An improved and scale-up synthesis of 6-hydroxybenzofuran

Article abstract of DOI:10.1007/s11164-015-2288-7

An optimized process for the preparation of 6-hydroxybenzofuran is described. This process consists of three steps: the reaction of 2-hydroxy-4-methoxybenzaldehyde with chloroacetic acid, the formation of the 6-methoxybenzofuran in acetic anhydride, and t

Full text of DOI:10.1007/s11164-015-2288-7

Res Chem Intermed
DOI 10.1007/s11164-015-2288-7
An improved and scale-up synthesis
of 6-hydroxybenzofuran
Shu-Yong Song1 He-Lin Lu1 Gui-Fei Wang1
•
•
•
Yi-Qiu Yang1 Yun-Sheng Huang1
•
Received: 14 August 2015 / Accepted: 21 September 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract An optimized process for the preparation of 6-hydroxybenzofuran is
described. This process consists of three steps: the reaction of 2-hydroxy-4-
methoxybenzaldehyde with chloroacetic acid, the formation of the 6-methoxyben-
zofuran in acetic anhydride, and the demethylation with sodium 1-dodecanethiolate
to afford the desired product. The entire process is safe, cost effective, environ-
mentally benign, and scalable. A production scale of over 2.6 kg product was
achieved in good overall yield.
Keywords 6-Hydroxybenzofuran Á 6-Methoxybenzofuran Á Sodium
1-dodecanethiolate
Introduction
Benzofuran is one of the most widely distributed structures and compounds
containing this structure have demonstrated a variety of biological activities [1–4].
Among them, 6-hydroxybenzofuran (6-HBF) is the most frequently occurring
scaffold in many natural and pharmaceutical products, such as moracins A–Z [2],
furochromones [5], psoralen and related analogs [2].
Many methods have been developed for the synthesis of benzofuran derivatives
[6, 7]. For the particular compound of 6-HBF and its closely related structures, there
are a few synthetic methods reported in the literature (Scheme 1), including the
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2288-
7) contains supplementary material, which is available to authorized users.
&
Yun-Sheng Huang
yshuang@gdmc.edu.cn
1
Guangdong Medical College School of Pharmacy, 1 Xincheng Ave, Songshan Lake
Technology Park, Dongguan 523808, China
123

S.-Y. Song et al.
NO2
O
COOH
O
H
O
MeO
OH
HO
OH
reduction
Nef
decarboxylation
demethylation
O
reduction
cyclization
acidification
O
HO
O
HO
demethylation
O
reduction
acidification
O
R
O
O
O
MeO
Scheme 1 Methods of preparation of 6-HBF
reduction of protected 6-hydroxy-[2H]-benzofuran-3-one [8, 9], cyclocondensation
of 2-(2,4-dihydroxyphenyl)-1-nitroethane via a Nef reaction [10], decarboxylation
of 6-hydroxybenzofuran-2-carboxylic acid or its ester [11], demethylation of the
corresponding 6-methoxybenzofuran [12], and cyclization of the corresponding
3-alkoxyphenyloxyacetaldyhyde [13]. However, each of the aforementioned
methods has some limitations, such as cost, difficulty of processing, scalability,
or environmental hazards. The drawbacks for the reduction of 6-hydroxy-[2H]-
benzofuran-3-one are the difficulty of producing the starting material itself, the
requirement of protecting the 6-hydroxy group, the cost of the reducing agent, and
the formation of dihydrobenzofuran byproduct due to over-reduction [14].
Cyclocondensation of the corresponding nitroethane involving the aldol condensa-
tion of 2,4-dihydroxybenzaldehyde and nitromethane, reduction of the double bond,
and a Nef reaction usually gives an overall low yield. Decarboxylation requires
heating of the corresponding 6-methoxybenzofuran-2-carboxylic acid in quinoline
in the presence of copper metal above 230 °C, and thus is difficult to scale up [11,
15, 16]. The available methods of demethylation of the corresponding 6-methoxy-
benzofuran can be furnished by boron tribromide at low temperature (-78 °C) [17],
sodium ethanthiolate (environmentally hazardous) [12, 18], or pyridine hydrochlo-
ride above 200 °C [11]. Lastly, the cyclization of the corresponding
3-methoxyphenyloxyacetaldehyde diethyl acetal usually gives an inseparable
mixture of both 4-methoxy- and 6-methoxy-substituted products [19].
Recently, we needed to scale up a project with an initial requirement of 2 kg of
6-HBF (1) as an intermediate. Due to the aforementioned shortcomings for these
methods in the literature, we decided to develop a scalable process to use
2-hydroxy-4-methoxybenzaldehyde (2) as the starting material. The new process
includes the following: 2 reacts with chloroacetic acid to give 2-(2-formyl-5-
methoxyphenoxy)acetic acid (3); 3 undergoes a cyclization process to afford
6-methoxybenzofuran (4); 4 goes a demethylation step to afford the desired product
1 (Scheme 2). Alternatively, we also used ethyl bromoacetate to react with 2 to
123

An improved and scale-up synthesis of 6-hydroxybenzofuran
CHO
CHO
c
b
a
OH
O
MeO
O
MeO
O
HO
MeO
OH
d
O
4
1
3
2
e
CHO
O
MeO
O
O
5
Scheme 2 Preparation of 6-HBF. Reagents and conditions: (a) chloroacetic acid/H2O/NaOH, 100 °C;
(b) Ac2O/NaOAc, 125–130 °C; (c) NaS(CH2)11CH3/DMF, 120–130 °C; (d) ethyl bromoacetate/acetone/
K2CO3, reflux; (e) NaOH/MeOH, rt
obtain ethyl 2-(2-formyl-5-methoxyphenoxy)acetate (5) that was easily converted to
3 by hydrolysis.
The first step was carried out according to a procedure described by Kalish et al.
[20], by reacting 2 with chloroacetic acid in basic condition in water. The
cyclization of 3 can be furnished by treating the intermediate with acetic anhydride
in the presence of sodium acetate, according to a reported procedure for a
structurally related product [21]. Finally, the 6-methoxybenzofuran was heated with
sodium dodecanethiolate, an odorless demethylation method [18, 22], to form the
desired product 1. The four-step procedure via intermediate 5 normally affords a
higher overall yield and is easy to process in small-scale. But in large-scale
production, the three-step procedure is preferred with a decreased overall cost.
Though Kalish et al. [20] described a similar two-step process for making
6-methoxybenzofuran, the optimized three step process of making 1 has not been
reported in the literature. Thus, we hereby report a simple, scalable, cost-effective,
environmentally benign process for the preparation of 6-HBF.
Results and discussion
Initially, we designed a four-step procedure by reacting 2-hydroxy-4-methoxyben-
zaldehyde (2) with ethyl bromoacetate to afford the ethyl 2-(2-formyl-5-
methoxyphenoxy)acetate (5), hydrolysis of ester 5 to give the corresponding 2-(2-
formyl-5-methoxyphenoxy)acetic acid (3), cyclization of 3 to give 6-methoxyben-
zofuran (4), and demethylation of 4 to afford the desired product 1. The first step
was conducted in acetone at refluxing to afford intermediate 5 in high yield
(Table 1).
The hydrolysis of intermediate 5 was conducted with NaOH in methanol
(Table 2). The reaction was best carried out at room temperature and produced
byproducts at high temperature (Table 2, entries 1 and 2). It required 1.5 mol
equivalents of 10 % NaOH to afford almost quantitative yields (Table 2, entries 5, 7
and 8).
123

S.-Y. Song et al.
Table 1 Optimization and scale up preparation of intermediate 5
Entry
2 (g)
Br–AcOEt (equiv)
K2CO3 (equiv)
Yield (%) of 5a
1
2
3
4
5
a
1
5
1
1
88
95
97
98
98
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
50
100
200
Yields were calculated as isolated product with purity [99 %
Table 2 Optimization and scale up preparation of intermediate 3
Entry
5 (g)
10 % NaOH (equiv)
Temp (°C)
Time (min)
Yield (%)of 3a
1
2
3
4
5
6
7
8
a
0.6
0.5
4
80
50
25
25
25
25
25
25
30
30
90b
95b
99
99
99
97
99
98
4
0.5
4
120
90
0.5
3
0.5
2
60
0.5
1.5
1.5
1.5
60
10.0
330.0
60
60
Yields were calculated as isolated product with purity [98 %
b
Formation of byproducts was observed
Alternatively, intermediate 3 can be prepared directly by reacting 2 with
chloroacetic acid in a one-step process according to a procedure described by Kalish
et al. [20]. In this preparation, the 2-hydroxy-4-methoxybenzaldehyde was dissolved
in 10 %NaOH, added to chloroacetic acid, and heated to reflux (Table 3). The
reaction did not proceed below 70 °C and it was difficult for the 2-hydroxy-4-
methoxybenzaldehyde to be completely consumed, despite long reaction time and
addition of excess chloroacetic acid. It is interesting to note that almost all runs
afforded a yield around 85 % with no significant improvement by the additional
amount of chloroacetic acid or sodium hydroxide. Fortunately, unreacted
4-methoxy-2-hydroxybenzaldehyde (5–10 %) does not affect the following cycliza-
tion reaction and can easily be removed in the next step. Thus, for large-scale
production, this one-step process provides significant advantages over the above
two-step process in terms of lower materials and operation cost.
It is well known that 2-(2-formylphenoxy)alkanoic acids can cyclize to form
benzofurans in acetic anhydride in the presence of sodium acetate [21, 24, 25].
Burgstahler et al. [23] described that 2-formylphenoxyactic acid was treated with
acetic anhydride in the presence of sodium acetate and acetic acid to give
benzofuran in up to 67.8 % yield, whereas Kalish et al. [20] described a similar
reaction condition for the synthesis of 6-methoxybenzofuran in only 20 % yield.
123

An improved and scale-up synthesis of 6-hydroxybenzofuran
Table 3 One-step preparation of intermediate 3
Entry
2 (g)
Cl–AcOH (equiv)
10 % NaOH (equiv)
Temp (°C)
Yield (%) of 3a
1
2
3
4
5
a
0.5
1
2
3
1
1
2
70
100
100
100
100
0
0.5
2.5
3.5
2.5
2.5
86
85
10
b
–
200
4000
b
–
Yields were calculated as isolated product with purity [97 %
Product was not purified and contained some unreacted 2
b
Thus, the cyclization reaction of intermediate 3 to form intermediate 4 was carried
out in acetic anhydride in the presence of sodium acetate. This reaction started at
around 110 °C with apparent carbon dioxide evolution, and was completed at
130 °C with the termination of gas production to give an average yield around 92 %
(Table 4). It should be noted that the product is volatile at high temperature or under
reduced pressure (such as removal of solvent on rotavap). Acetic anhydride was
used both as a reagent and as a solvent, and was used at 5 mL per gram of reactant 3
for small-scale reactions (Table 4, entries 1 and 2) and 2 mL per gram for large-
scale reactions (Table 4, entries 6, 7 and 8). One and a half molar equivalents of
NaOAc were adequate.
Two mechanisms were proposed in the literature for the cyclization of 2-(2-
formylphenoxy)alkanoic acids [23, 25]. It is generally accepted that in the presence
of acetic anhydride, sodium acetate and acetic acid, cyclization proceeds by a Perkin
reaction mechanism [23], which may form several products depending on the
substitution on the phenyl ring [26], as demonstrated by the low yields reported by
Kalish et al. [20], and by Burgstahler et al. [23]. In order to reduce the formation of
Table 4 Optimization and scale-up preparation of intermediate 4
Entry
3 (g)
NaOAc (equiv)
Ac2O (mL)
Temp (°C)
Yield (%) of 4a
1
2
3
4
5
6
7
8
a
2
5
3
10
20
110–130
110–130
110–130
110–150
110–130
110–130
110–130
110–130
92
91
2
5
1.5
2
20
85
86b
5
20
10
2
20
91
50
2
100
400
10,000
91
200
5100
1.5
1.5
91
77c
Yields were calculated as isolated product with purity [98 %
Product is volatile at high temperature
b
c
Combined yield for the first two step
123

S.-Y. Song et al.
O
O
O
O
O
O
O
O
H
O
OH
O
O
O
MeO
MeO
MeO
NaOAc
O
NaOAc
O
O
O
O
O
3a
Na
3
HOAc
3b
O
O
C
heat
heat
O
O
O
O
MeO
O
MeO
MeO
HOAc
3c
3d
CO2
4
Scheme 3 4-Methoxy-2-(2-formylphenoxy)acetic acid cyclization mechanism
other byproducts, it is better to carry out the cyclization reaction in only acetic
anhydride and sodium acetate [26], which is believed to undergo a [2 ? 2]
cyclization addition mechanism [24, 25]. In this work, the cyclization was carried
out in acetic anhydride in the presence of sodium acetate and only the desired
product was obtained without any noticeable byproduct formation. Thus, this
process is likely to undergo a [2 ? 2] cyclization to form 6-methoxybenzofuran
(Scheme 3). Briefly, 2-(2-formyl-5-methoxyphenoxy)acetic acid (3) reacts with
acetic anhydride to form a mixed anhydride 3b via 3a. Under heating, 3b eliminates
an acetic acid molecule to form 3c, which undergoes a [2 ? 2] cycloaddition to give
an unstable beta lactone 3d. Subsequently, the beta lactone 3d eliminates carbon
dioxide to afford 4.
The final step was to remove the methyl group of 6-methoxybenzofuran 4. There
are several methods for de-methylation of methoxyphenyl compounds, including
boron tribromide, AlCl3/AlBr3, sodium alkanethiolate, pyridine hydrochloride, or
some combination of these. Initially, the BBr3 was chosen for this work and was run
at room temperature with 4 in dichloromethane. The result was unsatisfactory due to
Table 5 Optimization and scale-up preparation of intermediate 1
Entry
4 (g)
Reagent (equiv)
NaS(CH2)11CH3 (equiv)
Temp (°C)
Yield (%) of 1a
b
1
2
3
4
5
6
7
8
a
1
1
BBr3 (2)
AlCl3 (1)
PyHCl (2)
-15 to 0
-15 to 0
180
–
b
–
1
0c
1
2
130
92
89
93
92
90
1
1.5
1.7
1.7
1.7
130
50
200
2950
130
130
130
Yields were calculated as isolated product with purity [99 %
A trail of byproducts were observed by TLC
No change was observed up to 180 °C
b
c
123

An improved and scale-up synthesis of 6-hydroxybenzofuran
the formation of many byproducts, even at -15 °C. Then AlCl3 was used for the
same purpose and was disappointing as well, due to side reactions. Pyridine
hydrochloride was also tried by heating the mixture up to 180 °C (due to the
limitation of heating device) without any de-methylated product formation. Finally,
sodium dodecanethiolate, an odorless demethylation reagent developed by Node
et al. [18], was selected for this work, and successfully removed the methyl group at
130 °C and afforded high yields of the desired product 1 (Table 5). In order to
obtain the best result, at least 1.5 mol equivalents of sodium dodecanethiolate are
required.
Conclusions
We have developed a reliable, cost effective, scalable, and environmentally benign
process for the preparation of 6-HBF in good overall yield. In small-scale synthesis,
the four-step synthetic route is preferred due to its high yield at each step. But in
large-scale production, the three-step route is more advantageous due to its lower
materials and operation cost.
In this study, extensive reaction conditions were conducted and an optimal result
was achieved for each step. This process has been successfully applied to the
synthesis of up to 2.6 kg of 6-HBF in 69.3 % combined yield over three steps, or an
average of 88.5 % yield per step. This process can easily be applied for
manufacturing scale production.
Experimental
All reagents and solvents that were purchased commercially were used directly
without prior treatment. Reaction temperatures were recorded using a regular
thermometer without correction. Reactions were monitored by analytical thin-layer
chromatography (TLC) on silica gel F254 glass plates and visualized under UV light
1
254 nm. H NMR spectra were recorded with a Bruker Avance III 400 MHz NMR
spectrometer at room temperature. Chemical shifts (in ppm) were recorded as parts
per million (ppm) downfield to tetramethylsilane (TMS). The following abbrevi-
ations are used for multiplicity of NMR signals: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; dd, double doublet; dt, double triplet; dq, double quartet; br,
broad. Only the largest scales of processing for each step are described in the
following sections.
Ethyl 2-(2-formyl-5-methoxyphenoxy)acetate (5)
Acetone (1000 mL) and Na2CO3 (273 g, 2 mol) were added to a flask and
2-hydroxy-4-methoxybenzaldehyde (200 g, 1.3 mol) was added portion wise under
stirring. After 30 min, ethyl bromoacetate (260 g, 1.56 mol) was added and the
solution was heated to reflux for 2 h. The reaction was cooled to room temperature
andthe solid was filtered off and washed with acetone. The solution was
123

S.-Y. Song et al.
concentrated, dissolved in ethyl acetate, washed with 1 N NaOH and brine, and
dried. After removal of the solvent, the product was recrystallized from petroleum
1
ether to afford 5 (306 g, 98 % yield, 99.5 % purity), m.p. 66–68 °C. H-NMR
(CDCl3, ppm): 10.41 (s, 1H), 7.86–7.89 (d, 1H), 6.61–6.64 (dd, 1H), 6.35–6.36 (d,
1H), 4.74 (s, 2H), 4.28–4.33 (q, 2H), 3.88 (s, 3H), 1.31–1.34 (t, 3H).
2-(2-Formyl-5-methoxyphenoxy)acetic acid (3)
Intermediate 5 (330 g, 1.38 mol), MeOH (800 mL), and 10 % NaOH (83 g in
830 mL water, 2.07 mol) were added to a flask and the solution was stirred at rt for
1 h. The reaction mixture was poured into ice-cold 1 N HCl (2 L) with stirring and
adjusted to pH 1 with additional 1 N HCl. The solid product was filtered, washed
with water, and dried to give 3 (284 g, 98 % yield, 97.4 % purity), m.p.
1
137–138 °C. H-NMR (DMSO-d6, ppm): 13.16 (br, 1H), 10.27 (s, 1H), 7.68–7.70
(d, 1H), 6.68–6.71 (q, 1H), 6.65–6.66 (d, 1H), 4.90 (s, 2H), 3.85 (s, 3H) [20].
One step synthesis of 2-(2-formyl-5-methoxyphenoxy)acetic acid (3)
Raw material 2 (4 kg, 26.3 mol), 10 % NaOH (2.63 kg in 26 L water, 65.75 mol),
and chloroacetic acid (2.5 kg, 26.4 mol) were added to a 50-L reactor. The reaction
mixture was heated and stirred at 100 °C for 6 h. It was then cooled to rt and
acidified to pH 1 with concentrated hydrochloric acid. The solid was filtered,
washed with water, petroleum ether (to remove the un-reacted 2), and dried to afford
3 (5.15 kg, 93 % yield, 94 % purity). The product still had some residual 2 and was
used directly in next step.
6-Methoxybenzofuran (4)
Intermediate 3 (5.1 kg, 24.3 mol), acetic anhydride (10 L), and sodium acetate
(3.0 kg, 36.6 mol) were added to a 50-L reactor. The mixture was heated under
stirring at 110–130 °C (large amount of gas evolution) and kept at 130 °C for 2 h.
After being cooled to 60 °C, ethanol (10 Lto consume the acetic anhydride) was
added portion-wise and the mixture was stirred at 60–80 °C for 2 h. It was then
cooled to rt andwater (10 L) and ethyl acetate (10 L) were added. The organic phase
was separated, washed with 2 N NaOH and water, and dried over sodium sulfate.
The solvent was removed by distillation to afford a colorless liquid 4 (2.98 kg, 83 %
1
yield, or 77 % combined yield from 2, 99.6 % purity). H-NMR (CDCl3, ppm): d
7.55–7.56 (d, 1H), 7.47–7.49 (d, 1H), 7.07 (s, 1H), 6.90–6.92 (dd, 1H), 6.71–6.72 (d,
1H), 3.88 (s, 3H) [27].
6-Hydroxybenzofuran (1)
DMF (18 L), sodium dodecanethiolate (7.6 kg, 33.9 mol), and 4 (2.95 kg, 19.9 mol)
were added to a 50-L reactor. The reaction mixture was heated and stirred at 130 °C
for 3 h, then cooled to rt, and 4 N NaOH was added to adjust the pH to 13. The
solution was extracted with petroleum ether three times. The aqueous phase was
123

An improved and scale-up synthesis of 6-hydroxybenzofuran
acidified with 2 N HCl to pH 2 and extracted with ethyl acetate three times. The
ethyl acetate phases were combined, washed with water, and dried over sodium
sulfate. The solvent was removed under vacuum and the residue was left overnight
at room temperature to afford 1 as a light brown solid (2.65 kg, 90 % yield, 99.5 %
1
purity), m.p. 54–56 °C. H-NMR (CDCl3, ppm): d 7.55 (s, 1H), 7.44–7.46 (d, 1H),
7.03 (s, 1H), 6.81–6.83 (d, 1H), 6.72 (s, 1H), 5.09 (br, 1H).
Acknowledgments This work was supported by Guangdong Medical College Research Foundation
(Grant JB12020).
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