Total synthesis of naturally occurring furan compounds 5-{[(4- hydroxybenzyl)oxy]methyl}-2-furaldehyde and pichiafuran C

Article abstract of DOI:10.1055/s-0030-1258455

The synthesis of the natural furan derivatives 5-{[(4-hydroxybenzyl)oxy] methyl}-2-furaldehyde and pichiafuran C is described. Diverse alternative synthetic approaches were developed for the preparation of these natural products. They were prepared through an etherification reaction of the key furan precursor 5-(hydroxymethyl)-2-furaldehyde (HMF), which can be readily obtained from d-fructose, d-glucose, or sucrose, with the corresponding alcohols. 5-{[(4-Hydroxybenzyl)oxy]methyl}-2-furaldehyde was not only obtained in a two-step methodology but also by a biomimetic single-step synthesis. Similarly, pichiafuran C was prepared by three different syntheses, each one by a two-step procedure, also including a biomimetic approach. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258455

1106
PAPER
Total Synthesis of Naturally Occurring Furan Compounds
5-{[(4-Hydroxybenzyl)oxy]methyl}-2-furaldehyde and Pichiafuran C
Synthesis of
N
atur
é
a
l
Furan De
c
rivatives tor Quiroz-Florentino,a R. Israel Hernández-Benitez,a Judit A. Aviña,a,b Eleuterio Burgueño-Tapia,a
Joaquín Tamariz*a
a
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas,
Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala, 11340 México, D.F., Mexico
Fax +52(55)57296300/46211; E-mail: jtamariz@woodward.encb.ipn.mx
Instituto de Investigaciones Quimicobiológicas, Universidad Michoacana de San Nicolas de Hidalgo,
b
Edif. B-1, Ciudad Universitaria, Francisco J. Mujica s/n, 58066 Morelia, Mich., Mexico
Received 5 November 2010; revised 21 December 2010
natural furan derivatives structurally related to 2, were
isolated from the fungus Cladosporium herbarum, which
is in turn extracted from the marine sponge Callyspongia
aerizusa. These two furan derivatives exhibit antimicrobi-
Abstract: The synthesis of the natural furan derivatives 5-{[(4-hy-
droxybenzyl)oxy]methyl}-2-furaldehyde and pichiafuran C is de-
scribed. Diverse alternative synthetic approaches were developed
for the preparation of these natural products. They were prepared
through an etherification reaction of the key furan precursor 5-(hy- al activity against Bacillus subtilis and Staphylococcus
aureus.5 Triketides such as dimethyl b-ketoadipate and
droxymethyl)-2-furaldehyde (HMF), which can be readily obtained
from D-fructose, D-glucose, or sucrose, with the corresponding al-
cohols. 5-{[(4-Hydroxybenzyl)oxy]methyl}-2-furaldehyde was not
were isolated from the marine sponge Plakortis simplex,
only obtained in a two-step methodology but also by a biomimetic
single-step synthesis. Similarly, pichiafuran C was prepared by
the monomethyl ester of the cis,cis-muconic acid, which
seem to be the bioprecursors of the C6 monofuran moiety
of 2 and pichiafurans A and B.4,6
three different syntheses, each one by a two-step procedure, also in-
cluding a biomimetic approach.
The potential pharmacological profile of these com-
Key words: 5-{[(4-hydroxybenzyl)oxy]methyl}-2-furaldehyde,
pichiafuran C, 5-(hydroxymethyl)-2-furaldehyde, Gastrodia elata
Blume, Pichia membranifaciens
pounds, and the interest in continuing with our research
program of carrying out the transformation of biomass
products into furan fine chemicals, as well as the total syn-
thesis of naturally occurring furan derivatives,7 prompted
us to synthesize compounds 1 and 2 through diverse ap-
proaches involving mono- and disaccharides as the start-
ing materials.
The naturally occurring furan compound, 5-{[(4-hydroxy-
benzyl)oxy]methyl}-2-furaldehyde (1) (Figure 1), was re-
cently isolated from the rhizome of Gastrodia elata
Blume (Orchidaceae), and exhibited weak cytotoxicity
against the HT-29 cell line.1 This rhizome has been tradi-
tionally used in Korean and Chinese traditional medicine
for the treatment of headaches, migraines, dizziness, epi-
lepsy, and infantile convulsion tetanus,2 and has many
biomedical properties such as enhancing strength and vi-
rility, improving circulation, and facilitating memory con-
solidation and retrieval.3
5-(Hydroxymethyl)-2-furaldehyde (3, HMF) is consid-
ered to be one of the key products in the transformation of
biomass towards the production of biofuels and fine
chemicals for the post-oil era of the near future.8 There-
fore, an intense effort has been made for its preparation
from diverse biomass sources.9 Among other proce-
dures,10 this seminal compound can be obtained by acid
treatment of mono-, di-, and polysaccharides.11 Due to its
strategic significance for the energetic future of the indus-
trial world, as well as its easy preparation and synthetic
potential, 3 was chosen as the precursor in the synthesis
design of the natural products 1 and 2 (Scheme 1). We
have used it before in the synthesis of some other natural
furan compounds.7 Inspired by a previous report,12 3 was
prepared by a H2SO4-catalyzed transformation of D-fruc-
tose (4a), albeit in a modest yield (68%).
OH
O
O
HO
O
Ph
O
O
1
2
Figure
1
5-{[(4-Hydroxybenzyl)oxy]methyl}-2-furaldehyde (1)
and pichiafuran C (2)
Optimization of the preparation of 3 gave rise to five re-
lated methods, differing in the starting saccharide and the
heating source (Table 1): (a) following the same proce-
Pichiafuran C (2) (Figure 1) is a rare example of a mono-
furan metabolite that was recently isolated from the yeast
Pichia membranifaciens, derived from the marine sponge
Petrosia sp.4 Sumiki’s acid and its acetyl derivative, two
D-fructose
or
H+
D-glucose
or
1
or
2
O
OH
O
sucrose
SYNTHESIS 2011, No. 7, pp 1106–1112
x
x
.
x
x
.2
0
1
1
3
Advanced online publication: 01.03.2011
DOI: 10.1055/s-0030-1258455; Art ID: M07410SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Natural Furan Derivatives
1107
dure as reported with D-fructose (4a) as the starting mate- The synthesis of natural furan compound 1 was designed
rial,7 but increasing the temperature to 115 °C, the yield through several approaches, which differ in the use of the
was improved up to 80%; (b) using method a but taking protected or the unprotected 4-(hydroxymethyl)phenols
D-glucose (4b) as the starting material, 3 was obtained in 6a–f. Although the most common method to prepare
70% yield; (c) using method a but taking sucrose (4c) as ethers is through the Williamson reaction between an al-
the starting material, 3 was obtained in 70% yield;13 (d) cohol and an alkyl halide under basic conditions, all at-
conducting microwave (MW) irradiation of a mixture of tempts failed to achieve the reaction by starting from 1-
4a and H2SO4 (10 mol%) at 125 °C for 15 minutes afford- (benzyloxy)-4-(bromomethyl)benzene (6b) and alcohol 3,
ed 3 in 36%; (e) using method d but taking 4c as the start- either when using potassium or cesium carbonates or so-
ing material, 3 was obtained in 35–64% yield. The yields dium hydride as the base (Scheme 2). With the former
of the latter method varied depending on the quality of the bases the reaction did not take place, and with the latter
chosen sugar, with muscovado sugar resulting in the best the aldehyde group of 3 was reduced. Also the reaction
yield, probably due to the fact that the content of water is failed when the etherification was carried out between 5-
higher, since the produced tarry material was lower (bromomethyl)-2-furaldehyde (8a) and alcohol 6c under
(Table 1, entries 5–7). In these assays, a side-product was similar conditions, due to the decomposition of the
also isolated that corresponded to the key fine chemical former. Therefore, we investigated the formation of the
and widely industrial used compound 2,5-bisformylfuran ether functionality by an acid-catalyzed dehydration reac-
(5).12 The latter is probably formed by oxidation of 3.14 tion between the two alcohols. The direct reaction be-
Although the yields were lower when MW irradiation was tween alcohol 3 and the unprotected phenol 6a, under
applied, several advantages can be taken into account, Brønsted acid catalysis (H2SO4) and a polar solvent
such as an almost solvent-free procedure (the amount of (DMF), furnished only the symmetrical ether from 6a, in-
DMSO used was just enough to moisten the sugar), short stead of the mixed ether. In contrast, when the benzyl pro-
reaction times, and the low prices of the unrefined com- tected alcohol 6c was used in dichloromethane as the
mercial sugars.
solvent, the expected ether 7a was obtained in high yield
(82%). However, the deprotection of the benzyl group by
hydrogenolysis led to the cleavage of all benzylic bonds,
resulting in the formation of a mixture of alcohols 3, 6a,
and 6c, along with other by-products. In order to avoid
this undesired effect, we used the methyl protected deriv-
ative 6d, to attain the wanted ether 7b in good yield (76%)
(Scheme 2). Although it is well known that sodium
ethanethiolate is a deprotection reagent under basic condi-
tions and is rather selective for the cleavage of aryl methyl
ethers,15 in the case of 7b, the reaction took place cleaving
also the remaining benzylic positions of the molecule.
Table 1 Methods for the Preparation of 3a
Entry Saccharide Solvent
MW Temp Time Yield 3/5
(W)b (°C)
(h)
48
48
48
(%)c
–
1
2
3
4
5
6
7
4a
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
115
3 (80)
3 (70)
3 (70)
–
4b
4cd
4a
115
–
115
180
180
180
180
125
125
125
125
0.25 3 (42)
4cd
4cf
4cg
0.25 3 (32)/5 (14)e
0.25 3 (34)/5 (10)e
0.25 3 (64)/5 (3)e
Owing to the previous unsuccessful attempts of deprotec-
tion of 7a and 7b, derivatives 6e and 6f were prepared,
which were protected with the more labile silyl and tosyl
groups, respectively. Then, the reaction of 1.2 mol equiv-
alents of these analogues with 3, in the presence of a cat-
alytic amount of sulfuric acid, led not to the formation of
the corresponding ethers 7c and 7d, but to the desired nat-
ural product 1 in modest yields, with large amounts of
starting alcohol 3 and unprotected alcohol 6a remaining.
Since these results indicated that the starting material 6e
a Reaction conditions: 4 (1 equiv), H2SO4 (10 mol%).
b Pressure of the vessel: 100 psi.
c After purification by column chromatography.
d As refined sugar.
e Calculated per mole of the fructose moiety of sucrose (see ref. 13).
f As standard brown sugar.
g As muscovado sugar.
OR
3
4
OR
H2SO4
2
5
+
O
O
O
X
Y
CH2Cl2
40 °C, 48 h
O
O
6
7
3, X = OH
8a, X = Br
6a, Y = OH, R = H
1, R = H
6b, Y = Br, R = Bn
6c, Y = OH, R = Bn
6d, Y = OH, R = Me
6e, Y = OH, R = TBS
6f, Y = OH, R = Ts
7a, R = Bn
7b, R = Me
7c, R = TBS
7d, R = Ts
H2SO4 115 °C
DMSO 48 h
4a + 6a
Scheme 2
Synthesis 2011, No. 7, 1106–1112 © Thieme Stuttgart · New York

1108
H. Quiroz-Florentino et al.
PAPER
or 6f, and the resulting ether 7c or 7d, respectively, under- analogous starting materials, of course not under our con-
went deprotection during the acid-catalyzed reaction, an ditions but by an enzymatic pathway.
excess (2 mol equiv) of the former was used. Thus, natural
product 1 was efficiently obtained in 81% and 70% yields
from 6e and 6f, respectively, in just two steps starting
from the carbohydrates.
Since pichiafuran (2) also possesses an ether functional
group, we designed several synthetic approaches taking
advantage of the acquired knowledge in the case of 1.
However, in contrast with the latter case, the sulfuric acid
The protected alcohol 6c was prepared in high yield catalyzed etherification reaction between alcohols 3 and
(93%) by direct reaction between the phenolic alcohol 6a 2-phenylethanol (10) yielded a complex mixture of prod-
and BnBr with NaH as the base. By treatment of the ucts, a situation which could be overcome by using cata-
former with PBr3, the benzylic bromide 6b was obtained lytic Yb(OTf)3 as the Lewis acid18 in acetonitrile to give
in almost quantitative yield (97%). The methyl protected furfural ether 11 in 88% yield (Scheme 4). The carbonyl
alcohol 6d was obtained in identical high yield by reduc- group of the latter was reduced by treatment with sodium
tion of the formyl group of commercially available 4- borohydride embedded in silica gel with methanol, pro-
methoxybenzaldehyde (9b) with sodium borohydride in viding the desired natural product 2 in high yield (95%),
wet silica gel.16 In the case of protected benzylic alcohols and in 84% overall yield by two steps.
6e and 6f, their preparation included protection of 4-hy-
Unlike the Williamson reaction between the bromo deriv-
droxybenzaldehyde (9a) with tert-butyldimethylsilyl
ative 8a and alcohol 6c, which failed to produce the ether
chloride and p-TsCl, respectively, followed by reduction
compound 7a, the cesium carbonate promoted reaction
of the aldehyde under analogous conditions as for 6d
between the chloro derivative 8b and alcohol 10 led to 11,
(Scheme 3). This procedure provided 6e and 6f in 93%
albeit in a modest yield (Scheme 4). Interestingly, ther-
mally treating (75 °C) D-fructose (4a) in the presence of
and 83% overall yield, respectively.
Considering that natural product 1 was isolated from Gas- HCl/MgCl2·H2O directly gave 8b in 88% yield.19
trodia elata along with alcohols 3 and 6a,1,17 it is likely
Pursuing a shorter approach to the synthesis of pichiafu-
that 1 is biosynthetically generated from the latter alco-
ran C (2), probably also biomimetic, D-fructose (4a) and
hols. Although 1 was unavailable by direct etherification
10 were used as starting materials (Scheme 4). By treating
of these alcohols, the procedure that we carried out in a
this mixture with H2SO4 in DMSO, and heating it to 125
single step by the use of protected derivatives 6e and 6f
°C for 15 minutes by MW irradiation (180 W), compound
11 was obtained. Because of the presence of an excess of
10 in the reaction mixture, the purification of 11 by col-
umn chromatography was inefficient. Then, the enriched
chromatographic fractions with 11 were submitted to the
next reduction process without further purification. Thus,
can be considered as a formal biomimetic synthesis of 1.
Moreover, we investigated the development of an alterna-
tive biomimetic synthesis of 1, which may entail a cascade
process starting from the originally occurring conversion
of a saccharide into the furan intermediate (probably in
situ formation of 3), and subsequent reaction with alcohol
the treatment of the partially separated residue of 11 with
6a, to give 1 in just one step. Consequently, a mixture of
D-fructose (4a) and 6a was treated with a catalytic amount
of concentrated sulfuric acid in DMSO and heated at 115
°C for 48 hours to afford the expected product 1
(Scheme 2). Even though a low yield was found (30%),
this result would support the idea that the furan product 1
may be eventually formed in nature by combination of
an excess of sodium borohydride embedded in silica gel16
with methanol provided, after purification of the crude by
a more efficient column chromatography, the desired nat-
ural product 2 in 30% overall yield by a two-step process
starting from the monosaccharide.
OR
OR
OR
iii
i or ii
O
O
HO
9a, R = H
9b, R = Me
9c, R = TBS
9d, R = Ts
6d, R = Me (97%)
6e, R = TBS (97%)
6f, R = Ts (98%)
Scheme 3 Reagents and conditions: i) TBDMS, imidazole, 20 °C, 12 h, 96% of 9c; ii) p-TsCl, Et3N, CH2Cl2, r.t., 7 h, 85% of 9d; iii) NaBH4,
MeOH, SiO2/H2O, CH2Cl2, r.t., 30 min.
3
4
i or ii
iv
8
Ph
2
5
+
O
2
O
O
X
HO
Ph
O
O
6
7
3, X = OH
8b, X = Cl
10
11
iii
4a + 10
Scheme 4 Reagents and conditions: i) 3, Yb(OTf)3, MeCN, 80 °C, 5 h, 88% of 11; ii) 8b, Cs2CO3, THF, r.t., 24 h, 58% of 11; iii) H2SO4, MW
(180 W), 125 °C, 15 min; iv) NaBH4, MeOH, SiO2, CH2Cl2, r.t., 30 min, 95% of 2.
Synthesis 2011, No. 7, 1106–1112 © Thieme Stuttgart · New York

PAPER
Synthesis of Natural Furan Derivatives
1109
Method E: Following Method D, with 4c (muscovado sugar) (1.0 g,
2.92 mmol) in DMSO (1 mL) and concd H2SO4 (0.028 g, 0.286
mmol), to give 3 (0.26 g, 64%) as a pale yellow oil.7a
Spectral data of the final products were in agreement with
those reported for the natural compounds.1,4 2D NMR ex-
periments (HMQC and HMBC) were performed to assign
the signals of the 1H and 13C NMR spectra of 1 and 2, and
of their synthetic precursors (see experimental section).
[4-(Benzyloxy)phenyl]methanol (6c)
To a solution of 6a (1.0 g, 8.06 mmol) in anhyd DMF (22 mL) at
0 °C and under N2 was added NaH (0.35 g, 8.0 mmol). At r.t., BnBr
(1.37 g, 8.01 mmol) was added, and the mixture was stirred for 6 h.
The solvent was removed under vacuum, the residue dissolved in
CH2Cl2 (30 mL), and washed with H2O (2 × 30 mL). The combined
organic layers were dried (Na2SO4), filtered, the solvent removed
under vacuum, and the residue was purified by column chromatog-
raphy (silica gel, 30 g, hexane–EtOAc, 7:3) to give 6c (1.6 g, 93%)
as a white solid; Rf = 0.26 (hexane–EtOAc, 7:3); mp 85–86.5 °C
(hexane–EtOAc, 8:2) (Lit.21 mp 84.5–85 °C).
In summary, we have described the first total syntheses of
natural products 1 and 2 through diverse routes. Most of
these involved the previous preparation of the furan pre-
cursor 3 and subsequent transformation to the desired nat-
ural products by formation of the key ether functional
group in a formal biomimetic total synthesis. Moreover,
when looking for a shorter and also a biomimetic ap-
proach, the synthesis of these molecules was also accom-
plished by direct conversion of the monosaccharide 4a in 1H NMR (300 MHz, CDCl3): d = 1.89 (br s, 1 H, OH), 4.58 (s, 2 H,
CH2OH), 5.05 (s, 2 H, CH2OPh), 6.92–6.98 (m, 2 H, ArH), 7.24–
the presence of the corresponding alcohols 6a and 10, by
7.31 (m, 2 H, ArH), 7.31–7.45 (m, 5 H, PhH).
acid-catalyzed etherification promoted by thermal or MW
irradiation.
13C NMR (75.4 MHz, CDCl3): d = 64.8 (CH2OH), 69.9 (CH2OPh),
114.8 (ArH), 127.4 (PhH), 127.9 (PhH), 128.5 (ArH), 128.6 (PhH),
133.3 (Ar), 136.8 (Ph), 158.2 (Ar).
Melting points (uncorrected) were determined with an Electrother-
mal capillary melting point apparatus. IR spectra were recorded on
1-(Benzyloxy)-4-(bromomethyl)benzene (6b)
To a solution of 6c (0.20 g, 1.03 mmol) in anhyd CH2Cl2 (5 mL) at
0 °C and under N2 was added dropwise PBr3 (0.28 g, 1.03 mmol) in
a Perkin-Elmer 2000 spectrophotometer. 1H and 13C NMR spectra
were recorded on a Varian Mercury (300 MHz) or a Varian VNMR
(500 MHz) instrument, with CDCl3 as the solvent and TMS as in-
anhyd CH2Cl2 (5 mL). After stirring at the same temperature and in
ternal standard. Mass spectra (MS) were taken, in electron impact
the dark for 2 h, the mixture was warmed to r.t., stirred for 1 h,
poured into ice, and extracted with Et2O (2 × 10 mL). The combined
organic layers were dried (Na2SO4), and the solvent removed under
mode (70 eV), on a Thermo-Finnigan Polaris Q spectrometer. High-
resolution mass spectra (HRMS), in electron impact and FAB+
modes, were obtained on Jeol JSM-GCMateII and Jeol JMS-SX
102 spectrometers, respectively. Microwave (MW) irradiation was
vacuum to give 0.25 g (97%) of 6b as a dark solid, which rapidly
decomposed when exposed to light; Rf = 0.75 (hexane–EtOAc,
performed on SEV/MIC-1 (Mexico)20 and CEM MW reactors. An-
alytical TLC was carried out using E. Merck silica gel 60 F254 coated
0.25 plates, visualized by a long and short wavelength UV lamp.
Flash column chromatography was performed over Natland Inter-
national Co. silica gel (230–400 mesh). All air moisture sensitive
reactions were carried out under N2 using oven-dried glassware.
THF was freshly distilled over Na; DMF, CH2Cl2, and EtOAc were
distilled over CaH2, prior to use. DMSO and acetone were dried by
distillation after treatment with 4Å molecular sieves. Et3N was
freshly distilled from NaOH. All other reagents were used without
further purification. Concd H2SO4 used was 98% and concd HCl
35%.
8:2); mp 85–85.5 °C (cold hexane–Et2O, 9:1) (Lit.21mp 85–86 °C).
1H NMR (300 MHz, CDCl3): d = 4.50 (s, 2 H, CH2Br), 5.05 (s, 2 H,
CH2OPh), 6.90–6.96 (m, 2 H, ArH), 7.28–7.45 (m, 7 H, ArH).
13C NMR (100 MHz, CDCl3): d = 33.9 (CH2Br), 70.0 (CH2OPh),
115.1 (C-3), 127.4 (ArH), 128.0 (ArH), 128.6 (C-2), 130.2 (ArH),
130.4 (C-1), 136.7 (Ar), 158.8 (C-4).
4-(tert-Butyldimethylsilyloxy)benzaldehyde (9c)
To a solution of 9a (0.25 g, 2.05 mmol) in anhyd CH2Cl2 (5 mL) at
0 °C were added tert-butyldimethylsilyl chloride (0.25 g, 1.66
mmol) and imidazole (0.25 g, 3.68 mmol), and the mixture was
stirred at r.t. overnight. H2O (5 mL) was added and the mixture ex-
tracted with CH2Cl2 (2 × 10 mL). The combined organic layers were
dried (Na2SO4), and the solvent removed under vacuum to give 9c
(0.46 g, 96%) as a pale yellow oil, which was used without further
purification;22 Rf = 0.80 (hexane–EtOAc, 8:2).
5-(Hydroxymethyl)-2-furaldehyde (3)
Method A: A solution of 4a (1.0 g, 5.55 mmol) in DMSO (5 mL) and
concd H2SO4 (0.055 g, 0.56 mmol) contained in a flask fitted with
a Dean–Stark trap and condenser was stirred at 20 °C for 30 min,
then heated to 115 °C for 48 h. The mixture was diluted with EtOAc
(20 mL), stirred at 20 °C for 20 min, filtered over Celite, and the sol-
vent was removed under high vacuum. The residue was purified by
column chromatography over silica gel (30 g, hexane–EtOAc, 7:3)
to give 3 (0.56 g, 80%).
[4-(tert-Butyldimethylsilyloxy)phenyl]methanol (6e)
To a suspension of 9c (0.5 g, 2.1 mmol) in anhyd CH2Cl2 (5 mL) and
silica gel (0.64 g, 10.7 mmol) at 0 °C was added NaBH4 (0.08 g, 2.1
mmol) and the mixture was stirred for 5 min. MeOH (1 mL) was
added and the mixture stirred at r.t. for 30 min, then filtered by col-
umn chromatography over silica gel (5 g, CH2Cl2) to give 6e (0.49
g, 97%) as a colorless oil,23 which was used without further purifi-
cation; Rf = 0.40 (hexane–EtOAc, 8:2).
Method B: Following Method A, with 4b (1.0 g, 5.6 mmol) in
DMSO (5 mL) and concd H2SO4 (0.055 g, 0.56 mmol), to give 3
(0.49 g, 70%).
Method C: Following Method A, with 4c (refined sugar) (1.0 g, 2.92
mmol) in DMSO (5 mL) and concd H2SO4 (0.028 g, 0.286 mmol),
to give 3 (0.26 g, 70%).
4-(Formyl)phenyl 4-Methylbenzenesulfonate (9d)
To a mixture of 9a (1.0 g, 8.2 mmol) in anhyd CH2Cl2 (50 mL) and
Et3N (0.84 g, 8.3 mmol) at 0 °C and under N2 was added dropwise
a solution of p-TsCl (2.7 g, 14.2 mmol) in CH2Cl2 (30 mL), and the
mixture was stirred at r.t. for 7 h. The mixture was washed with H2O
(2 × 50 mL), the combined organic layers were dried (Na2SO4), and
the solvent removed under vacuum to give 9d (1.92 g, 85%) as a
pale purple solid; mp 72–74 °C (hexane) (Lit.24b mp 72–73 °C);
Rf = 0.40 (hexane–EtOAc, 7:3).
Method D: A suspension of 4a (1.0 g, 5.6 mmol) in DMSO (1 mL)
and concd H2SO4 (0.055 g, 0.56 mmol) was subjected to microwave
irradiation (180 W) at 125 °C for 15 min. The mixture was diluted
with CH2Cl2 (10 mL) and filtered through a short column chroma-
tography over silica gel (10 g, CH2Cl2). The residue was purified by
column chromatography over silica gel (20 g, hexane–EtOAc, 7:3)
to give 3 (0.29 g, 42%).
Synthesis 2011, No. 7, 1106–1112 © Thieme Stuttgart · New York

1110
H. Quiroz-Florentino et al.
PAPER
IR (film): 1703, 1597, 1497, 1374, 1297, 1200, 1173, 1150, 1092,
864, 709 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.46 (s, 3 H, ArCH3), 7.16–7.22
(m, 2 H, ArH), 7.26–7.38 (m, 2 H, ArH), 7.66–7.74 (m, 2 H, ArH),
7.80–7.88 (m, 2 H, ArH), 9.98 (s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 63.7 (C-6), 69.9 (CH2OPh), 72.5
(C-7), 111.2 (C-4), 114.8 (ArH), 122.2 (C-3), 127.4 (PhH), 127.9
(PhH), 128.6 (PhH), 129.4 (Ar), 129.6 (ArH), 136.8 (Ar), 152.5 (C-
2), 158.4 (C-5), 158.6 (Ar), 177.7 (CHO).
HRMS (EI): m/z [M + H]+ calcd for C20H18O4: 323.1283; found:
323.1278.
13C NMR (125 MHz, CDCl3): d = 21.8 (ArCH3), 123.1 (ArH),
128.4 (ArH), 129.9 (ArH), 131.3 (ArH), 131.8 (Ar), 134.7 (Ar),
145.9 (Ar), 153.8 (Ar), 190.7 (CHO).
5-{[(4-Methoxybenzyl)oxy]methyl}-2-furaldehyde (7b)
Following the procedure for 7a, a mixture of 6d (0.25 g, 1.81
mmol), 3 (0.23 g, 1.83 mmol), and concd H2SO4 (0.02 g, 0.20
mmol) in anhyd CH2Cl2 (10 mL) gave, after purification of the
crude by column chromatography (silica gel, 10 g, hexane–EtOAc,
9:1), 7b (0.34 g, 76%) as a pale yellow oil; Rf = 0.67 (hexane–
EtOAc, 7:3).
MS: m/z (%) = 276 ([M]+, 14), 155 (93), 91 (100), 65 (32).
4-(Hydroxymethyl)phenyl 4-Methylbenzenesulfonate (6f)
Following the procedure for 6e, a mixture of 9d (5.0 g, 1.81 mmol),
silica gel (1.1 g, 18.3 mmol), and NaBH4 (0.07 g, 1.84 mmol) in
anyhd CH2Cl2 (5 mL) gave, after purification of the crude by col-
umn chromatography over silica gel (15 g, hexane–EtOAc, 7:3), 6f
(0.49 g, 98%) as a brown yellow oil;24c Rf = 0.20 (hexane–EtOAc,
7:3).
IR (film): 1677, 1611, 1512, 1246, 1174, 1070, 1030, 815, 754
cm–1.
1H NMR (300 MHz, CDCl3): d = 3.77 (s, 3 H, CH3O), 4.51 (s, 2 H,
H-6), 4.52 (s, 2 H, H-7), 6.51 (d, J = 3.6 Hz, 1 H, H-4), 6.82–6.91
(m, 2 H, ArH), 7.20 (d, J = 3.6 Hz, 1 H, H-3), 7.22–7.30 (m, 2 H,
ArH), 9.57 (s, 1 H, CHO).
13C NMR (75.4 MHz, CDCl3): d = 54.9 (CH3O), 63.4 (C-6), 72.2
(C-7), 111.1 (C-4), 113.6 (ArH), 122.0 (C-3), 129.0 (Ar), 129.3
(ArH), 152.2 (C-2), 158.2 (C-5), 159.1 (Ar), 177.4 (CHO).
IR (film): 3367, 1597, 1503, 1369, 1197, 1174, 1151, 1092, 1015,
866, 814 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.20 (br s, 1 H, OH), 2.44 (s, 3 H,
ArCH3), 4.62 (s, 2 H, CH2OH), 6.92–6.96 (m, 2 H, ArH), 7.23–7.27
(m, 2 H, ArH), 7.28–7.32 (m, 2 H, ArH), 7.66–7.70 (m, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 21.6 (ArCH3), 64.2 (CH2OH),
122.3 (ArH), 127.9 (ArH), 128.4 (ArH), 129.7 (ArH), 132.2 (Ar),
139.8 (Ar), 145.4 (Ar), 148.8 (Ar).
HRMS (EI): m/z [M + H]+ calcd for C14H15O4: 247.0970; found:
247.0970.
MS: m/z (%) = 278 ([M]+, 47), 261 (11), 249 (5), 155 (51), 123 (37),
107 (53), 91 (100), 77 (13), 65 (33).
5-{[(4-Hydroxybenzyl)oxy]methyl}-2-furaldehyde (1)
Method A: To a mixture of 3 (0.25 g, 1.98 mmol) and 6e (0.47 g,
1.97 mmol) in CH2Cl2 (15 mL) at 20 °C and under N2 was added
concd H2SO4 (0.02 g, 0.20 mmol) in anhyd CH2Cl2 (5 mL). The
mixture was stirred at 40 °C for 24 h. Then, an additional amount of
6e (0.47 g, 1.97 mmol) in CH2Cl2 (5 mL) was added, and the mix-
ture was again stirred at 40 °C for 24 h. The mixture was washed
with H2O (2 × 10 mL), the organic layer dried (Na2SO4), the solvent
removed under vacuum, and the residue was purified by column
chromatography (silica gel, 10 g, hexane–EtOAc 95:5) to give 1
(0.37 g, 81%) as a pale yellow solid.
(4-Methoxyphenyl)methanol (6d)
Following the procedure for 6f, a mixture of 9b (0.50 g, 3.68 mmol),
silica gel (2.2 g, 36.7 mmol), and NaBH4 (0.14 g, 3.68 mmol) in an-
hyd CH2Cl2 (5 mL) gave, after purification of the crude by column
chromatography over silica gel (15 g, hexane–EtOAc, 7:3), 6d (0.49
g, 97%) as a colorless oil;25 Rf = 0.44 (hexane–EtOAc, 7:3).
IR (CH2Cl2): 3365, 2058, 1996, 1885, 1770, 1612, 1586, 1513,
1462, 1442, 1421, 1369, 1301, 1247, 1175, 1110, 1033, 933, 817,
753, 708, 637, 572, 515 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.73 (s, 3 H, CH3O), 4.48 (s, 2 H,
CH2OH), 6.78–6.85 (m, 2 H, H-3), 7.15–7.24 (m, 2 H, H-2).
13C NMR (125 MHz, CDCl3): d = 55.0 (CH3O), 64.2 (CH2OH),
113.6 (C-3), 128.4 (C-2), 133.0 (C-1), 158.7 (C-4).
Method B: Following Method A, to a mixture of 3 (0.25 g, 1.98
mmol) and 6f (0.55 g, 1.98 mmol) was added concd H2SO4 (0.02 g,
0.20 mmol) in anhyd CH2Cl2 (20 mL). After adding the second por-
tion of 6f (0.55 g, 1.98 mmol), the mixture was stirred at 40 °C for
48 h to give 1 (0.32 g, 70%) as a pale yellow solid.
Method C: In a flask fitted with a Dean–Stark trap and condenser, a
mixture of 4a (1.0 g, 5.56 mmol) and concd H2SO4 (0.055 g, 0.56
mmol) in DMSO (5 mL) was stirred at 20 °C for 30 min; then 6a
(0.55 g, 4.44 mmol) was added and the mixture was stirred at 115
°C for 48 h. The mixture was diluted with EtOAc (20 mL), stirred
at 20 °C for 20 min, and filtered over Celite. The solvent was re-
moved under vacuum and the residue purified by column chroma-
tography (silica gel, 30 g, hexane–EtOAc, 7:3) to give 1 (0.30 g,
30%) as a pale yellow solid;1 mp 84–85 °C; Rf = 0.22 (hexane–
EtOAc, 7:3).
MS: m/z (%) = 138 ([M]+, 36), 122 (9), 121 (100), 109 (7), 91 (4),
77 (4).
5-({[(4-Benzyloxy)benzyl]oxy}methyl)-2-furaldehyde (7a)
To a mixture of 6c (0.20 g, 0.93 mmol) and 3 (0.12 g, 0.95 mmol)
in anhyd CH2Cl2 (15 mL) at 20 °C and under N2 was added concd
H2SO4 (0.01 g, 0.10 mmol) in anhyd CH2Cl2 (5 mL). The mixture
was stirred at 40 °C for 48 h, washed with H2O (2 × 10 mL), and the
organic layer was dried (Na2SO4). The solvent was removed under
vacuum, and the residue purified by column chromatography (silica
gel, 10 g, hexane–EtOAc, 9:1) to give 7a (0.38 g, 82%) as a pale
yellow oil; Rf = 0.44 (hexane–EtOAc, 7:3).
IR (KBr): 3341, 3108, 2933, 1677, 1610, 1517, 1439, 1401, 1371,
1264, 1199, 1050, 1033, 949, 839, 819, 794 cm–1.
1H NMR (500 MHz, CD3OD): d = 4.47 (s, 2 H, H-7), 4.53 (s, 2 H,
H-6), 6.61 (d, J = 3.5 Hz, 1 H, H-4), 6.73–6.78 (m, 2 H, ArH), 7.14–
7.19 (m, 2 H, ArH), 7.36 (d, J = 3.5 Hz, 1 H, H-3), 9.54 (s, CHO),
13C NMR (125 MHz, CD3OD): d = 64.5 (C-6), 73.6 (C-7), 112.7
(C-4), 116.2 (C-3¢), 124.4 (C-3), 129.7 (C-1¢), 131.0 (C-2¢), 154.2
(C-2), 158.6 (C-4¢), 160.3 (C-5), 179.6 (CHO).
IR (CH2Cl2): 2929, 1697, 1610, 1511, 1454, 1361, 1242, 1173,
1078, 1021, 816, 738, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.53 (s, 2 H, H-6), 4.54 (s, 2 H, H-
7), 5.06 (s, 2 H, CH2OPh), 6.51 (d, J = 3.6 Hz, 1 H, H-4), 6.90–7.02
(m, 2 H, ArH), 7.20 (d, J = 3.6 Hz, 1 H, H-3), 7.22–7.46 (m, 7 H,
ArH), 9.61 (s, 1 H, CHO).
HRMS (FAB): m/z [M]+ calcd for C13H12O4: 232.0736; found:
232.0732.
Synthesis 2011, No. 7, 1106–1112 © Thieme Stuttgart · New York

PAPER
Synthesis of Natural Furan Derivatives
1111
5-(Chloromethyl)-2-furaldehyde (8b)
mL) was added at r.t. and under N2. The mixture stirred at r.t. for 10
min and MeOH (1 mL) was added. The mixture was stirred at r.t.
for 30 min, diluted with CH2Cl2 (20 mL), and stirred at r.t. for 20
min. The mixture was then filtered over Celite, the solvent removed
under vacuum, and the residue purified by column chromatography
(silica gel, 30 g, hexane–EtOAc, 99:1) to give 2 (0.39 g, 30%) as a
pale yellow oil.
Method A: A solution of 4b (1.0 g, 5.55 mmol) in toluene (10 mL)
contained in a flask fitted with a Dean-Stark trap and condenser was
stirred at 0 °C. To this was added a 5% solution of MgCl2·6H2O in
concd HCl, and then the mixture was heated to 75 °C for 2.5 h. Sat.
aq NaHCO3 (20 mL) was added, the organic layer was separated,
and dried (Na2SO4). The solvent was removed under vacuum and
the residue was purified by column chromatography over silica gel
(30 g, hexane–EtOAc, 95:5) to give 8b (0.65 g, 81%) as a brown oil.
Method B: A suspension of 11 (0.45 g, 1.96 mmol), silica gel (1.0 g,
16.7 mmol), and NaBH4 (0.074 g, 1.95 mmol) in CH2Cl2 (5 mL)
was stirred at r.t. and under N2. The mixture was stirred at r.t. for 10
min, then MeOH (1 mL) was added. The mixture was stirred at r.t.
for 30 min, diluted with CH2Cl2 (20 mL), stirred at r.t. for 20 min,
and then filtered over Celite. The solvent was removed under vacu-
um, and the residue purified by column chromatography (silica gel,
30 g, hexane–EtOAc, 99:1) to give 2 (0.43 g, 95%) as a pale yellow
oil;4 Rf = 0.29 (hexane–EtOAc, 7:3).
Method B: Compound 4a (1.8 g, 0.1 mol) was mixed with toluene
(15 mL), H2O (0.22 mL), and MgCl2·6H2O (2.04 g, 1.0 mol), and
the mixture was heated to 75 °C for 30 min. Concd HCl (3.14 g) was
added, and the mixture was heated to 75 °C for 1 h. The solid resi-
due was filtered and washed with toluene (50 mL), and the organic
layer was washed with brine (2 × 100 mL) and dried (Na2SO4). The
solvent was removed under vacuum and the residue was purified by
column chromatography over silica gel (30 g, CH2Cl2) to give 8b
(1.16 g, 88%) as a pale brown oil;19a Rf = 0.51 (hexane–EtOAc,
7:3).
IR (film): 3391, 2924, 2855, 1731, 1454, 1376, 1274, 1082, 935,
822, 749, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.91 (t, J = 7.3 Hz, 2 H, H-8), 3.69
(t, J = 7.3 Hz, 2 H, H-7), 4.44 (s, 2 H, H-6), 4.58 (br s, 2 H, CH2OH),
6.24 (s, 2 H, H-3, H-4), 7.19–7.23 (m, 2 H, H-2¢, H-4¢), 7.26–7.31
(m, 2 H, H-3¢).
13C NMR (125 MHz, CDCl3): d = 36.2 (C-8), 57.6 (CH2OH), 64.9
(C-6), 71.2 (C-7), 108.4 (C-3), 110.0 (C-4), 126.2 (C-4¢), 128.3 (C-
2¢), 128.9 (C-3¢), 138.7 (C-1¢), 151.8 (C-5), 154.3 (C-2).
IR (CH2Cl2): 1676, 1519, 1398, 1261, 1197, 1021, 970, 807, 771,
754, 721 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.45 (s, 2 H, CH2Cl), 6.53 (d,
J = 3.6 Hz, 1 H, H-4), 7.15 (d, J = 3.6 Hz, 1 H, H-3), 9.55 (s, CHO),
13C NMR (125 MHz, CDCl3): d = 36.4 (CH2Cl), 111.9 (C-4), 121.9
(C-3), 152.6 (C-2), 155.9 (C-5), 177.6 (CHO).
HRMS (EI): m/z [M]+ calcd for C14H16O3: 232.1099; found:
232.1100.
5-{[1-(2-Phenyl)ethoxy]methyl}-2-furaldehyde (11)
Method A: To a mixture of 3 (0.25 g, 1.98 mmol) and 10 (1.21 g,
9.92 mmol) in MeCN (2 mL) at 20 °C and under N2 was added
Yb(OTf)3 (99.9%) (0.012 g, 0.02 mmol). The mixture was stirred at
80 °C for 5 h and filtered over Celite. The solvent was removed un-
der vacuum, and the residue purified by column chromatography
over silica gel (30 g, hexane–EtOAc, 99:1) to give 11 (0.4 g, 88%)
as a pale yellow oil.
Acknowledgment
We thank Ehecatl M. Labarrios, Alberto Jerezano, and Fabiola
Jiménez for their help in spectrometric measurements, and Bruce
Allan Larsen for reviewing the English of the manuscript. J.T.
acknowledges SIP/IPN (Grants 20070339, 20080527, 20090519,
and 20100236) and CONACYT (Grants 43508Q and 83446) for fi-
nancial support. H.Q.-F. and R.I.H.-B. thank CONACYT for the
award of a scholarship, and SIP/IPN (PIFI) and Ludwig K. Hellweg
Foundation for scholarship complements. J.A.A. gratefully
acknowledges CONACYT for a postdoctoral fellowship. E.B.-T.
and J.T. are fellows of the EDI-IPN and COFAA-IPN programs.
Method B: To a mixture of 8b (0.236 g, 1.64 mmol) and 10 (0.2 g,
1.64 mmol) in anhyd THF (2 mL) at 20 °C and under N2 was added
Cs2CO3 (0.534 g, 1.64 mmol). The mixture was stirred at 20 °C for
24 h, filtered, and diluted with EtOAc (20 mL) and H2O (10 mL).
The aqueous layer was washed with EtOAc (2 × 10 mL), the com-
bined organic layers dried (Na2SO4), and the solvent removed under
vacuum. The residue purified by column chromatography over sili-
ca gel (10 g, hexane–EtOAc, 8:2) to give 11 (0.22 g, 58%) as a pale
yellow oil;26 Rf = 0.66 (hexane–EtOAc, 7:3).
References
IR (film): 1679, 1521, 1453, 1353, 1276, 1191, 1019, 808, 751, 699
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.92 (t, J = 7.0 Hz, 2 H, H-8), 3.74
(t, J = 7.0 Hz, 2 H, H-7), 4.54 (s, 2 H, H-6), 6.44 (d, J = 3.5 Hz, 1
H, H-4), 7.19 (d, J = 3.5 Hz, 1 H, H-3), 7.21–7.34 (m, 5 H, PhH),
9.60 (s, 1 H, CHO).
13C NMR (125 MHz, CDCl3): d = 36.2 (C-8), 65.1 (C-6), 71.6 (C-
7), 111.0 (C-4), 121.9 (C-3), 126.3 (C-4¢), 128.4 (C-2¢), 128.9 (C-
3¢), 138.5 (C-1¢), 152.5 (C-2), 158.5 (C-5), 177.7 (CHO).
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