Highly efficient and scalable process for demethylation of 6-(2,4-dimethoxybenzoyl)chromen-2-one and other aryl methyl ethers

Article abstract of DOI:10.1080/00397910903161769

Demethylation of 6-(2,4-dimethoxybenzoyl)chromen-2-one and some other aryl methyl ethers was achieved with pyridinium bromide as demethylating agent and sulfolane as solvent. Compared with other demethylation methods, this combination offers advantages of clean conversion, excellent yields, easy operation and workup, and manageable reaction temperatures. This process could be particularly useful for large-scale production because it avoids use of corrosive or moisture-sensitive reagents. Copyright

Full text of DOI:10.1080/00397910903161769

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Highly Efficient and Scalable
Process for Demethylation of 6-(2,4-
Dimethoxybenzoyl)chromen-2-one and
Other Aryl Methyl Ethers
Amit Srivastava a , Jason Yang a , Baoshu Zhao a , Yong Jiang a
Wade Blackmon a & Bernd Kraemer a
,
a Chemical Development, PTDA-FL, Roche Carolina, Inc., Florence,
South Carolina, USA
Published online: 17 May 2010.
To cite this article: Amit Srivastava , Jason Yang , Baoshu Zhao , Yong Jiang , Wade Blackmon
& Bernd Kraemer (2010) Highly Efficient and Scalable Process for Demethylation of 6-(2,4-
Dimethoxybenzoyl)chromen-2-one and Other Aryl Methyl Ethers, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:12, 1765-1771,
DOI: 10.1080/00397910903161769
To link to this article: http://dx.doi.org/10.1080/00397910903161769
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Synthetic Communications1, 40: 1765–1771, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903161769
HIGHLY EFFICIENT AND SCALABLE PROCESS FOR
DEMETHYLATION OF 6-(2,4-DIMETHOXYBENZOYL)-
CHROMEN-2-ONE AND OTHER ARYL METHYL ETHERS
Amit Srivastava, Jason Yang, Baoshu Zhao, Yong Jiang,
Wade Blackmon, and Bernd Kraemer
Chemical Development, PTDA-FL, Roche Carolina, Inc., Florence,
South Carolina, USA
Demethylation of 6-(2,4-dimethoxybenzoyl)chromen-2-one and some other aryl methyl
ethers was achieved with pyridinium bromide as demethylating agent and sulfolane as
solvent. Compared with other demethylation methods, this combination offers advantages
of clean conversion, excellent yields, easy operation and workup, and manageable reaction
temperatures. This process could be particularly useful for large-scale production because it
avoids use of corrosive or moisture-sensitive reagents.
Keywords: Aryl methyl ethers; demethylation; 6-(2,4-dimethoxybenzoyl)chromen-2-one; pyridinium bromide;
sulfolane
INTRODUCTION
Protection and deprotection of ethers is one of the oldest and most common
strategies in organic synthesis.[1] Methyl ethers, in particular, have been widely used
because of their compatibility with different functional groups and stability under
various reaction conditions. However, this stability sometimes leads to difficulties
in the subsequent demethylation, which explains why deprotection of methyl ethers
is in general considered more challenging than deprotection of other ethers. Most
methods for demethylation of methyl ethers involve Lewis acid– or hydrohalic acid–
promoted CꢀO bond cleavage or direct nucleophilic attack of the methyl group by a
strong nucleophile.[2–4] Lewis acids are generally effective and are commonly used in
small-scale laboratory studies. However, some of them (e.g., BBr3)[5] are extremely
corrosive and moisture sensitive, and thus very difficult to handle on a large scale,
whereas others (e.g., AlCl3) produce by-products that could pose a burden for waste
disposal. Demethylation using strong nucleophiles (e.g., RSNa)[6–9] is only limited to
those substrates that do not contain other functional groups that could be subject to
nucleophilic reaction. Demethylation using pyridinium chloride has been relatively
well documented;[10–12] however, the use of pyridinium bromide has been sparsely
Received April 17, 2009.
Address correspondence to Amit Srivastava, Chemical Development, PTDA-FL, Roche Carolina,
Inc., 6173 E. Old Marion Hwy, Florence, SC 29506, USA. E-mail: amit.srivastava@roche.com
1765

1766
A. SRIVASTAVA ET AL.
Scheme 1. Demethylation of 6-(2,4-dimethoxybenzoyl)chromen-2-one (1).
reported.[13] In either case, the reaction is typically carried out under molten
conditions at extremely high temperatures (>200 ꢁC).
In the course of developing a process for the manufacture of an investigational
new drug,[14] we needed to develop a scalable and cost-effective demethylation process
to convert 6-(2,4-dimethoxybenzoyl)chromen-2-one (1) to 6-(2,4-dihydroxybenzoyl)
chromen-2-one (2), a key process intermediate (Scheme 1). The demethylation of 1
went through mono-demethylated intermediates 3 and 4, which could be the major
products depending on the reaction conditions (see Results and Discussion for more
details). The original process that had been used for this conversion involved heating
a mixture of 1, pyridine, conc. HCl, toluene, and N-methylpyrrolidone (NMP);
carrying out a distillation at ꢂ200 ꢁC to remove solvents; and then continuing to heat
the misture at 205 ꢁC until the reaction reached completion. The high temperature
(>200 ꢁC), especially during the distillation, was considered a major problem for
large-scale production. Also, the reaction mixture solidified when cooled to less than
100 ꢁC for in-process control sampling. After an extensive investigation, we have
found that a combination of pyridinium bromide (PyHBr) with sulfolane as solvent
gave almost quantitative yield while avoiding all these issues. This procedure has been
successfully extended to include some other aryl methyl ethers, all giving clean and
quantitative conversion.
RESULTS AND DISCUSSION
6-(2,4-Dimethoxybenzoyl)chromen-2-one (1) contains an a,ß-unsaturated ester
and a ketone, both of which could react with a nucleophile. In fact, when 1 was
treated with sodium methoxide in tetrahydrofuran, the corresponding 3-(20-
hydroxyphenyl)methyl acrylate (5) was formed as the only product (Scheme 2).
Strong nucleophiles, which are traditionally used for demethylation, are expected
to participate in similar nucleophilic reactions; therefore, this methodology was not
considered feasible for the demethylation of 1. Boron tribromide (BBr3) and boron
trifluoride etherate (BF3 ꢃ Et2O) were extensively evaluated. When BBr3 was used,

DEMETHYLATION OF ARYL METHYL ETHERS
1767
Scheme 2. Nucleophilic ring opening of 1 by sodium methoxide.
we found that the reaction was fast (with a strong exotherm), but the initially formed
product–boron complex crashed out of the solution as soon as BBr3 was added. In
most of the solvents we tried (methylene chloride, chlorobenzene, toluene, etc.), the
batch eventually became a big, sticky ball. This caused at least two problems. One
was that the reaction could not go to completion because some of the starting material
1 was brought out of the solution and eventually trapped in the big ball, thus never
having a chance to react with BBr3. The other was that the massive, sudden pre-
cipitation of the product–boron complex and the formation of a big ball during the
reaction would cause significant safety and operational issues in large-scale
production. BF3 ꢃ Et2O did not reveal these problems; however, it is much less power-
ful than BBr3, and only the ortho-methoxy group was demethylated.
Hydrobromic acid (HBr, 48% solution) and hydriodic acid (HI, 57% solution)
were also evaluated for demethylation of 1. They were used either alone or with acetic
acid as solvent, and the reaction was generally carried out at reflux temperatures.
In most cases, the reaction did not go to completion even after 2–3 days. The
para-methoxy group was very difficult to demethylate under these conditions.
In concurrence with these investigations, we also evaluated pyridinium halides
for demethylation of 1, with goals of good yield and good purity of the product,
simple operation, use of a single solvent, and avoidance of molten conditions and
extremely high temperatures (>200 ꢁC). Based on the literature work and our own
experience, we believed that sulfolane could be a good solvent for this reaction: it
is highly stable in the presence of an acid even at high temperatures; it has a high
polarity, which helps dissolve pyridinium halides relatively easily; and it is miscible
with water, which could render easy product isolation by simply adding water to
the reaction mixture. Pyridium chloride, bromide, and iodide were evaluated at
different temperatures. Pyridinium chloride (PyHCl) reacted slowly; even after
24 h at 180 ꢁC, there was still ꢂ30% para-methoxy intermediate left. Both pyridinium
Table 1. Temperature effect on demethylation of 1 using PyHBr in sulfolane
Entry
Temp. (ꢁC)
Time (h)
SM left
Product (area %)a
Isolated yield (%)
1
2
3
4
150
160
170
180
30
18
10
3
—
—
—
—
97.3
99.1
99.6
96.9
96
98
98
96
aProduct area % based on in-process control HPLC analysis.

1768
A. SRIVASTAVA ET AL.
Scheme 3. Demethylation of 1 using PyHBr in sulfolane.
bromide (PyHBr) and iodide (PyHI) gave clean and complete conversion at
150–160 ꢁC. Because pyridinium bromide is less expensive and widely commercially
available, it was chosen for further process optimization. A number of solvents,
including sulfolane, N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO),
dimethylformamide (DMF), and methyl ethyl ketone (MEK), were subsequently
evaluated in parallel, and sulfolane gave the best overall results. Theoretically, two
equivalents of pyridinium bromide would be needed to cleave the two methyl ether
groups, but a stoichiometric study revealed that greater equivalents resulted in faster
reaction rate. We also found that the reaction rate was highly dependent on the
reaction temperature used (Table 1). After the key reaction conditions were finalized,
Table 2. Demethylation of aryl methyl ethers using PyHBr in sulfolane at 160 ꢁC
Entry
Aryl methyl ether
Demethylated product Time Product (area %)a Isolated yield (%)
1
18 h
24 h
99.1
99.8
98
93
2
3
4
7 h
97.3
99.0
98
24 h
NAb
5
3 h
98.3
NAb
aProduct area % based on in-process control HPLC analysis.
bReaction was clean, but product isolation was not attempted.

DEMETHYLATION OF ARYL METHYL ETHERS
1769
we started looking at the product isolation, which turned out to be the easiest part of
the process. The solubility studies suggested that the product (2) is almost insoluble
in water. Thus, simply adding water to the reaction mixture resulted in the product
directly precipitating out of the solution. Because the reaction was very clean, the
product thus isolated was very pure (generally 98–100% by wt%) even without
further purification. In a typical procedure (Scheme 3), a mixture of 1, pyridinium
bromide, and sulfolane was heated to 150–160 ꢁC. After the reaction was complete,
water was added to the reaction mixture, and the desired product directly precipi-
tated out of the solution, which was filtered and washed with water (96–98% yield
after drying). We briefly extended our work to include some other aryl methyl ethers,
and the results are summarized in Table 2. All the reactions proceeded very cleanly
and went to completion. The by-product of this reaction was believed to be
1-methylpyridinium bromide.
In summary, we have developed an efficient and scalable process for demethyla-
tion of 6-(2,4-dimethoxybenzoyl)chromen-2-one and some other aryl methyl ethers.
A combination of excellent yield, simple operation, easy product isolation, and
manageable reaction temperatures makes it an attractive alternative to other
demethylation procedures. This process could be particularly useful for large-scale
production because it avoids the use of corrosive or moisture-sensitive reagents, in
addition to having the advantages mentioned here.
EXPERIMENTAL
All glassware used in these experiments was dry, and reactions were run under
a nitrogen atmosphere. 6-(2,4-Dimethoxybenzoyl)chromen-2-one (1) was obtained
from Toyama Chemical Co., Ltd., Japan. Pyridinium bromide, pyridinium chloride,
sulfolane, and aryl methyl ethers were purchased from Aldrich. Pyridinium iodide
was prepared in our laboratory. All products were identified by their spectral data.
1H and 13C NMR spectra were recorded on a Varian 500-MHz spectrometer. All
in-process control samples and the product assay were run on Agilent 1200 series
high-performance liquid chromatography (HPLC) instrument.
General Procedure for Demethylation of 6-(2,4-Dimethoxybenzoyl)
chromen-2-one (1) and Aryl Methyl Ethers Using Pyridinium
Bromide in Sulfolane
A 250-mL, four-necked, round-bottomed flask equipped with overhead stirrer,
reflux condenser, and temperature probe was charged with 6-(2,4-dimethoxybenzoyl)
chromen-2-one (1) (10.0 g, 32.22 mmol), pyridinium bromide (21 g, 128.88 mmol),
and sulfolane (20 mL). The mixture was heated to 150–160 ꢁC and stirred at this
temperature for 18 h. The reaction mixture was then cooled to ꢂ80 ꢁC, and 60 mL
of water was added over ꢂ20 min while maintaining the batch temperature at
70–80 ꢁC. (The product started precipitating out of the solution during the water
addition.) The resulting slurry was further cooled to 0 ꢁC, stirred for 1 h, and then
filtered via a sintered glass filter. The wet cake was washed twice with water
(2 ꢄ 40 mL) and then dried overnight at 50 ꢁC under full vacuum to yield the desired
product 2 as yellow crystals (8.9 g, 98% yield).

1770
A. SRIVASTAVA ET AL.
6-(2,4-Dihydroxybenzoyl)chromen-2-one (2)
1H NMR (500 MHz, DMSO-d6) d: 11.86 (brs, 1H), 10.70 (brs, 1H), 8.15 (d,
J ¼ 10 Hz, 1H), 8.03 (d, J ¼ 5 Hz, 1H), 7.84 (dd, J ¼ 5 Hz, 10 Hz, 1H), 7.50 (d,
J ¼ 10 Hz, 1H), 7.40 (d, J ¼ 10 Hz, 1H), 6.57 (d, J ¼ 10 Hz, 1H), 6.41–6.37 (m, 2H);
13C NMR (125 MHz, DMSO-d6) d: 197.1, 165.4, 164.5, 160.2, 156.0, 144.7, 135.7,
134.9, 132.9, 130.1, 119.1, 117.6, 117.1, 113.5, 108.9, 103.4.
1-(4-Hydroxyphenyl)-1-phenylmethanone (7)
Mp: 135 ꢁC (observed), 133–137 ꢁC (literature);[15] 1H NMR (500 MHz,
DMSO-d6) d: 10.43 (brs, 1H), 7.70–7.60 (m, 5H), 7.54–7.51 (m, 2H), 6.92–6.88 (m,
2H); 13C NMR (125 MHz, DMSO-d6) d: 195.0, 162.6, 138.8, 133.2, 132.4, 129.8,
129.0, 128.6, 115.9.
7-Hydroxy-2H-chromen-2-one (9)
Mp: 233 ꢁC (observed), 234–237 ꢁC (reported);[16] 1H NMR (500 MHz, DMSO-
d6) d: 10.55 (brs, 1H), 7.91 (d, J ¼ 10 Hz, 1H), 7.50 (d, J ¼ 5 Hz, 1H), 6.77 (dd,
J ¼ 5 Hz, 10 Hz, 1H), 6.70 (d, J ¼ 5 Hz, 1H), 6.19 (d, 10 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6) d: 161.9, 161.1, 156.1, 145.1, 130.3, 113.8, 112.0, 111.9, 102.8.
ACKNOWLEDGMENT
We thank Toyama Chemical Co., Ltd., Toyama, Japan, for providing a sample
of 6-(2,4-dimethoxybenzoyl)chromen-2-one (1) and initial laboratory procedures.
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