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Tetrahedron 1993, 49, 1701. (h) Bendaas, A.; Hamdi, M.; Sellier,
N. J. Heterocycl. Chem. 1999, 36, 1291. (i) Boutemeur-Kheddis,
B.; Hamdi, M.; Sellier, N.; Silva, A. M. S. J. Heterocycl. Chem. 2001,
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Duval, O.; Helesbeux, J. J. J. Heterocycl. Chem. 2009, 46, 18.
(9) Synthesis of 3-Bromoacetyl-4-hydroxy-6-methyl-2H-pyran-
2-one (2)
(d, J = 7.8 Hz, 1 H, H-6′′) 8.19 (dd, J = 1.7, 7.9 Hz, 1 H, H-4′′), 8.36
(d, J = 1.7 Hz, 1 H, H-2′′) ppm. 13C NMR (75.47 MHz, DMSO-d6): δ
= 20.7 (6-CH3), 69.8 (C-1′), 90.7 (C-2), 96.7 (C-7), 99.7 (C-9),
121.1 (C-2′′), 122.5 (C-4′′), 129.7 (C-5′′), 133.1 (C-6′′), 143.4 (C-
1′′), 147.7 (C-3′′), 155.4 (C-4), 174.3 (C-6), 188.2 (C-8), 192.2 (C-
3) ppm. ESI+-HRMS: m/z calcd for [C15H11NO7 + Na]+: 340.0433;
found: 340.0439.
2-[Hydroxy(2-hydroxyphenyl)methyl]-6-methyl-2H-
furo[3,2-c]pyran-3,4-dione (3c)
C
15H12O6 (grey solid, MW = 288.25 g/mol, 0.27 g, 94%; mp
A solution of bromine (0.27 mL, 5 mmol) in AcOH (10 mL) was
added portionwise to a solution of DHA (1, 0.84 g, 5 mmol) in
AcOH (20 mL). After heating to reflux for 2 h, the reaction
mixture was poured into H2O (100 mL) and ice (50 g). The solid
obtained was filtered off and recrystallized from a 1:1 mixture
of hexane–CHCl3 to afford compound 2.
185 °C). 1H NMR (300.13 MHz, DMSO-d6): δ = 2.34 (s, 3 H, 6-
CH3), 5.11 (d, J = 1.5 Hz, 1 H, H-2), 5.38 (dd, J = 1.5, 4.8 Hz, 1 H,
H-1′), 5.76 (d, J = 4.8 Hz, 1 H, 1′-OH), 6.66 (s, 1 H, H-7), 6.81–
6.88 (m, 2 H, H-3′′, H-5′′), 7.09–7.17 (m, 1 H, H-4′′), 7.40 (dd, J =
7.7, 1.1 Hz, 1 H, H-6′′), 9.81 (s, 1 H, 2′′-OH) ppm. 13C NMR (75.47
MHz, DMSO-d6): δ = 20.7 (6-CH3), 66.2 (C-1′), 89.8 (C-2), 96.8
(C-7), 99.8 (C-9), 114.6 (C-3′′), 118.8 (C-5′′), 126.9 (C-6′′), 127.4
(C-1′′), 128.2 (C-4′′), 153.2 (C-2′′), 155.5 (C-4), 173.9 (C-6), 188.4
Analytical Data for Compd 2
C8H7BrO4 (yellow crystals, MW = 247.04 g/mol, 0.75 g, 61%; mp
118–119 °C [111–114 °C]7). 1H NMR (300.13 MHz, CDCl3): δ =
2.31 (s, 3 H, 6-CH3), 4.71 (s, 2 H, CH2Br), 6.03 (s, 1 H, H-5), 15.51
(s, 1 H, OH) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 20.8 (6-CH3),
35.2 (CH2Br), 99.4 (C-3), 101.3 (C-5), 160.6 (C-6), 170.1 (C-2),
180.9 (C-4), 197.2 (C-3) ppm. ESI+-MS: m/z = 271 (81Br, 18) [M +
Na]+, 269 (79Br, 20) [M + Na]+, 249 (81Br, 90) [M + H]+, 247 (79Br,
95) [M + H]+, 167 (100) [M – Br]+. Anal. Calcd (%) for C8H7BrO4:
C, 38.89; H, 2.86. Found: C, 39.10; H, 2.80.
(C-8), 193.3 (C-3) ppm. ESI+-HRMS: m/z calcd for [C15H12O6
+
Na]+: 311.0532; found: 311.0541.
2-[Hydroxy(3-hydroxyphenyl)methyl]-6-methyl-2H-
furo[3,2-c]pyran-3,4-dione (3d)
C
15H12O6 (pale violet solid, MW = 288.25 g/mol, 0.26 g, 90%; mp
205–206 °C). 1H NMR (300.13 MHz, DMSO-d6): δ = 2.35 (s, 3 H,
6-CH3), 5.07 (dd, J = 1.3, 5.4 Hz, 1 H, H-1′), 5.15 (d, J = 1.3 Hz, 1 H,
H-2), 5.91 (d, J = 5.4 Hz, 1 H, 1′-OH), 6.68 (s, 1 H, H-7), 6.70–6.71
(m, 1 H, H-4′′), 6.87–6.90 (m, 2 H, H-2′′, H-6′′), 7.13–7.19 (m, 1
H, H-5′′), 9.41 (s, 1 H, 3′′-OH) ppm. 13C NMR (75.47 MHz, DMSO-
d6): δ = 20.7 (6-CH3), 70.8 (C-1′), 91.5 (C-2), 96.7 (C-7), 99.7 (C-
9), 113.3 (C-2′′), 114.3 (C-4′′), 116.7 (C-6′′), 129.1 (C-5′′), 142.5
(C-1′′), 155.4 (C-3′′), 157.2 (C-4), 174.1 (C-6), 188.3 (C-8), 192.9
(10) Synthesis of 2-[Aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-
c]pyran-3,4-diones 3a–j
A suspension of the appropriate benzaldehyde (1 mmol), 3-
(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (2, 0.25 g,
1 mmol), and Et3N (0.2 mL, 1.5 mmol) was stirred in EtOH (3
mL) at ambient temperature for 15 min. The powder formed
was collected by filtration, washed with H2O and then allowed
to dry. The crude compounds thus obtained were recrystallized
from EtOH to give pure compounds 3a–j.
(C-3) ppm. ESI+-HRMS: m/z calcd for [C15H12O6
+
Na]+:
311.0532; found: 311.0535.
2-[Hydroxy(4-chlorophenyl)methyl]-6-methyl-2H-furo[3,2-
c]pyran-3,4-dione (3e)
Representative Analytical Data
2-[Hydroxy(phenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-
3,4-dione (3a)
C15H11ClO5 (pale yellow solid, MW = 306.69 g/mol, 0.28 g, 91%;
mp 268 °C). 1H NMR (300.13 MHz, DMSO-d6): δ = 2.34 (s, 3 H, 6-
CH3), 5.17–5.20 (m, 2 H, H-1′, H-2), 6.10 (d, J = 5.5 Hz, 1 H, 1′-
OH), 6.67 (s, 1 H, H-7), 7.44 and 7.52 (2 d, J = 8.5 Hz, 2 × 2 H, H-
2′′,3′′, H-5′′,6′′) ppm. 13C NMR (75.47 MHz, DMSO-d6): δ = 20.7
(6-CH3), 70.2 (C-1′), 91.1 (C-2), 96.7 (C-7), 99.8 (C-9), 128.1 and
128.2 (C-2′′,3′′ and C-5′′,6′′), 132.1 (C-4′′), 140.0 (C-1′′), 155.4 (C-
4), 174.2 (C-6), 188.3 (C-8), 192.6 (C-3) ppm. ESI+-HRMS: m/z
calcd for [C15H11ClO5 + Na]+: 329.0193; found: 329.0192.
2-[Hydroxy(o-tolyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-
3,4-dione (3f)
C15H12O5 (violet solid, MW = 272.26 g/mol, 0.25 g, 92%; mp
160 °C). 1H NMR (300.13 MHz, DMSO-d6): δ = 2.34 (s, 3 H, 6-
CH3), 5.16 (dd, J = 1.5, 3.7 Hz, 1 H, H-1′), 5.20 (d, J = 1.5 Hz, 1 H,
H-2), 5.99 (d, J = 3.7 Hz, 1 H, 1′-OH), 6.69 (s, 1 H, H-7), 7.20–7.41
(m, 5 H, H-2′′3 ′′,4′′,5′′,6′′) ppm. 13C NMR (75.47 MHz, DMSO-d6):
δ = 20.7 (6-CH3), 70.9 (C-1′), 91.4 (C-2), 96.8 (C-7), 99.7 (C-9),
126.2 (C-2′′,6′′), 127.4 (C-4′′), 128.0 (C-3′′,5′′), 140.9 (C-1′′),
155.4 (C-4), 174.1 (C-6), 188.3 (C-8), 192.8 (C-3) ppm. ESI+-
HRMS: m/z calcd for [C15H12O5
295.0588.
Crystal Data for Compound 3a
+
Na]+: 295.0582; found:
C16H14O5 (red violet solid, MW = 286.27 g/mol, 0.25 g, 87%; mp
207 °C). 1H NMR (300.13 MHz, DMSO-d6): δ = 2.35 and 2.36 (2 s,
6 H, 2′′-CH3, 6-CH3), 5.12 (d, J = 1.0 Hz, 1 H, H-2), 5.33 (dd, J =
1.0, 5.3 Hz, 1 H, H-1′), 5.87 (d, J = 5.3 Hz, 1 H, 1′-OH), 6.72 (s, 1 H,
H-7), 7.16–7.30 (m, 3 H, H-3′′, H-4′′, H-5′′), 77.56 (dd, J = 7.5, 5.3
Hz, 1 H, H-6′′) ppm. 13C NMR (75.47 MHz, DMSO-d6): δ = 18.5
(2′′-CH3), 20.6 (6-CH3), 67.8 (C-1′), 89.7 (C-2), 96.6 (C-7), 99.6
(C-9), 125.5 (C-5′′), 126.9 (C-6′′), 127.2 (C-3′′), 130.0 (C-4′′),
133.7 (C-2′′), 138.6 (C-1′′), 155.3 (C-4), 174.1 (C-6), 188.3 (C-8),
192.9 (C-3) ppm. ESI+-HRMS: m/z calcd for [C16H14O5 + Na]+:
309.0793; found: 309.0777.
(C15H12O5)2·H2O, M = 562.51, triclinic, space group P1, Z = 1,
a = 7.1249(5) Å, b = 8.0504(6) Å, c = 12.2442(10) Å,
α = 107.237(4)°, β = 96.608(5)°, γ = 102.845(4)°, V = 641.51(9)
Å3, μ(Mo-Kα) = 0.112 mm–1, Dc = 1.456 g cm–3, red block, crystal
size of 0.20 × 0.12 × 0.10 mm3. Of a total of 4402 reflections col-
lected, 2331 were independent (Rint = 0.0292). Final R1 = 0.0391
[I > 2σ(I)] and wR2 = 0.0966 (all data). Data completeness to
θ = 25.24°, 98.8%; CCDC 1050452.
2-[Hydroxy(3-nitrophenyl)methyl]-6-methyl-2H-furo[3,2-
c]pyran-3,4-dione (3b)
2-[Hydroxy(4-methoxyphenyl)methyl]-6-methyl-2H-
furo[3,2-c]pyran-3,4-dione (3g)
C
15H11NO7 (pale violet solid, MW = 317.25 g/mol, 0.29 g, 91%;
C16H14O6 (pale brown solid, MW = 302.27 g/mol, 0.27 g, 89%; mp
mp 208 °C). 1H NMR (??? MHz, DMSO-d6): δ = 2.35 (s, 3 H, 6-
CH3), 5.35–5.36 (m, 2 H, H-1′, H-2), 6.37 (d, J = 6.4 Hz, 1 H, 1′-
OH), 6.70 (s, 1 H, H-7), 7.69 (dd, J = 7.8, 7.9 Hz, 1 H, H-5′′), 7.98
195 °C). 1H NMR (300.13 MHz, DMSO-d6): δ = 2.35 (s, 3 H, 6-
CH3), 3.76 (s, 3 H, 4′′-OCH3), 5.11 (dd, J = 1.5, 5.2 Hz, 1 H, H-1′),
5.13 (d, J = 1.5 Hz, 1 H, H-2), 5.89 (d, J = 5.2 Hz, 1 H, 1′-OH), 6.89
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1749–1754

1754
Y. Abdi et al.
Letter
Synlett
(s, 1 H, H-7), 6.94 (d, J = 8.7 Hz, 2 H, H-3′′,5′′), 7.39 (d, J = 8.7 Hz,
2 H, H-2′′,6′′) ppm. 13C NMR (75.47 MHz, DMSO-d6): δ = 20.7 (6-
CH3), 55.1 (4′′-OCH3), 70.6 (C-1′), 91.6 (C-2), 96.8 (C-7), 99.8 (C-
9), 113.4 (C-3′′,5′′), 127.5 (C-2′′,6′′), 132.9 (C-1′′), 155.4 (C-4),
158.6 (C-4′′), 174.0 (C-6), 188.2 (C-8), 192.8 (C-3) ppm. ESI+-
(12) (a) Marais, J. P. J.; Ferreira, D.; Slade, D. Phytochemistry 2005, 66,
2145. (b) Rajesh, U. C.; Manohar, S.; Rawat, D. S. Adv. Synth.
Catal. 2013, 355, 3170. (c) Van Rensburg, H.; Van Heerden, P. S.;
Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron 1997, 53,
14141. (d) Patonay, T.; Lévai, A.; Nemes, C.; Timar, T.; Toth, G.;
Adam, W. J. Org. Chem. 1996, 61, 5375. (e) Samir, B. J. Heterocycl.
Chem. 2014, 51, 127.
HRMS: m/z calcd for [C16H14O6
325.0721.
+
Na]+: 325.0688; found:
(11) (a) Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules 2003, 8,
793. (b) Shibata, I.; Yamasaki, H.; Baba, A.; Matsuda, H. Synlett
1990, 490.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1749–1754