Fries rearrangement: Scalable synthesis of key fluoro building blocks 3-fluoro-4-methoxybenzoyl chloride and 1,2-diethoxy-3-fluorobenzene

Article abstract of DOI:10.1016/j.tetlet.2014.02.119

Lewis acid catalyzed Fries rearrangement of 2-fluorophenyl acetate (3) was performed on kg scale. The ortho 5 and para 4 isomers obtained were separated in an industrially feasible way. Compound 4 was then converted into fluorinated building block 3-fluoro-4-methoxybenzoyl chloride (1) while compound 5 was converted into 1,2-diethoxy-3-fluorobenzene (2) in high yields.

Full text of DOI:10.1016/j.tetlet.2014.02.119

Tetrahedron Letters 55 (2014) 2426–2429
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fries rearrangement: scalable synthesis of key fluoro
building blocks 3-fluoro-4-methoxybenzoyl chloride
and 1,2-diethoxy-3-fluorobenzene
a
a
a
Swapnil G. Yerande a, , Deepak M. Shendage , Prasad B. Wakchaure , Ganesh R. Phadtare ,
⇑
Madhavrao Y. Bhoite a, Ashok Kumar Gangopadhyay a, Kuppuswamy Nagarajan b, Richard Helmut Rupp a
a Acoris Research (A Division of Hikal Ltd), 3A, International Biotech Park, Hinjewadi, Pune 411 057, Maharashtra, India
b Hikal R&D Centre, No. 32/1, Kalena Agrahara, Bannerghatta Road, Bangalore 560 076, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Lewis acid catalyzed Fries rearrangement of 2-fluorophenyl acetate (3) was performed on kg scale. The
ortho 5 and para 4 isomers obtained were separated in an industrially feasible way. Compound 4 was then
converted into fluorinated building block 3-fluoro-4-methoxybenzoyl chloride (1) while compound 5 was
converted into 1,2-diethoxy-3-fluorobenzene (2) in high yields.
Received 22 January 2014
Revised 26 February 2014
Accepted 27 February 2014
Available online 5 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Acylation
Lewis acid
Fries rearrangement
Dakin oxidation
Process development
As many as 30% agrochemicals and 20% pharmaceuticals are
estimated to contain fluorine, including half of the top ten drugs
sold in 2005.1 The applications of fluorinated molecules in pharma-
ceuticals and agrochemicals are continuously increasing owing to
their metabolic stability and also due to their usefulness as bioiso-
stere of the hydrogen atom. An estimated one fifth of pharmaceu-
ticals contain fluorine, including several of the top drugs. Therefore
there is a growing requirement of fluorinated building blocks.
Our literature search revealed that 3-fluoro-4-methoxybenzoyl
chloride (1) and 1,2-diethoxy-3-fluorobenzene (2) (Fig. 1) are key
fluorinated building blocks for the synthesis of several biologically
active molecules.
Fluoro-4-methoxybenzoyl chloride (1) has been used as build-
ing blocks for preparing compounds which are active against vari-
ous diseases. To cite a few examples (a) preparation of potent and
selective agonist of estrogen receptor b ligand capable of treating
inflammatory diseases.2a (b) preparation of inhibitors of heat shock
protein 90, inhibition of which has shown beneficiary effects in the
treatment of cancers and neurodegenerative diseases.2b (c) prepa-
ration of activators of SIRT1 which improves glucose metabolism in
various skeletal muscles, and helps in treatment of type II diabetes
and other metabolic disorders.2c 1,2-Diethoxy-3-fluorobenzene (2)
COCl
OMe
F
O
O
F
1,2-Diethoxy-3-fluoro-
3-Fluoro-4-methoxy
benzene (2)
benzoyl chloride (1)
Figure 1. 3-Fluoro-4-methoxybenzoyl chloride (1) and 1, 2-diethoxy-3-fluoroben-
zene (2).
is a building block in the preparation of 2-iminopyrrolidine deriv-
atives which have shown promising antithrombotic activity.3
Hence we became interested in developing a process for synthe-
sizing these important fluorinated building blocks. The literature
search has revealed 1 and 2 have been prepared using various
approaches. Starting form 3-fluoro-4-methoxybenzoic acid a num-
ber of synthetic approaches toward 1 has been reported in the lit-
erature. The key starting material 3-fluoro-4-methoxybenzoic acid
is synthesized by chromate or permanganate oxidation of 3-fluoro-
4-methoxytoluene,4 carboxylation of 3-fluoro-4-methoxybromo-
benzene,5 or by hydrolysis of 3-fluoro-4-methoxybenzonitrile.6
Hikal has reported a process for the synthesis of 2 via Claisen
rearrangement of allyl-2-fluorophenyl ether followed by Dakin
oxidation and ethylation.7 Asahi and Charna have reported a
⇑
Corresponding author. Fax: +91 (20) 2727 2014.
E-mail address: swapnil_yerande@acorisresearch.com (S.G. Yerande).
http://dx.doi.org/10.1016/j.tetlet.2014.02.119
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. G. Yerande et al. / Tetrahedron Letters 55 (2014) 2426–2429
2427
process for the synthesis of 2 starting from commercially available
2-fluorophenol.8 Another strategy of Asahi and Charna reports
alkylation of 3-fluorocatechol (8).8
Fries Rearrangement
1 kg Scale
4 + 5 Mixture
Precipitation
The key building block 3-fluorocatechol (8) is accessible via
enzymatic oxidation of fluorobenzene followed by dehydrogenation
of resultant fluoro-diol.9 Corse et al. have reported the synthesis of
3-fluorocatechol (8) starting from 2,3-dimethoxynitrobenzene.10
We envisaged that compounds 1 and 2 can be prepared via Fries
rearrangement of 2-fluoro-phenylacetate (3) (Scheme 1). The ortho
isomer 5 and para isomer 4 can easily be converted into target
compounds 1 and 2.This communication summarizes our efforts
to develop an improved, less expensive, simpler, safer, and easily
scalable manufacturing process for synthesis of 1 and 2 starting
from 4 and 5 respectively.
4, 416 g,
(Yield 39%)
4 + 5 Mixture
530 g
Steam
distillation
5, 257 g,
(Yield 24%)
Crystallization
4, 205 g,
(Yield 19%)
Figure 2. Flowchart for the separation of Fries rearrangement products.
Valoti et al. reported the synthesis of 3-fluoro-4-hydroxyaceto-
phenone (4) and 3-fluoro-2-hydroxy-acetophenone (5) using Lewis
acid catalyzed Fries rearrangement of 2-fluorophenyl acetate (3).11
We focused our attention on this approach with keeping a goal of
carrying out this transformation on large scale and secondly, to
avoid column chromatography used to separate both isomers 4/5
which would not be a practical proposition during large scale
production.
The substrate for Fries rearrangement 2-fluorophenyl acetate
(3) was synthesized in high yields from commercially available
2-fluorophenol using acetyl chloride and triethyl amine. In order
to study the ratio of ortho/para isomer obtained during the Fries
rearrangement we developed a HPLC method (see Supporting
information) Fries rearrangement was carefully studied using dif-
ferent Lewis acid catalysts and temperatures. Thus, using BF3.OEt2
we did not observe any product formation while the use of TiCl4
gave hydrolyzed product 2-fluorophenol in 75% yield. When 1.1
or 1.2 equiv of AlCl3 was used, we observed product formation
(4/5) in 50% yield.
Based on above results AlCl3 was chosen as a Lewis acid to study
the impact of temperature on the ortho/para selectivity observed
during Fries rearrangement. Toward this goal, Fries rearrangement
was performed at various temperatures ranging from 40 °C to
170 °C. The results are summarized in Table 1. Use of 1.5 equiv of
AlCl3 in the Fries rearrangement gave us consistent results; hence
all the optimizations were carried out using 1.5 equiv of AlCl3. It
was also observed that when the temperature of reaction was in-
creased from 40 °C to 80 °C the reaction rate as well as the percent-
age of conversion of 3 into the product 4/5 increased (entries 1–3).
When the Fries rearrangement was carried out in monochloroben-
zene at 100 °C, the formation of Fries rearranged products 4 and 5
was observed in the ratio of 3.03:1.0 (Table 1, entry 4). At 120 °C
the reaction went to completion with 90% isolated crude yield
COCl
F
OH
F
OMe
O
4
F
1
Fries Rearrangment
O
+
F
F
O
O
O
3
OH
O
2
5
Scheme 1. Synthetic strategy toward 3-fluoro-4-methoxybenzoyl chloride (1) and 1,2-diethoxy-3-fluorobenzene (2).
Table 1
Optimization of reaction conditions for Fries rearrangement
F
F
F
OH
OH
O
Fries Rearrangment
O
+
O
O
3
4
5
Entry
Solvent
Temp (°C)/time (h)
% Crudeyield
% Conversion#
O:P ratio (4:5)§
1
2
3
4
5
6
7
MCB
MCB
MCB
MCB
MCB
DCB
DCB
40/4
60/4
80/4
100/3
120/3
150/2
170/2
84
86
85
90
90
74
62
37.2
46.4
80.8
90.2
100
100
100
2.44:1.0
1.33:1.0
2.84:1.0
3.03:1.0
2.84:1.0
1.92:1.0
1.72:1.0
#
In all the reaction AlCl3 (1.5 equiv) was used as a Lewis acid. MCB = Monochlorobenzene, DCB = o-dichlorobenzene.
O/P ratios were calculated on the basis of HPLC analysis of reaction mass.
§

2428
S. G. Yerande et al. / Tetrahedron Letters 55 (2014) 2426–2429
O
O
CO2H
COCl
DMS, K2CO3
Acetone
aq. NaOCl
(95 %)
SOCl2
(96 %)
F
F
F
F
OMe
OMe
OH
OMe
4
[6]
7
1
Scheme 2. Synthesis of 3-fluoro-4-methoxybenzoyl chloride (1).
F
F
O
DES, K2CO3
(53 %)
H2O2 , NaOH
OH
OH
O
F
[8]
2
OH
O
DES, K2CO3 (96 %)
O
F
5
F
mCPBA, NaOH
(75 %)
DES, K2CO3
(97 %)
O
O
OH
10
9
Scheme 3. Synthesis of 1, 2-diethoxy-3-fluorobenzene (2).
(entry 5). The ortho/para regioselectivity obtained was 2.84:1.0.
This result is in line with the well known fact that the increase
in the reaction temperature increases the ortho-selectivity in the
Fries rearrangement. Taking a clue from these results we carried
out Fries rearrangement in high boiling o-dichlorobenzene at an
elevated temperature (entries 6 and 7). At 170 °C the ortho product
formation was significantly increased (ortho/para, 1.72:1), however
the isolated crude yield of the reaction was only 62% (entry 7). It
can be noted from Table 1 that the reaction below 100 °C leads
to incomplete conversion while above 150 °C leads to lower iso-
lated yields due to significant formation of other side products.
Based on the above study we chose to do Fries rearrangement in
monochlorobenzene at 120 °C.
Our approach used for the separation of 4 and 5 is summarized
in Figure 2. During the work-up of Fries rearrangement upon acid-
ification of the reaction mass and cooling at 5–10 °C, the yellow
product precipitated out (yield 38.8%). This precipitated product
was filtered and found to be 4 after spectroscopic characterization.
The HPLC purity of 4 was >98%. The mother liquor obtained after
the filtration when analyzed by HPLC showed mixture of 4 and 5.
For the further purification and separation of 4 from 5, at this stage
it was anticipated that due to intramolecular hydrogen bonding,
compound 5 could be steam volatile. This proved to be the case
as we were able to efficiently separate 5 (yield 24%, >98% purity
by HPLC) from 4 (remained in residue) by steam distillation. Thus
steam distillation was found to be an efficient technique to sepa-
rate pure 4 from 5. The steam distillation residue when analyzed
by HPLC showed compound 4 (92.7% HPLC Purity). This residue
was further purified by recrystalization with a mixture of MTBE:
Hexane to provide 4 (19.2%, >98% HPLC Purity). Thus the total yield
of 4 was increased to 58%.
subjected to Dakin oxidation which resulted in the formation of
fluorocatechol 8; this unisolated intermediate was o-ethylated to
furnish the target compound in 53% yield. The second approach in-
volved o-ethylation of compound 5 by using diethyl sulfate in the
presence of potassium carbonate to give compound 9, which was
then subjected to Baeyer–Villiger oxidation using m-CPBA to ob-
tain fluorophenol 10. Finally the synthesis of target compound 2
was achieved by ethylation of 10 in 96% yield in a chromatography
free manner.
In conclusion, practical and scalable synthesis of fluorinated
building blocks 3-fluoro-4-methyl benzoyl chloride (1) and 1,2-
diethoxy-3-fluorobenzene (2) was achieved using AlCl3 mediated
Fries rearrangement starting from a common starting material 2-
fluorophenol. Both the isomers 4/5 obtained from Fries rearrange-
ment were separated efficiently using steam distillation and
crystallization techniques. They were subsequently transformed
into versatile fluorinated building blocks 1 and 2 in high yield.
Acknowledgments
The authors would like to thank Acoris Research (Hikal Ltd)
management for providing necessary facilities. Special thanks are
extended to Analytical department of Acoris Research for giving
analytical support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
02.119.
With sufficient quantity of pure 4 in hand we turned our atten-
tion for transforming it into 1 (Scheme 2). Toward this goal first
phenolic hydroxyl group was methylated with dimethyl sulfate
to obtain 6. Compound 6 was subjected to hypochlorite oxidation
to get the benzoic acid derivative 7 which upon refluxing in thionyl
chloride gave targeted compound 1. All these three steps were
realized with high yields. Thus the synthesis of 1 was achieved
starting from commercially available 2-fluorophenol in 5 steps
avoiding any chromatographic purification.
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proaches (Scheme 3). In the first approach, compound 5 was first

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2429
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