Regiodivergent synthesis of trisubstituted furans through Tf 2O-catalyzed Friedel-Crafts acylation: A tool for access to tetrahydrofuran lignan analogues

Article abstract of DOI:10.1039/c1ob06560b

3-or 4-Aroylfurans have been prepared selectively and in high yields from a common precursor by simple tuning of reaction conditions in Friedel-Crafts acylation promoted by triflic anhydride. The formation of products can be explained on the basis of the ring-chain tautomerism occurring in compounds equipped with two neighbouring carboxylic functions. Since 4-aroylfuran derivatives show a typical lignan backbone, suitable hydrogenation conditions were found out to gain tetrahydrofuran lignans. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c1ob06560b

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2012, 10, 1219
www.rsc.org/obc
PAPER
Regiodivergent synthesis of trisubstituted furans through Tf2O-catalyzed
Friedel–Crafts acylation: a tool for access to tetrahydrofuran lignan
analogues†
Daniela Comegna,* Marina DellaGreca,* M. Rosaria Iesce, Lucio Previtera, Armando Zarrelli and
Simona Zuppolini
Received 12th September 2011, Accepted 1st November 2011
DOI: 10.1039/c1ob06560b
3- or 4-Aroylfurans have been prepared selectively and in high yields from a common precursor by
simple tuning of reaction conditions in Friedel–Crafts acylation promoted by triflic anhydride. The
formation of products can be explained on the basis of the ring-chain tautomerism occurring in
compounds equipped with two neighbouring carboxylic functions. Since 4-aroylfuran derivatives show
a typical lignan backbone, suitable hydrogenation conditions were found out to gain tetrahydrofuran
lignans.
FC reaction to a readily accessible furancarboxilic acid, namely
Introduction
3-methoxycarbonyl-2-phenylfuran-4-carboxylic acid (1).17,18
Furans are an intriguing class of heterocycles frequently occurring
The regioselective formation of 4- or 3-aroylderivatives takes
both in pharmaceuticals and in natural compounds endowed with
advantage of a tautomerism evidenced some decades ago that
significant biological activity.1–4 Besides, the versatility of poly-
occurs when a free carboxylic acid is activated in the presence
of a neighbouring ester functionality.19 To the best of our
knowledge this behaviour has never been purposely exploited for
a regiodivergent synthetic approach.
substituted furans makes them very useful intermediates in organic
synthesis.5–7 Establishment of new synthetic methods for their
preparation and elaboration would provide a significant tool with
important implications in pharmacological applications.8–10
In this paper we report a simple and rapid way of accessing
either 3- or 4-aroylfurans starting from a polysubstituted furan
equipped with an acid carboxylic function at C-4 position.
The strategy is based on the Friedel–Crafts (FC) acylation
reaction and the use of trifluoromethylsulfonic anhydride (Tf2O)11
as promoter. Currently, there is a great interest towards FC
acylation with the aim to minimize some drawbacks of the classical
procedure such as the use of acid chlorides and, generally, high
amounts of the metallic oxophilic promoters that cause strongly
acidic conditions.12 New methods involve carboxylic acids as
acylating agents in the presence of Lewis acid or Brønsted acid-
catalysts,13 or using anhydrides as activating agents in combina-
tion with a catalyst such as p-trifluoromethylbenzoic anhydride
The obtained aroylfurans are very interesting intermediates; in
particular, 4-aroyl-2-phenylfurans show a C6C3–C3C6 backbone,
typical of lignans, that are widespread plant secondary metabolites
holding a large series of bioactivities.20,21 For this purpose we at-
tempted the conversion of 1 into an acylating agent of opportunely
substituted aryl compounds to obtain aryl ketones suitable for
subsequent elaboration to lignan scaffolds.
Results and discussion
In initial experiments reported conditions of classical FC
acylation18 were used, performing the reaction with anisole as
the aryl substrate, and acid chloride of 1, prepared by 1 with stoi-
chiometric AlCl3. Under these conditions the formation of a 1 : 1
regioisomeric mixture of both 3- and 4-aroylfuran was observed at
room temperature. Attempts to improve regioselectivity working
at lower temperatures failed because of the very sluggish activation
of the furan reactant. These disappointing results spurred us to
explore different FC conditions reported in the literature. Actually,
direct activation of the 2-phenyl-4-furoic acid 1 was contemplated
and the use of trifluoromethylsulfonic anhydride emerged as the
most promising reagent since it can work within a large range of
temperatures (Table 1).
and SiCl4–AgClO4,14 trifluoroacetic anhydride and H3PO4 or
15
AlPW12O40.16 A recent methodology applied to acetic and benzoic
acids employs trifluoromethylsulfonic anhydride without the use
of a catalyst and works in short times and within a large range of
temperatures.11 We therefore decided to apply this Tf2O-mediated
Dipartimento di Chimica Organica e Biochimica, Universita` Federico II,
Complesso Universitario di Monte S. Angelo, via Cinthia 4, I-80126, Naples,
Italy. E-mail: daniela.comegna@unina.it, dellagre@unina.it; Fax: +39 081
6741393; Tel: +39 081 674162
† Electronic supplementary information (ESI) available: 1D and 2D NMR
spectra. See DOI: 10.1039/c1ob06560b
Data in Table 1 show that the regioisomeric ratio of products
in favour of 4-aroylfuran 3a was remarkably improved on using
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1219–1224 | 1219
©

View Article Online
Table 1 Tf2O-promoted FC-acylation of anisole
Entry
Substrate
Solvent
Tf2O (eq)
T/◦C
Time
Products and yields (%)a
1
2
3
2a
2a
2a
CH2Cl2
Neat
Neat
1.1
1.1
2.5
rt
rt
-30
2 h
2 h
12 h
3a (25), 4a (35), 5 (10)
3a (50), 4a (17), 5 (5)
3a (83), 4a (10), 5 (5)
a Isolated compounds from column chromatography.
anisole as the solvent under neat conditions (compare entry 1
with entries 2 and 3). An especially satisfying result (Table 1,
entry 3) was obtained by performing the reaction at a lower
the furan C-3. When the Friedel–Crafts acylation of anisole was
performed at higher temperature (refluxing dichloromethane) the
corresponding 3-aryl ketone 4a was indeed the main product
(Table 2, entry 1). This result indicated that anhydride 6¢ should be
a more reactive intermediate than the initially generated anhydride
6. This indication allowed us to achieve a further regioselectivity
improvement through a procedural modification based on the
slow addition of anisole to the reaction medium (conditions B),
which actually led to best isomeric ratio in favour of 4a (Table 2,
entry 2 and Table 3, entry 2). The latter method was effective
in reversing the regioselectivity of the acylation even working
at room temperature rather than at refluxing conditions. Both
procedures were then examined on a range of other aromatic
substrates (Table 3). At low temperatures the acylation involved
the starting carboxylated position of 1 to give 4-aroylfurans as
major products (Table 3, odd entries). Under these conditions
a satisfying regioisomeric control was achieved even when neat
conditions could not be used (Table 3, entries 3, 7, and 9).
On the other hand the slow addition of the arene at room
temperature allowed to obtain mainly 3-aroylfurans in all the
cases examined (Table 3, even entries). Dichloromethane was the
solvent of choice for these conditions, although in the case of
1,2-benzodioxole (Table 3, entry 6) and 1,3,5-trimethoxybenzene
(Table 3, entry 8) the best yields were obtained in benzene at
4 ◦C.
◦
temperature (-30 C) and increasing both Tf2O equivalents and
reaction time; these conditions (conditions A) resulted in a
sensibly reduced generation of compound 4a, likely arising from a
rearrangement of the acylating agent prior to the electrophilic
attack to anisole. Interestingly, in all cases (Table 1) the only
detectable ortho-product (5) (5–10% yield) was that deriving
from the rearrangement of the acylating reagent, despite the
apparently higher steric crowding of the corresponding furan
product.
Formation of both regioisomers starting from furoic acid
1 can be consistent with a previously proposed mechanism
of interchange between the ester function and the leaving
group.19
Actually, when an acid halide function is sufficiently close to
an ester function in a dibasic acid, ring-chain tautomerism can
occur leading to the generation of two reactive isomeric open
chain forms. Very likely, this also happens when a triflate is used as
leaving group, with intermediates 6 and 6¢ being the corresponding
acylating species (Scheme 1).
4-Aroyl-2-phenyl-3-methoxycarbonylfurans are very interest-
ing products since they possess a typical lignan scaffold
(Fig. 1). Hydrogenation of the furan moieties of the read-
ily obtained 4-aroylfurans 3a–e, would thus offer a versatile
and straightforward route to lignan derivatives or analogues
thereof.
To test this synthetic opportunity, model furan 3a was hydro-
genated at high pressure (100 atm) with Pd on carbon, as already
reported for 2-arylfuran-3,4-dicarboxylate esters,22 under different
temperature conditions.
Tuning of the temperature was indeed useful for obtain-
ing in high yields furan derivatives with a differentiated pro-
file of functional groups or the corresponding tetrahydrofuran
(9, Scheme 2) in which the carbonyl function also under-
went reduction to methylenic group because of its dibenzylic
character.23
Scheme 1 Interchange mechanism between the ester function and the
leaving group by a ring-chain tautomerism.
Keeping in mind these mechanistic considerations, the in-
vestigation was focused on establishing whether precursor 1,
bearing the activatable carboxyl function at C-4, could provide
exclusively 3-aryl ketones, resulting from carboxyl activation at
Performing the hydrogenation reaction at room temperature
only reduction of the carbonyl function to hydroxyl group
1220 | Org. Biomol. Chem., 2012, 10, 1219–1224
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Table 2 Regioselectivity improvement in the synthesis of the 3-aroylfuran 4a
Entry
Substrate
Solvent
Tf2O (equiv)
T/◦C
Time
Products and yields (%)a
1
2
2a
CH2Cl2
CH2Cl2
1.1
1.1
Reflux
rt
2 h
2 h
3a (15), 4a (47), 5 (12)
3a (0), 4a (71), 5 (27)
2ab
a Isolated yields after column chromatography. b Slow addition of the arene to the reaction medium.
Table 3 Results of FC-acylation related to the synthesis of 4-aroylfurans 3i (conditions A, even entries) and the synthesis of 3-aroylfurans 4i (conditions
B, odd entries)
Entry
1
Substrate
Conditions
T/◦C
-30
Products and yields (%)a
A. Neat, 12 h, 2.5 equiv Tf2O
2
3
2ab
B. CH2Cl2, 4 h, 1.1 equiv Tf2O
A. CH2Cl2, 12 h, 2.0 equiv Tf2O
rt
-30
4
5
2bb
2cb
2db
B. CH2Cl2, 3 h, 1.5 equiv Tf2O
A. Neat, 12 h, 2.5 equiv Tf2O
rt
-15
6
7
8
B. Benzene, 3 h, 2.0 equiv Tf2O
A. CH2Cl2, 12 h, 2.0 equiv Tf2O
B. Benzene, 3 h, 2.0 equiv Tf2O
4
-30
4
9
A. CH2Cl2, 12 h, 2.0 equiv Tf2O
B. CH2Cl2, 3 h, 1.1 equiv Tf2O
-30
10
2eb
rt
a Isolated yields after column chromatography. b Slow addition of the arene to the reaction medium.
occurs in very high yield (7, Scheme 2), while, increasing the
temperature to 50 ◦C, the 4-acylfuran 3a was converted, via
the intermediate compound 7, to the 4-alkylfuran 8 in moderate
yield likely due to the subsequent hydrogenolysis of the hydroxyl
group.23,24
Hydrogenation of the furan ring occurs at higher temperature
(80 ◦C) with high stereoselectivity evidencing a non-conjugated
hydrogenation mechanism.22
This hydrogenation product (9) is an analogue of tetrahydro-
furan plant lignans with antimicrobial (taxiresinol, Fig. 1) and
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1219–1224 | 1221
©

View Article Online
Experimental
General procedure for the synthesis of
4-aroyl-2-phenyl-3-methoxycarbonylfurans (conditions A)
In a typical experiment 50 mg (0.2 mmol) of 1 were coevaporated
three times with toluene, the residue was dried and then mixed
under nitrogen with the desired arene and dissolved in 1 mL of
CH2Cl2, excepted for anisole and 1,2-benzodioxole in which the
substrate was directly dissolved (1 mL). The reaction mixture was
stirred at the reported temperature (Table 3) for few minutes. Triflic
anhydride (84 mL, 0.5 mmol) was then added. After the complete
conversion of the reactant the reaction was diluted with diethyl
ether (20 mL) and washed with saturated NaHCO3 solution. The
organic layer was collected, dried over anhydrous Na2SO4, filtered
and concentrated to give a residue that was purified by column
chromatography (mixture of petroleum ether/diethyl ether).
General procedure for the synthesis of
3-aroyl-2-phenyl-4-methoxycarbonylfurans (conditions B)
Fig. 1 Some examples of natural tetrahydrofuran lignans with anti-in-
flammatory and antimicrobial activities.
Typically, 50 mg (0.2 mmol) of 1 were coevaporated three times
with toluene, the residue was dried and dissolved in 1 mL of
CH2Cl2 (for details, see Table 3). Triflic anhydride (37 mL, 0.22
mmol) was added and a solution of the desired arene (1 mmol) in
2 mL of CH2Cl2 was then added dropwise in 2 h by a syringe-pump.
The reaction mixture was stirred at room temperature one more
hour. The reaction was then diluted with diethyl ether (20 mL) and
washed with saturated NaHCO3 solution. The organic layer was
collected, dried over anhydrous Na2SO4, filtered and concentrated
to give a residue that was purified by column chromatography
(mixture of petroleum ether/diethyl ether).
General procedure for hydrogenation
Compound 3a (0.3 mmol) was dissolved in dry MeOH (40 mL)
and 10% Pd/C catalyst (20 mg) was then added under nitrogen
atmosphere. Hydrogenation was performed at 100 atm (for details,
see Scheme 2). After releasing the pressure, the mixture was filtered
and the solvent was removed in vacuo. The products were purified
by flash chromatography (petroleum ether/diethyl ether).
Scheme 2 Hydrogenation reactions. Reagents and conditions: reactions
were performed in the presence of 10 mol % Pd/C 10% catalyst at 100 atm
of H2 in 40 mL of MeOH. Isolated yields after column chromatography
were reported.
Methyl 4-(4-methoxybenzoyl)-2-phenyl-3-furoate (3a). IR
(CH2Cl2): 3010, 2928, 2853, 1727, 1652, 1600, 1205, 1168, cm-1;
1H NMR (500 MHz, CDCl3) d 7.91 (d, J = 8.9 Hz, 2H, ArH),
7.88 (dd, J = 8.4, 1.6 Hz, 2H, ArH), 7.74 (s, 1H, H-5), 7.46-7.44
(m, 3H, ArH), 6.97 (d, J = 9.0 Hz, 2H, ArH), 3.89 (s, 3H,
–OCH3), 3.65 (s, 3H, –COOCH3); 13C NMR (125 MHz, CDCl3)
d 187.4, 164.1, 163.7, 156.2, 143.9, 131.5 (¥ 2), 130.9, 129.7, 128.5
(¥ 2), 127.8 (¥ 2), 120.9, 120.6, 113.9 (¥ 2), 111.7, 55.5, 52.0;
MALDI-MS m/z 359.39 [M+Na]+. Anal. Calcd for C20H16O5: C,
71.42; H, 4.79. Found: C, 71.76; H, 5.12.
anti-inflammatory (magnone A, magnone B, lariciresinol glyco-
side, Fig. 1) activities.21
Conclusions
In summary, herein we have reported a strategy allowing the
preparation of either 3-aroyl-2-phenyl- or 4-aroyl-2-phenylfurans
starting from a unique easily accessible mono-acid precursor 1.
This method is based on tunable Tf2O-mediated FC-acylation and
takes advantage of a ring-chain tautomeric interchange occurring
on the acylating agent.
Methyl 4-(4-methoxybenzoyl)-5-phenyl-3-furoate (4a). IR
(CH2Cl2): 3020, 1725, 1660, 1598, 1217, 1165 cm-1; 1H NMR (400
MHz, CDCl3) d 8.11 (s, 1H, H-2), 7.90 (d, J = 8.7 Hz, 2H, ArH),
7.55 (dd, J = 8.0, 1.7 Hz, 2H, ArH), 7.31–7.27 (m, 3H, ArH),
6.91 (d, J = 8.9 Hz, 2H, ArH), 3.85 (s, 3H, –OCH3), 3.66 (s, 3H,
–COOCH3); 13C NMR (100 MHz, CDCl3) d 190.9, 164.1, 162.4,
152.1, 146.5, 131.8 (¥ 2), 130.5 (¥ 2), 128.9 (¥ 2), 128.8, 125.7 (¥
2), 120.9, 119.6, 114.0 (¥ 2), 55.5, 51.7; MALDI-MS m/z 359.98
4-Aroyl-2-phenylfurans show
a
suitable scaffold for
the elaboration of lignan structures as demonstrated by
the hydrogenation of the model compound methyl 4-(4-
methoxybenzoyl)-2-phenyl-3-furoate (3a) which led to tetrahy-
drofuran analogue of some bioactive natural lignans in useful
yield.
1222 | Org. Biomol. Chem., 2012, 10, 1219–1224
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
[M+Na]+. Anal. Calcd for C20H16O5: C, 71.42; H, 4.79. Found: C,
71.85; H, 4.98.
6.72 (d, J = 8.7 Hz, 1H, ArH), 3.92 (s, 3H, –OCH3), 3.89 (s, 3H, –
OCH3), 3.83 (s, 3H, –OCH3), 3.70 (s, 3H, –OCH3); 13C NMR (100
MHz, CDCl3) d 186.8, 164.5, 157.0, 155.1, 153.3, 145.7, 142.4,
129.6, 128.9, 128.6 (¥ 2), 127.2 (¥ 2), 126.5, 125.8, 113.6, 106.8,
106.7, 62.0, 61.0, 56.1, 52.2; MALDI-MS m/z 419.43 [M+Na]+.
Anal. Calcd for C22H20O7: C, 66.66; H, 5.09. Found: C, 66.76; H,
5.54.
Methyl 4-(2-methoxybenzoyl)-5-phenyl-3-furoate (5). IR
(CH2Cl2): 3053, 1726, 1657, 1598, 1218, 1048 cm-1; 1H NMR (500
MHz, CDCl3) d 8.02 (s, 1H, H-2), 7.79 (dd, J = 9.7, 1.8 Hz, 1H,
ArH), 7.61 (dd, J = 9.8, 1.7 Hz, 2H, ArH), 7.54 (t, J = 9.4 Hz,
1H, ArH), 7.45 (t, J = 8.9 Hz, 1H, ArH), 7.31–7.26 (m, 2H, ArH)
6.97 (t, J = 9.4 Hz, 1H, ArH), 6.91 (d, J = 10.4 Hz, 1H, ArH),
3.71 (s, 3H, –OCH3), 3.60 (s, 3H, –OCH3); 13C NMR (125 MHz,
CDCl3) d 190.7, 162.6, 159.4, 152.5, 145.9, 134.5, 131.9, 131.3,
128.9, 128.8, 128.6 (¥ 2), 126.2 (¥ 2), 120.4, 113.8, 112.0, 79.2,
55.7, 51.5; MALDI-MS m/z 359.16 [M+Na]+. Anal. Calcd for
C20H16O5: C, 71.42; H, 4.79. Found: C, 71.56; H, 5.02.
Methyl 4-(2,3,4-trimethoxybenzoyl)-5-phenyl-3-furoate (4d).
IR (CH2Cl2): 3051, 1726, 1657, 1588, 1218, 1097 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.04 (s, 1H, H-2), 7.61–7.57 (m, 2H, ArH),
7.30–7.28 (m, 4H, ArH), 6.69 (d, J = 8.9 Hz, 1H, ArH), 3.89 (s,
3H, –OCH3), 3.80 (s, 3H, –OCH3), 3.69 (s, 3H, –OCH3), 3.67 (s,
3H, –OCH3); 13C NMR (50 MHz, CDCl3) d 189.6, 162.5, 158.1,
154.8, 151.8, 146.0, 142.3, 129.1, 128.6 (¥ 2), 127.3, 125.9 (¥ 2),
125.7, 122.7, 120.6, 106.8 (¥ 2), 61.2, 60.8, 56.1, 51.6; MALDI-MS
m/z 420.55 [M+Na]+. Anal. Calcd for C22H20O7: C, 66.66; H, 5.09.
Found: C, 66.99; H, 5.23.
Methyl 4-(3,4-dimethoxybenzoyl)-2-phenyl-3-furoate (3b). IR
(CH2Cl2): 3020, 1731, 1658, 1598, 1218, 1048 cm-1; 1H NMR (500
MHz, CDCl3) d 7.89 (dd, J = 10.1, 2.2 Hz, 2H, ArH), 7.76 (s, 1H,
H-5), 7.54–7.44 (m, 5H, ArH), 6.92 (d, J = 10.1 Hz, 1H, ArH),
3.96 (s, 3H, –OCH3), 3.95 (s, 3H, –OCH3), 3.66 (s, 3H, -OCH3);
13C NMR (50 MHz, CDCl3) d 187.4, 164.2, 156.1, 153.5, 149.2,
144.0, 131.0, 129.7, 128.9, 128.5 (¥ 2), 127.5 (¥ 3), 124.3, 114.0,
110.8, 110.0, 56.1 (¥ 2), 52.1; MALDI-MS m/z 389.32 [M+Na]+.
Anal. Calcd for C21H18O6: C, 68.85; H, 4.95. Found: C, 69.34; H,
5.44.
Methyl 4-(2,4,6-trimethoxybenzoyl)-2-phenyl-3-furoate (3e).
IR (CH2Cl2): 3055, 1731, 1666, 1606, 1218, 1131 cm-1; 1H NMR
(400 MHz, CDCl3) d 7.72 (dd, J = 8.4, 1.6 Hz, 2H, ArH), 7.68
(s, 1H, H-5), 7.40 (m, 3H, ArH), 6.14 (s, 2H, ArH), 3.85 (s, 3H,
–OCH3), 3.81 (s, 3H, –OCH3), 3.74 (s, 6H, –OCH3); 13C NMR
(100 MHz, CDCl3) d 186.4, 165.4, 162.7, 159.1 (¥ 2), 153.7, 147.7,
129.9, 129.2 (¥ 2), 128.6 (¥ 2), 126.3 (¥ 2), 113.2, 111.6, 90.6 (¥ 2),
55.9 (¥ 2), 55.4, 52.6; MALDI-MS 420.22 [M+Na]+. Anal. Calcd
for C22H20O7: C, 66.66; H, 5.09. Found: C, 67.23; H, 5.71.
Methyl 4-(3,4-dimethoxybenzoyl)-5-phenyl-3-furoate (4b). IR
(CH2Cl2): 3057, 1726, 1658, 1592, 1218, 1145 cm-1; 1H NMR (400
MHz, CDCl3) d 8.10 (s, 1H, H-2), 7.66 (d, J = 3.9 Hz, 1H, ArH),
7.59–7.56 (m, 2H, ArH), 7.40–7.27 (m, 4H, ArH), 6.78 (d, J = 16.8
Hz, 1H, ArH), 3.94 (s, 3H, -OCH3), 3.90 (s, 3H, -OCH3), 3.67 (s,
3H, -OCH3); 13C NMR (100 MHz, CDCl3) d 190.8, 162.3, 153.9,
149.3, 146.5, 144.0, 130.6, 129.7, 128.7 (¥ 2), 127.5, 125.7 (¥ 2),
125.3, 120.8, 110.2, 110.1, 110.0, 56.0 (¥ 2), 51.7; MALDI-MS
m/z 389.52 [M+Na]+. Anal. Calcd for C21H18O6: C, 68.85; H 4.95.
Found: C, 69.76; H, 5.53.
Methyl 4-(2,4,6-trimethoxybenzoyl)-5-phenyl-3-furoate (4e).
IR (CH2Cl2): 3056, 1731, 1664, 1604, 1218, 1156 cm-1; 1H NMR
(400 MHz, CDCl3) d 7.93 (s, 1H, H-2), 7.66–7.63 (m, 2H, ArH),
7.29–7.27 (m, 3H, ArH), 6.00 (s, 2H, ArH), 3.77 (s, 3H, –OCH3),
3.66 (s, 6H, –OCH3), 3.64 (s, 3H, –OCH3); 13C NMR (100 MHz,
CDCl3) d 187.9, 163.6, 163.0, 161.0 (¥ 2), 154.0, 145.8, 129.5, 128.7
(¥ 2), 128.1 (¥ 2), 126.9 (¥ 2), 120.3, 112.8, 90.7 (¥ 2), 56.0 (¥ 2),
55.3, 51.5; MALDI-MS m/z 419.27 [M+Na]+. Anal. Calcd for
C22H20O7: C, 66.66; H, 5.09. Found: C, 67.11; H, 5.42.
Methyl
4-(3,4-(benzo[d][1,3]dioxole-5-carbonyl)-2-phenyl-3-
furoate (3c). IR (CH2Cl2): 3052, 1727, 1654, 1605, 1217, 1041
1
cm-1; H NMR (200 MHz, CDCl3) d 7.90–7.88 (m, 2H, ArH),
7.74 (s, 1H, H-5), 7.52–7.43 (m, 5H, ArH), 6.87 (d, J = 8.0 Hz, 1H,
ArH), 6.08 (s, 2H, –OCH2O–), 3.69 (s, 3H, –OCH3); 13C NMR (50
MHz, CDCl3) d 186.8, 164.2, 156.3, 151.9, 148.2, 143.8, 132.8,
129.7, 128.6, 128.4 (¥ 2), 127.5 (¥ 2), 125.9, 118.4, 113.6, 108.6,
107.8, 101.9, 52.1; MALDI-MS m/z 373.62 [M+Na]+. Anal.
Calcd for C20H14O6: C, 68.57; H, 4.03. Found: C, 68.73; H, 4.42.
Methyl
4-(hydroxy(4-methoxyphenyl)methyl)-2-phenyl-3-
furoate (7). IR (CH2Cl2): 3447, 3016, 1692, 1611, 1512, 1214,
1033 cm-1; H NMR (400 MHz, CDCl3) d 7.68–7.65 (m, 2H,
1
ArH), 7.43–7.38 (m, 5H, ArH), 7.02 (s, 1H, H-5), 6.91 (d, J = 8.7
Hz, 2H, ArH), 5.90 (bs, 1H, -CHOH), 4.43 (bs, 1H, –CHOH),
3.82 (s, 3H, –OCH3), 3.73 (s, 3H, –COOCH3); 13C NMR (100
MHz, CDCl3) d 165.5, 159.3, 159.0, 140.6, 133.8, 131.4, 130.0,
129.5 (¥ 2), 128.7 (¥ 2), 128.0 (¥ 2), 127.7 (¥ 2), 113.6, 112.3, 67.8,
55.2, 51.8; MALDI-MS m/z 361.39 [M+Na]+. Anal. Calcd for
C20H18O5: C, 70.99; H, 5.36. Found: C, 71.43; H, 5.48.
Methyl
4-(3,4-(benzo[d][1,3]dioxole-5-carbonyl)-5-phenyl-3-
furoate (4c). IR (CH2Cl2): 3050, 1726, 1663, 1489, 1217, 1041
cm-1; 1H NMR (400 MHz, CDCl3) d 8.09 (s, 1H, H-2), 7.57–7.54
(m, 2H, ArH), 7.49–7.41 (m, 2H, ArH), 7.34–7.27 (m, 3H, ArH),
6.77 (d, J = 8.1 Hz, 1H, ArH), 6.04 (s, 2H, –OCH2O–), 3.69 (s,
3H, –OCH3); 13C NMR (100 MHz, CDCl3) d 190.5, 162.2, 152.5,
152.1, 148.4, 147.4, 146.5, 132.4, 128.6, 128.5 (¥ 2), 126.7, 125.6
(¥ 2), 120.6, 119.5, 108.4, 108.2, 102.0, 51.8; MALDI-MS m/z
373.28 [M+Na]+. Anal. Calcd for C20H14O6: C, 68.57; H 4.03.
Found: C, 68.97; H 4.35.
Methyl
4-(4-methoxybenzyl)-2-phenyl-3-furoate
(8). IR
(CH2Cl2): 3021, 2942, 1716, 1612, 1604, 1240, 1035 cm-1; 1H
NMR (400 MHz, CDCl3) d 7.76 (dd, J = 8.2, 1.8 Hz, 2H, ArH),
7.40 (m, 3H, ArH), 7.17 (d, J = 8.6 Hz, 2H, ArH), 7.03 (s, 1H,
H-5), 6.86 (d, J = 8.6 Hz, 2H, ArH), 3.93 (s, 2H, CH2), 3.80 (s,
3H, –OCH3), 3.74 (s, 3H, –COOCH3); 13C NMR (100 MHz,
CDCl3) d 164.7, 158.2, 158.0, 140.1, 131.7, 130.2, 129.7 (¥ 2),
129.1, 128.3 (¥ 2), 128.0 (¥ 2), 126.1, 113.8 (¥ 2), 113.2, 55.2,
51.3, 30.4; MALDI-MS m/z 345.76 [M+Na]+. Anal. Calcd for
C20H18O4: C, 74.52; H, 5.63. Found: C, 74.76; H, 5.83.
Methyl 4-(2,3,4-trimethoxybenzoyl)-2-phenyl-3-furoate (3d).
IR (CH2Cl2): 3056, 1729, 1656, 1590, 1217, 1097 cm-1; 1H NMR
(400 MHz, CDCl3) d 7.83 (dd, J = 8.2, 1.6 Hz, 2H, ArH), 7.72
(s, 1H, H-5), 7.43 (m, 3H, ArH), 7.36 (d, J = 8.7 Hz, 1H, ArH),
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1219–1224 | 1223
©

View Article Online
Methyl
4-(4-methoxybenzyl)-2-phenyl-tetrahydrofuran-3-
5 H.-K. Lee, K.-F. Chan, C.-W. Hui, H.-K. Yim, X.-W. Wu and H. N. C.
Wong, Pure Appl. Chem., 2005, 77, 139.
6 H. N. C. Wong, P. Yu and C.-Y. Yick, Pure Appl. Chem., 1999, 71, 1041.
7 B. H. Lipshutz, Chem. Rev., 1986, 86, 795.
carboxylate (9). IR (CH2Cl2): 3006, 2951, 1732, 1661, 1512,
1176, 1034 cm-1; H NMR (400 MHz, CDCl3) d 7.29–7.24 (m,
1
5H, ArH), 7.11 (d, J = 6.8 Hz, 2H, ArH), 6.84 (d, J = 6.8 Hz,
2H, ArH), 5.26 (d, J = 6.7 Hz, 1H, H-2), 4.34 (t, J = 6.4 Hz, 1H,
H-5b), 3.79 (s, 3H, –OCH3), 3.66 (t, J = 6.8 Hz, 1H, H-5a), 3.14 (s,
3H, –COOCH3), 3.12 (m, 1H, H-3), 3.08 (m, 1H, H-4), 2.81 (dd,
J = 11.1, 5.1 Hz, 1H, CHaHAr), 2.67 (dd, J = 11.1, 6.8 Hz, 1H,
CHHbAr); 13C NMR (100 MHz, CDCl3) d 171.8, 158.1, 138.9,
131.3, 127.9 (¥ 2), 127.8, 127.7 (¥ 2), 126.2 (¥ 2), 113.9 (¥ 2), 82.2,
73.7, 55.8, 55.2, 51.2, 43.7, 37.3; MALDI-MS 349.54 [M+Na]+.
Anal. Calcd for C20H22O4: C, 73.60; H, 6.79. Found: C, 73.76; H
6.97.
8 S. F. Kirsch, Org. Biomol. Chem., 2006, 4, 2076.
9 B. Konig, in Science of Synthesis, ed. G. Maas, Georg Thieme,
Stuttgart, 2001, vol. 9.
10 X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan, T. H. Lo, S. Y. Tong
and H. N. C. Wong, Tetrahedron, 1998, 54, 1955.
11 M. M. Khodaei, A. Alizadeh and E. Nazari, Tetrahedron Lett., 2007,
48, 4199.
12 G. A. Olah, in Friedel–Crafts Chemistry, Wiley-Interscience, New York,
1973.
13 M. Kawamura, D.-M. Cui and S. Shimada, Tetrahedron, 2006, 62, 9201.
14 K. Suzuki, H. Kitagawa and T. T. Mukaiyama, Bull. Chem. Soc. Jpn.,
1993, 66, 3729.
15 (a) C. Galli, Synthesis, 1979, 303; (b) T. P. Smyth and B. W. Corby, J.
Org. Chem., 1998, 63, 8946.
16 H. Firouzabadi, N. Iranpoor and F. Nowrouzi, Tetrahedron Lett., 2004,
45, 4723.
17 M. Fan, Z. Yan, W. Liu and Y. Liang, J. Org. Chem., 2005, 70, 8204.
18 S.-S. Lin, X.-P. Nie, J.-H. Yu and X.-L. Ye, Heterocycles, 2001, 55, 265.
19 B. H. Chase and D. H. Hey, J. Chem. Soc., 1952, 553.
20 J.-Y. Pan, S.-L. Chen, M.-H. Yang, J. Wu, J. Sinkkonen and K. Zou,
Nat. Prod. Rep., 2009, 26, 1251.
Notes and references
1 X. L. Hou, Z. Yang and H. N. C. Wong, in Progress in Heterocyclic
Chemistry, ed. G. W. Gribble and T. L. Gilchrist, Pergamon, Oxford,
2003, vol. 15.
2 B. A. Keay and P. W. Dibble, in Comprehensive Heterocyclic Chemistry
II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Elsevier, Oxford,
1997, Vol. 2.
3 M. J. Meegan and D. M. X. Donnelly, in Comprehensive Heterocyclic
Chemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon, Oxford,
1984, vol. 4.
21 M. Saleem, H. J. Kim, M. S. Ali and Y. S. Lee, Nat. Prod. Rep., 2005,
22, 696.
22 W. Pei, J. Pei, S. Li and X. Ye, Synthesis, 2000, 14, 2069.
23 C. M. Cirtiu, A. Brisach-Wittmeyer and H. Menard, Catal. Commun.,
2007, 8, 751.
4 K. Nakanishi, in Natural Products Chemistry, Kodansha Ltd Tokyo,
1974.
24 S. P. Bawane and S. B. Sawant, Org. Process Res. Dev., 2003, 7, 769.
1224 | Org. Biomol. Chem., 2012, 10, 1219–1224
This journal is
The Royal Society of Chemistry 2012
©