Synthesis of Two Natural Furan-Cyclized Diarylheptanoids via 2-Furaldehyde

Article abstract of DOI:10.1002/hlca.201400274

Two natural diarylheptanoids, 2-benzyl-5-(2-phenylethyl)furan (1) and 2-methoxy-4-{[5-(2-phenylethyl)furan-2-yl]methyl}phenol (2), were synthesized starting from 2-furaldehyde. A Wittig reaction of 2-furaldehyde with benzyltriphenylphosphonium bromide followed by reduction of the alkene C=C bond with Mg gave 2-(2-phenylethyl)furan (5). Lithiation of 5 with BuLi at -78 followed by alkylation with benzyl bromide gave natural product 1. In another approach, Friedel-Crafts acylation of compound 5 with benzoyl chloride followed by deoxygenation of the C=O group afforded 1. The natural product 2 was also synthesized by acylation of 5 with 4-acetoxy-3-methoxybenzoyl chloride (16) followed by deoxygenation and deacetylation.

Full text of DOI:10.1002/hlca.201400274

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Synthesis of Two Natural Furan-Cyclized Diarylheptanoids via 2-Furaldehyde
by Hatice SeÅinti and Hasan SeÅen*
Department of Chemistry, Faculty of Science, Ataturk University, TR-25240 Erzurum
(fax: 90-442-2360948; e-mail: hsecen@atauni.edu.tr)
Two natural diarylheptanoids, 2-benzyl-5-(2-phenylethyl)furan (1) and 2-methoxy-4-{[5-(2-phenyl-
ethyl)furan-2-yl]methyl}phenol (2), were synthesized starting from 2-furaldehyde. AWittig reaction of 2-
furaldehyde with benzyltriphenylphosphonium bromide followed by reduction of the alkene C¼C bond
with Mg gave 2-(2-phenylethyl)furan (5). Lithiation of 5 with BuLi at À 788 followed by alkylation with
benzyl bromide gave natural product 1. In another approach, FriedelÀCrafts acylation of compound 5
with benzoyl chloride followed by deoxygenation of the C¼O group afforded 1. The natural product 2
was also synthesized by acylation of 5 with 4-acetoxy-3-methoxybenzoyl chloride (16) followed by
deoxygenation and deacetylation.
Introduction. – Diarylheptanoids, bearing two aryl groups at C(1) and C(7) of a C7-
chain, are a special class of natural products. So far, over 400 naturally occurring
diarylheptanoids have been isolated from nature and reviewed in different articles
[1 – 6]. In general, diarylheptanoids are classified into three categories: i) linear
diarylheptanoids, ii) macrocyclic biarylheptanoids, and iii) macrocyclic diaryl ether
heptanoids. Besides these three classes, there are also few C7 chain-cyclized diaryl-
heptanoids. In particular, ꢀpyran-cyclizedꢁ natural diarylheptanoids with the structure
of 2-arylethyl-6-aryl-tetrahydro-2H-pyran have been long known. However, ꢀfuran-
cyclizedꢁ natural diarylheptanoids were only recently discovered, and there are only
two examples of them in the literature (Fig.). Sun et al. [7] isolated two furan-cyclized
diarylheptanoids 1 and 2 from rhizomes of Alpinia officinarum Hance (Zingiberaceae)
as minor components in milligram quantities and reported compound 2 as having
moderate cytotoxic activity against the IMR-32 human neuroblastoma cell line. In a
different study, An et al. [8] also isolated compound 2 from rhizomes of Alpinia
officinarum. To the best of our knowledge, there is no described synthetic method for
the preparation of compounds 11) and 2. We assume that a synthetic methodology for
the preparation of compounds 1 and 2 would facilitate further chemical and biological
studies on these compounds. Therefore, we herein present a synthetic methodology for
preparation of compounds 1 and 2.
Results and Discussion. – We used 2-furaldehyde as the starting compound to
synthesize natural product 1. First benzyl bromide 3 was reacted with PPh3 to give
benzylphosphonium bromide, which was then condensed with 2-furaldehyde by Wittig
1
)
In spite of the use of compound 1 in the synthesis of some naphthofuran derivatives, no descriptions
for its preparation are given. See [9].
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 98 (2015)
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Figure. ꢀFuran-cyclizedꢁ natural diarylheptanoids
reaction to give (E/Z)-2-styrylfuran (4) in a yield of 87%. Cabares and Mavoungou-
Gomes [10] selectively reduced 4 with Mg to afford 2-(2-phenylethyl)furan (5).
Following this procedure, we reduced 4 to give 5 in a good yield (82%). Lithiation of 5
by treatment with BuLi followed by addition of benzyl bromide (3) gave natural
product 1 (78%). In a second synthetic method, we reacted 2-(2-phenylethyl)furan
with benzoyl chloride in the presence of AlCl3 to give ketone 6 (73%). Box and
Meleties [11] developed a method for deoxygenation of aromatic aldehydes and
ketones by reduction with NaBH3CN/TMSCl. We applied this methodology for the
reduction of 6 to give 1 (81%; Scheme 1).
We assumed that the synthesis of natural product 2 could be performed by
incorporating a 4-hydroxy-3 methoxy-benzyl(benzoyl) moiety to 2-(2-phenylethyl)fur-
an (5) as in the synthesis of 1. In this context, we thought that the most suitable starting
material was vanillin (7) for the preparation of the 4-hydroxy-3-methoxy-benzyl(ben-
zoyl) residue. For this purpose, starting with 7, we prepared two O-MOM and O-
TBDPS protected vanillin compounds 8 and 9 (Scheme 2) and submitted them to a
reaction with lithiated 5. Although a reaction occurred, the product decomposed within
a short time. Secondly, we prepared the O-TBDPS protected benzyl iodide 11 as an
alkylating reagent and submitted it to the reaction with lithiated 5. In this reaction, an
alkylation product was not observed. Thirdly, benzoyl chloride 13 was prepared as an
Scheme 1
a) PPh3, MeCN, N2 atm, reflux, 24 h, quant. b) NaH, CH2Cl2, N2 atm, 08, then 2-furaldehyde, 48 h, 87%.
c) Mg, MeOH, reflux, 6 h, 82%. d) BuLi, THF, N2 atm, À 788 !À 58, then PhCH2Br, r.t., 12 h, 78%.
e) PhCOCl, AlCl3, CH2Cl2, N2 atm, 08, 30 min, 73%. f) NaBH3CN/TMSCl, MeCN, N2 atm, 08 ! 258,
12 h, 81%.

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acylating reagent and submitted to the reaction with 5 in the presence of AlCl3.
Unfortunately, no acylation occurred. We supposed that the bad reactivity of
compounds 11 and 13 was due to the protecting groups. Therefore, we decided to
change the protecting group, and we prepared 4-(acetyloxy)-3-methoxybenzoyl
chloride (16) as outlined in Scheme 2.
After the preparation of benzoyl chloride 16, it was condensed with 2-(2-
phenylethyl)furan (5) by FriedelÀCrafts reaction to give ketone 17 in a moderate
yield (59%). Deoxygenation of ketone by reduction with NaBH3CN/TMSCl afforded
18 (80%), from which the natural product 2 was obtained by deacetylation with
aqueous NaHCO3 solution (83%; Scheme 3).
Scheme 2
a) MOMCl, NaH, DMF, N2 atm, 08 ! 258, 5 h, 86%. b) TBDPSCl, imidazole, CH2Cl2, 258, 12 h, 91%.
c) NaBH4, EtOH, 08 ! 258, 4 h, 86%. d) PPh3, imidazole, I2, CH2Cl2, 08 ! 258, 36 h, 64%. e) Jones
reagent, acetone, 08 ! 258, 12 h, 73%. f) SOCl2, reflux, 12 h, quant. g) Ac2O, pyridine, 08 ! 258, 24 h,
90%. h) Jones reagent, acetone, 08 ! 258, 12 h, 76%. i) SOCl2, reflux, 12 h, quant.
Scheme 3
a) 4-(Acetyloxy)-3-methoxybenzoyl chloride (16), AlCl3, CH2Cl2, N2 atm, 08, 30 min, 59%. b)
NaBH3CN/TMSCl, MeCN, N2 atm, 08 ! 258, 12 h, 80%. c) NaHCO3, MeOH/H2O 4 :1, 258, 4 h, 83%.

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In conclusion, starting from 2-furaldehyde, we developed two alternative strategies
for the synthesis of natural product 1 in three or four steps. We also synthesized the
natural product 2 for the first time by a convergent method in eight steps. We think that
our synthetic methods will be valuable for the preparation of various 2,5-dialkylated
furan derivatives.
The authors thank the Scientific and Technological Research Council of Turkey for support
˙
(TÜBITAK, 113Z197). They are also thankful to Prof. Dr. Simeon Arseniyadis for providing some
literature, and Prof. Dr. Ramazan Altundas¸ and Dr. Ahmet C. Gçren for helpful discussions.
Experimental Part
General. Anh. THF was distilled over Na in the presence of benzophenone. CH2Cl2 and MeCN were
obtained by distillation from molecular sieve (4 Š). All other solvents and reagents were used as
received. Reactions were monitored by thin-layer chromatography (TLC) with TLC Merck silica gel 60
F254. Column chromatography (CC): Fluka silica gel 60 (SiO2; 0.063 – 0.2 mm). Column eluents were
visualized using UV light (254 nm) and a soln. of phosphomolybdic acid in EtOH (5wt.-%). M.p.: Büchi
1
539 capillary melting apparatus; uncorrected. H- and 13C-NMR spectra: Varian 400 MHz instrument
(1H-NMR at 400 MHz and 13C-NMR at 100 MHz).
(E/Z)-2-Styrylfuran (¼2-[(E/Z)-2-Phenylethenyl]furan; 4) [12]. To a soln. of benzyl bromide
(¼(bromomethyl)benzene, 3; 5.00 g, 29.2 mmol) in MeCN (150 ml), PPh3 (8.43 g, 32.2 mmol) was
added, and the mixture was heated at reflux for 24 h. Evaporation of the solvent afforded
benzyltriphenylphosphonium bromide as a colorless solid, which was used for further reaction without
purification (13.43 g, quant.). To a slurry of NaH (540 mg, 22.5 mmol) in CH2Cl2 (25 ml) was added a
soln. of benzyltriphenylphosphonium bromide (4.00 g, 10.5 mmol) in CH2Cl2 (60 ml) under N2 atm at 08;
the mixture was stirred for 1 h. 2-Furaldehyde (720 mg, 7.5 mmol) was added to the mixture and it was
stirred for 48 h at r.t. A sat. aq. NH4Cl soln. (20 ml) was added to the mixture. The org. phase was
separated and dried (Na2SO4), and the solvent was evaporated. CC of the residue with AcOEt/hexane
1:4 gave 4 as a yellow oil (1.09 g, 87%). The (E/Z) mixture was used in the next step without purification.
2-(2-Phenylethyl)furan (5) [10]. Compound 5 was synthesized from 4 according to the procedure
described in [10] (colorless oil, 82%). 1H-NMR (400 MHz, CDCl3): 7.33 – 7.18 (m, 5 arom. H, HÀC(5));
6.28 (br. t, J ¼ 2.9, HÀC(4)); 5.98 (br. d, J ¼ 3.2, HÀC(3)); 3.00 – 2.92 (m, CH2CH2). 13C-NMR (100 MHz,
CDCl3): 155.6 (C(2)); 141.4 (C(1’’)); 141.1 (C(5)); 128.6 (C(2’’/6’’)); 128.5 (C(3’’/5’’)); 126.2 (C(4’’)); 110.4
(C(4)); 105.4 (C(3)); 34.6 (PhCH2); 30.1 (furylÀCH2).
2-Benzyl-5-(2-phenylethyl)furan (1) [7][9]. A soln. of 5 (1.00 g, 5.81 mmol) in THF (20 ml) was
cooled to À 788 and BuLi (1.6m, 4.35 ml, 6.97 mmol) was added dropwise. The mixture was warmed to À
58 and then recooled to À 788. At this temp., benzyl bromide (3; 1.09 g, 6.39 mmol) was added. The
mixture was allowed to warm to r.t. and stirred for 12 h. An aq. sat. NH4Cl soln. (10 ml) was added to the
mixture at 08. THF was evaporated, and the org. phase was extracted with AcOEt (3 Â 50 ml) and dried
(Na2SO4). CC of the crude product with hexane/AcOEt (98 :2) gave 1 as a yellow oil (1.19 g, 78%).
1H-NMR (400 MHz, CDCl3): 7.34 – 7.15 (m, 10 arom. H); 5.87 (br. s, HÀC(3), HÀC(4)); 3.95 (br. s,
PhCH2Àfuryl)); 2.94 – 2.90 (m, CH2CH2). 13C-NMR (100 MHz, CDCl3): 154.5, 153.0 (C(5), C(2)); 141.5,
138.7 (C(1’), (C(1’’)); 128.9, 128.67 (C(2’/6’), C(2’’/6’’)); 128.62, 128.56 (C(3’/5’), C(3’’/5’’)); 126.6, 126.2
(C(4’), C(4’’)); 107.0 (C(4)); 106.0 (C(3)); 34.8 (PhCH2); 34.6 (PhCH2); 30.2 (furylÀCH2). The 1H- and
13C-NMR data are in agreement with the data given for isolated 1 in [7].
Phenyl[5-(2-phenylethyl)furan-2-yl]methanone (6) [13]. Under N2 atmosphere, a soln. of benzoyl
chloride (1.50 g, 10.7 mmol) in CH2Cl2 (30 ml) was cooled to 08 and AlCl3 (2.85 g, 21.3 mmol) was added
to the soln. At the same temp., a soln. of 2-(2-phenylethyl)furan (5; 1.83 g, 10.7 mmol) in CH2Cl2 (10 ml)
was added. The mixture was stirred for 30 min, and then, ice (50 g) was added to quench the reaction. The
org. phase was extracted with CH2Cl2 (3 Â 70 ml), washed (5% aq. NaHCO3), and dried (Na2SO4).
Evaporation of the solvent and CC of the residue with hexane/AcOEt 95 :5 gave 6 as a yellow oil (2.15 g,
73%). Rf (AcOEt/hexanes 7:3) 0.55. 1H-NMR (400 MHz, CDCl3): 7.90 (dd, J ¼ 7.3, 1.1, HÀC(2’/6’)); 7.57

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Helvetica Chimica Acta – Vol. 98 (2015)
(quasi-t, J ¼ 7.9, HÀC(4’)); 7.30 (quasi-t, J ¼ 7.6, HÀC(3’’’/5’’’)); 7.26 – 7.19 (m, HÀC(4’’’), HÀC(2’’’),
HÀC(6’’’)); 7.12 (d, J ¼ 3.1, HÀC(3’’)); 6.18 (d, J ¼ 3.1, HÀC(4’’)); 3.11 – 3.04 (m, CH2CH2). 13C-NMR
(100 MHz, CDCl3): 182.5 (C¼O); 161.6 (C(5’’)); 151.2 (C(2’’)); 140.6 (C(1’’’)); 137.9 (C(1’)); 132.5 (C(4’));
129.3 (C(2’/6’)); 128.8 (C(2’’’/6’’’)); 128.60 (C(3’/5’)); 128.57 (C(3’’’/5’’’)); 126.6 (C(4’’’)); 122.8 (C(3’’));
109.0 (C(4’’)); 34.1 (PhCH2); 30.5 (furylÀCH2). HR-ESI-MS: 277.1231 ([M þ H]þ, C19H17O2þ ; calc.
277.1223).
Preparation of Compound 1 from Ketone 6. Under N2 atmosphere, a soln. of ketone 6 (0.80 g,
2.9 mmol) in MeCN (50 ml) was cooled to 08 and NaBH3CN (1.09 g, 17.4 mmol) was added in portions
over the course of 30 min. At the same temp., TMSCl (2.39 g, 2.79 ml; 22.0 mmol) was added dropwise.
The mixture was stirred at r.t. for 12 h. To the mixture was added 5% NaHCO3 soln. (10 ml), and the
mixture was stirred for 5 min. The org. phase was extracted with CH2Cl2 (3 Â 60 ml) and dried (Na2SO4).
Removal of the solvent under reduced pressure and CC of the residue with hexane/AcOEt 95 :5 gave 1 as
a yellow oil (0.61 g, 81%).
3-Methoxy-4-(methoxymethoxy)benzaldehyde (8). Compound 8 was synthesized from vanillin (7)
1
according to [14]. H-NMR (400 MHz, CDCl3): 9.85 (s, CHO); 7.42 (s, HÀC(2)); 7.41 (dd, J ¼ 8.4, 1.8,
HÀC(6)); 7.25 (d, J ¼ 8.4, HÀC(5)); 5.31 (s, OCH2O); 3.93 (s, MeO); 3.50 (s, MeO). 13C-NMR (100 MHz,
CDCl3): 191.2 (CHO); 152.2 (C(4)); 150.3 (C(3)); 131.3 (C(1)); 126.6 (C(6)); 114.9 (C(5)); 109.7 (C(2));
95.2 (OCH2O); 56.7 (MeO); 56.3 (MeO). 1H- and 13C-NMR data are in agreement with the data given in
[15].
4-{[tert-Butyl(diphenyl)silyl]oxy}-3-methoxybenzaldehyde (9) [16]. To a soln. of 7 (2.50 g,
16.4 mmol) in CH2Cl2 (60 ml) was added imidazole (2.23 g, 32.9 mmol). After the mixture was stirred
for 15 min, tert-butyl(diphenyl)silyl chloride (¼tert-butyl(chloro)diphenylsilane; 4.29 g, 4.05 ml,
15.6 mmol) was added dropwise. The mixture was stirred at r.t. for 12 h, then H2O (20 ml) was added,
and the org. phase was extracted with CH2Cl2 (3 Â 60 ml) and dried (Na2SO4). After removal of the
solvent under reduced pressure, the residue was subjected to CC with hexane/AcOEt 95 :5 to give 9 as a
yellow oil (5.84 g, 91%). Rf (AcOEt/hexanes 1:4) 0.80. 1H-NMR (400 MHz, CDCl3): 9.77 (CHO); 7.72 –
7.69 (m, 2 Â HÀC(1’), 2 Â HÀC(2’)); 7.42 – 7.34 (m, 2 Â HÀC(3’), 2 Â HÀC(4’), 2 Â HÀC(5’)); 7.31 (d,
J(2,6) ¼ 2.0, HÀC(2)); 7.17 (dd, J(5,6) ¼ 8.0, J(2,6) ¼ 2.0, HÀC(6)); 6.79 (d, J(5,6) ¼ 8.0, HÀC(5)); 3.64 (s,
MeO); 1.13 (s, Me3C). 13C-NMR (100 MHz, CDCl3): 191.1 (CHO); 151.3 (C(4)); 151.1 (C(3)); 135.2
(C(2’/6’)); 132.7 (C(1’)); 130.7 (C(1)); 129.9 (C(4’)); 127.7 (C(3’/5’)); 126.0 (C(6)); 120.0 (C(5)); 110.1
1
(C(2)); 55.3 (MeO); 26.5 Me3C); 19.8 (Me3C). H- and 13C-NMR data are in agreement with the data
given in [17].
(4-{[tert-Butyl(diphenyl)silyl]oxy}-3-methoxyphenyl)methanol (10) [17]. To a soln. of benzaldehyde
9 (5.20 g, 13.3 mmol) in EtOH (80 ml) was added NaBH4 (0.60 g, 16.0 mmol), and the mixture was
stirred for 4 h. The solvent was removed under reduced pressure. AcOEt (10 ml) and aq. sat. NH4Cl
(20 ml) were added to the residue at 08. The org. phase was extracted with AcOEt (3 Â 80 ml) and dried
(Na2SO4). Removal of the solvent under reduced pressure gave 10 as a colorless oil (4.50 g, 86%). Rf
(AcOEt/hexane 3 :7) 0.44. 1H-NMR (400 MHz, CDCl3): 7.70 (d, J ¼ 7.3, 2 Â HÀC(2’’), 2 Â HÀC(6’’));
7.42 – 7.25 (m, 2 Â HÀC(3’’), 2 Â HÀC(4’’), 2 Â HÀC(5’’)); 6.81 (d, J(2’,6’) ¼ 1.8, HÀC(2’)); 6.66 (d,
J(5’,6’) ¼ 8.1, HÀC(5’)); 6.61 (dd, J(5’,6’) ¼ 8.1, J(2’,6’) ¼ 1.8, HÀC(6’)); 4.54 (s, CH2OH), 3.59 (s, MeO);
1.10 (s, Me3C). 13C-NMR (100 MHz, CDCl3): 150.8 (C(4’)); 144.8 (C(3’)); 135.5 (2 Â C(2’’/6’’)); 134.3
(C(1’)); 133.7 (2 Â C(1’’)); 129.8 (2 Â C(4’’)); 127.7 (2 Â C(3’’/5’’)); 120.2 (C(6’)); 119.5 (C(5’)); 111.6
(C(2’)); 65.6 (CH2OH); 55.6 (MeO); 26.9 (Me3C); 20.0 (Me3C). 1H- and 13C-NMR data are in
agreement with the data given in [17].
tert-Butyl[4-(iodomethyl)-2-methoxyphenoxy]diphenylsilane (11). Compound 11 was synthesized
following the procedure described for the iodination of benzyl alcohols in [18] as a yellow oil (64%).
Compound 11 decomposes when stored, even in refrigerator. Therefore, it was used immediately after
synthesis. 1H-NMR (400 MHz, CDCl3): 7.70 – 7.67 (m, 2 Â HÀC(2’), 2 Â HÀC(6’)); 7.41 – 7.32 (m, 2 Â
HÀC(3’), 2 Â HÀC(4’), 2 Â HÀC(5’)); 6.77 (d, J(3,5) ¼ 2.2, HÀC(3)); 6.67 (dd, J(5,6) ¼ 8.2, J(3,5) ¼ 2.2,
HÀC(5)); 6.58 (d, J(5,6) ¼ 8.2, HÀC(6)); 4.39 (s, CH2I), 3.56 (s, MeO); 1.10 (s, Me3C). 13C-NMR
(100 MHz, CDCl3): 150.7 (C(1)); 145.1 (C(2)); 135.6 (2 Â C(2’/6’)); 133.6 (2 Â C(1’)); 132.4 (C(4)); 129.9
(2 Â C(4’)); 127.7 (2 Â C(3’/5’)); 121.2 (C(5)); 120.3 (C(6)); 113.0 (C(3)); 55.6 (MeO); 26.8 (Me3C); 20.0
(Me3C); 7.5 (CH2I).

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4-{[tert-Butyl(diphenyl)silyl]oxy}-3-methoxybenzoic Acid (12). A soln. of benzaldehyde 9 (2.50 g,
6.40 mmol) in acetone (40 ml) was cooled to 08 and Jones reagent (2.67m, 12 ml, 32.0 mmol) was added.
The mixture was allowed to warm to r.t. and was stirred for 12 h. 2-Propanol (60 ml) was added, and the
mixture was stirred for 20 min, and then filtered, and the solid parts were separated. The solvent of the
filtrate was removed under reduced pressure, and the residue was filtered over a short SiO2 column
eluting with AcOEt to give colorless 12 (1.90 g, 73%). M.p. 123 – 1248. Rf (AcOEt/hexane 1:1) 0.65.
1H-NMR (400 MHz, CDCl3): 12.70 – 11.30 (br. s, OH); 7.74 (d, J ¼ 7.7, 2 Â HÀC(2’), 2 Â HÀ6’)); 7.54 (d,
J(2,6) ¼ 1.5, HÀC(2)); 7.53 (dd, J(5,6) ¼ 8.8, J(2,6) ¼ 1.5, HÀC(6)); 7.44 – 7.37 (m, 2 Â HÀC(3’), 2 Â
HÀC(4’), 2 Â HÀC(5’)); 6.79 (d, J(5,6) ¼ 8.8, HÀC(5)); 3.64 (s, MeO); 1.17 (s, Me3C). 13C-NMR
(100 MHz, CDCl3): 172.5 (COOH); 150.64 (C(4)); 150.60 (C(3)); 135.5 (2 Â C(2’/6’)); 133.2 (2 Â C(1’));
130.1 (2 Â C(4’)); 127.9 (2 Â C(3’/5’)); 124.3 (C(6)); 122.7 (C(1)); 120.1 (C(5)); 113.7 (C(2)); 55.5 (MeO);
26.8 (Me3C); 20.0 (Me3C). HR-ESI-MS: 407.1677 ([M þ H]þ, C24H27O4Siþ; calc. 407.1673).
4-{[tert-Butyl(diphenyl)silyl]oxy}-3-methoxybenzoyl Chloride (13). Benzoic acid 12 (0.82 g,
2.01 mmol) was dissolved in SOCl2 (2 ml) and the mixture was heated at reflux for 12 h. The unreacted
SOCl2 was removed under reduced pressure to give 13 as a yellow oil (0.86 g, quant.), which was used for
further reaction without purification. 1H-NMR (400 MHz, CDCl3): 7.71 (dd, J ¼ 8.1, 1.5, 2 Â HÀC(2’), 2 Â
HÀC(6’)); 7.50 – 7.48 (m, HÀC(2), HÀC(6)); 7.42 – 7.34 (m, 2 Â HÀC(3’), 2 Â HÀC(4’), 2 Â HÀC(5’)); 6.75
(d, J(5,6) ¼ 8.8, HÀC(5)); 3.62 (s, MeO); 1.14 (s, Me3C). 13C-NMR (100 MHz, CDCl3): 172.3 (COCl);
150.6 (C(4)); 150.5 (C(3)); 135.5 (2 Â C(2’/6’)); 133.1 (2 Â C(1’)); 130.1 (2 Â C(4’)); 127.9 (2 Â C(3’/5’));
124.2 (C(6)); 122.6 (C(1)); 120.0 (C(5)); 113.6 (C(2)); 55.6 (MeO); 26.8 (Me3C); 20.0 (Me3C).
4-(Acetyloxy)-3-methoxybenzaldehyde (¼4-Formyl-2-methoxyphenyl Acetate; 14) [19]. Vanillin (7)
was acetylated with Ac2O/pyridine as described in [19] to give yellow solid 14 (90%). M.p. 76 – 778 ([20]:
76 – 778). 1H-NMR (400 MHz, CDCl3): 9.93 (s, 1 H, CHO); 7.48 (d, J(2,6) ¼ 1.7, HÀC(2)); 7.46 (dd,
J(5,6) ¼ 7.7, J(2,6) ¼ 1.7, HÀC(6)); 7.20 (d, J(5,6) ¼ 7.7, HÀC(5)); 3.89 (s, MeO); 2.33 (s, C(O)Me).
13C-NMR (100 MHz, CDCl3): 191.2 (CHO); 168.5 (CO of Ac); 152.2 (C(4)); 145.1 (C(3)); 135.5 (C(1));
1
124.9, 123.6 (C(6), C(5)); 111.0 (C(2)); 56.3 (MeO); 20.8 (C(O)Me). H-NMR data are in agreement
with the data given in [19].
4-(Acetyloxy)-3-methoxybenzoic Acid (15) [21]. The procedure described above for the synthesis of
benzoic acid 12 was applied to benzaldehyde 14 to give 15 (76%). M.p. 141 – 1428 ([20]: 141 – 1428). Rf
(AcOEt/hexane 4 :1) 0.46. 1H-NMR (400 MHz, CDCl3): 12.23 (br. s, COOH), 7.76 (dd, J(5,6) ¼ 8.0,
J(2,6) ¼ 1.8, HÀC(6)); 7.71 (d, J(2,6) ¼ 1.8, HÀC(2)); 7.14 (d, J(5,6) ¼ 8.0, HÀC(5)); 3.90 (s, MeO); 2.34 (s,
C(O)Me). 13C-NMR (100 MHz, CDCl3): 171.6 (COOH); 168.7 (CO of ester); 151.4 (C(4)); 144.6 (C(3));
1
128.1 (C(1)); 123.6, 123.2 (C(6), C(5)); 114.0 (C(2)); 56.3 (MeO); 20.9 (C(O)Me). H- and 13C-NMR
data are in agreement with the data given in [21].
4-(Acetyloxy)-3-methoxybenzoyl Chloride (¼4-(Chlorocarbonyl)-2-methoxyphenyl Acetate; 16). 4-
(Acetyloxy)-3-methoxybenzoic acid (15) was reacted with SOCl2 as described in [22] to give 16 as a
colorless oil. Yield: quantitative. Benzoyl chloride 16 was used for further reaction without purification.
1H-NMR (400 MHz, CDCl3): 7.80 (dd, J(5,6) ¼ 8.4, J(2,6) ¼ 2.0, HÀC(6)); 7.65 (d, J(2,6) ¼ 2.0, HÀC(2));
7.18 (d, J(5,6) ¼ 8.4, HÀC(5)); 3.90 (s, MeO); 2.34 (s, C(O)Me). 13C-NMR (100 MHz, CDCl3): 168.3
(CO); 167.8 (CO); 151.6 (C(4)); 145.9 (C(3)); 131.9 (C(1)); 125.5, 123.5 (C(6), C(5)); 114.5 (C(2)); 56.4
(MeO); 20.8 (C(O)Me).
2-Methoxy-4-{[5-(2-phenylethyl)furan-2-yl]carbonyl}phenyl Acetate (17). The FriedelÀCrafts reac-
tion described above for the synthesis of compound 6 was applied to 12 to give ketone 17 as a yellow oil
(59%). Rf (AcOEt/hexane 7:3) 0.33. 1H-NMR (400 MHz, CDCl3): 7.54 (br. s, HÀC(3), overlapped with
HÀC(5)); 7.53 (dd, J(5,6) ¼ 8.0, J(3,5) ¼ 1.8, HÀC(5)); 7.32 – 7.19 (m, 5 arom. H); 7.16 (d, J(3’,4’) ¼ 3.5,
HÀC(3’)); 6.20 (d, J(3’,4’) ¼ 3.5, HÀC(4’)); 3.90 (s, MeO); 3.10 – 3.03 (m, CH2CH2); 2.35 (s, C(O)Me).
13C-NMR (100 MHz, CDCl3): 180.9 (CO of ketone); 168.6 (CO of ester); 161.7 (C(5’)); 151.3 (C(2’));
150.8 (C(1)); 143.2 (C(2)); 140.3 (C(1’’)); 136.2 (C(4)); 128.6 (C(2’’/6’’)); 128.3 (C(3’’/5’’)); 126.4 (C(4’’));
122.6, 122.5, 122.3 (C(6), C(5), C(3’)); 113.0 (C(3)); 108.9 (C(4’)); 56.1 (MeO); 34.0 (PhCH2); 30.2
(furyl CH2); 20.6 (C(O)Me). HR-ESI-MS: 365.1384 ([M þ H]þ, C22H20O5þ ; calc. 365.1384).
2-Methoxy-4-{[5-(2-phenylethyl)furan-2-yl]methyl}phenyl Acetate (18). The reduction method
described above for 6 was applied to ketone 17 to give 18 as a yellow oil (80%). Rf (AcOEt/hexane
7:3) 0.50. 1H-NMR (400 MHz, CDCl3): 7.27 (quasi-t, J ¼ 7.1, HÀC(2’’), HÀC(6’’)); 7.21 – 7.15 (m, HÀC(3’’/

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Helvetica Chimica Acta – Vol. 98 (2015)
4’’/5’’)); 6.96 (d, J(5,6) ¼ 8.0, HÀC(6)); 6.85 (d, J(3,5) ¼ 2.0, HÀC(3)); 6.80 (dd, J(5,6) ¼ 8.0, J(3,5) ¼ 2.0,
HÀC(5)); 5.91, 5.88 (2d, J(3’,4’) ¼ 2.9, HÀC(3’), HÀC(4’)); 3.91 (s, ArCH2Àfuryl); 3.80 (s, MeO);
2.95 – 2.87 (m, CH2CH2); 2.31 (s, C(O)Me). 13C-NMR (100 MHz, CDCl3): 169.5 (CO); 154.7, 152.5
(C(5’), C(2’)); 151.1 (C(1)); 141.5 (C(2)); 138.4 (C(1’’)); 137.7 (C(4)); 128.60 (C(2’’/6’’)); 128.57 (C(3’’/
5’’)); 126.2 (C(4’’)); 122.8 (C(5)); 121.0 (C(6)); 113.0 (C(3)); 107.2 (C(4’)); 106.0 (C(3’)); 56.0 (MeO);
34.6 (2 Â PhCH2); 30.2 (furylÀCH2); 20.9 (C(O)Me). HR-ESI-MS: 373.1410 ([M þ Na]þ, C22H22NaO4þ ;
calc. 373.1410).
2-Methoxy-4-{[5-(2-phenylethyl)furan-2-yl]methyl}phenol (2) [7]. To a soln. of acetate 18 (0.20 g,
0.57 mmol) in MeOH (8 ml) was added a sat. NaHCO3 soln. (2 ml). The mixture was stirred at r.t. for 4 h.
MeOH was evaporated, and org. phases were extracted with AcOEt (3 Â 50 ml) and dried (Na2SO4).
The solvent was removed and the residue was purified by CC with AcOEt/hexane (15 :85) to give 2 as a
yellow oil (149 mg, 83%). Rf (AcOEt/hexane 2 :3) 0.60. 1H-NMR (400 MHz, CDCl3):7.27 (quasi-t, J ¼ 7.4,
HÀC(3’’/5’’)); 7.21 – 7.15 (m, HÀC(2’’/4’’/6’’)); 6.86 (d, J(5,6) ¼ 8.0, HÀC(6)); 6.75 (br. s, HÀC(3)); 6.74
(d, J(5,6) ¼ 8.0, HÀC(5)); 5.87 (br. s, HÀC(3’), HÀC(4’)); 5.50 (s, OH); 3.86 (s, MeO, ArCH2Àfuryl);
2.95 – 2.87 (m, CH2CH2). 13C-NMR (100 MHz, CDCl3): 154.3, 153.2 (C(5’), C(2’)); 146.4 (C(1)); 144.2
(C(2)); 141.3 (C(1’’)); 130.3 (C(4)); 128.35 (C(2’’/6’’)); 128.31 (C(3’’/5’’)); 126.0 (C(4’’)); 121.4 (C(5));
114.2 (C(6)); 111.2 (C(3)); 106.5 (C(4’)); 105.7 (C(3’)); 55.8 (MeO); 34.4 (PhCH2); 34.2 (PhCH2); 30.0
(furyl CH2). 1H- and 13C-NMR data are in agreement with the data given in [7]. HR-ESI-MS: 309.1480
([M þ H]þ, C20H21Oþ3 ; calc. 309.1485).
REFERENCES
[1] P. Claeson, P. Tuchinda, V. Reutrakul, J. Indian Chem. Soc. 1994, 71, 509.
[2] G. M. Keserü, M. Nogradi, Stud. Nat. Prod. Chem. 1995, 17, 357.
[3] P. Rüedi, M. Juch, Curr. Org. Chem. 1999, 3, 623.
[4] P. Claeson, U. P. Claeson, P. Tuchinda, V. Reutrakul, Stud. Nat. Prod. Chem. 2002, 26, 881.
[5] H. Lv, G. She, Nat. Prod. Commun. 2010, 5, 1687.
[6] H. Lv, G. She, Rec. Nat. Prod. 2012, 6, 321.
[7] Y. Sun, K. Tabata, H. Matsubara, S. Kitanaka, T. Suzuki, K. Yasukawa, Planta Med. 2008, 74, 427.
[8] N. An, H.-W. Zhang, L.-Z. Xu, S.-I. Yang, Z.-M. Zou, Food. Chem. 2010, 119, 513.
[9] L. Mavoungou-Gomes, C. R. Seances Acad. Sci., Ser. C. 1970, 270, 750.
[10] J. Cabares, L. Mavoungou-Gomes, Bull. Soc. Chim. Fr. 1986, 401.
[11] V. G. S. Box, P. C. Meleties, Tetrahedron Lett. 1998, 39, 7059.
[12] R. Antonioletti, F. Bonadies, A. Ciammaichella, A. Viglianti, Tetrahedron 2008, 64, 4644.
[13] A. Palmieri, S. Gabrielli, R. Ballini, Chem. Commun. 2010, 46, 6165.
[14] J. J. Heynekamp, W. M. Weber, L. A. Hunsaker, A. M. Gonzales, R. A. Orlando, L. M. Deck, D. L.
Vander Jagt, J. Med. Chem. 2006, 49, 7182.
[15] K. Tangdenpaisal, S. Sualek, S. Ruchirawat, P. Ploypradith, Tetrahedron 2009, 65, 4316.
[16] J. S. Yadav, B. V. S. Reddy, S. Raghavendra, M. Satyanarayana, Tetrahedron Lett. 2002, 43, 4679.
[17] D. Gonzµlez-Calderón, L. J. Benitez-Puebla, C. A. Gonzalez-Gonzalez, M. A. Garcia-Eleno, A.
Fuentes-Benitez, E. Cuevas-YaÇez, D. Corona-Becerril, C. Gonzµlez-Romero, Synth. Commun.
2014, 44, 1258.
[18] V. F. V. Prazeres, L. Castedo, H. Lamb, A. R. Hawkins, C. Gonzµlez-Bello, ChemMedChem 2009, 4,
1980.
[19] D. Takaya, A. Yamashita, K. Kamijo, J. Gomi, M. Ito, S. Maekawa, N. Enomoto, N. Sakamoto, Y.
Watanabe, R. Arai, H. Umeyama, T. Honma, T. Matsumoto, S. Yokoyama, Bioorg. Med. Chem.
2011, 19, 6892.
[20] F. Misani, M. T. Bogert, J. Org. Chem. 1945, 10, 347.
[21] L. Mialon, R. Vanderhenst, A. G. Pemba, S. A. Miller, Macromol. Rapid Commun. 2011, 32, 1386.
[22] K. W. Rosenmund, F. Zetzsche, Ber. Dtsch. Chem. Ges. 1923, 56, 1481.
Received August 23, 2014