LETTER
▌1927
lAettner Improved Synthesis of Hydroxy Aryl Ketones by Fries Rearrangement
with Methanesulfonic Acid/Methanesulfonic Anhydride
Improved Synthesis of Hydroxy Aryl Ketones
Ingyu Jeon,* Ian K. Mangion
Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Fax +1(732)5941499; E-mail: Ingyu.jeon@merck.com
Received: 21.03.2012; Accepted after revision: 26.05.2012
rearrangements to give hydroxy aryl ketones with high
Abstract: Methanesulfonic acid treated with methanesulfonic an-
yields.
hydride effectively mediates the Fries rearrangement of aryl esters
to give hydroxy aryl ketones with high yields.
Br
Key words: rearrangement, ketones, esters, methanesulfonic acid,
methanesulfonic anhydride
O
acid
O
O
OH
Br
Aryl esters readily rearrange to hydroxy aryl ketones via
Lewis acid catalysis, a reaction known as the Fries rear-
rangement.1,2 While the selective Fries rearrangement of
esters of aromatic alcohols has been used to significant
advantage in the production of industrial pharmaceuti-
cals,1,2 classical Fries rearrangements are typically cata-
lyzed by metal halides or Brønsted acids. Often these
reagents are corrosive, toxic, and react violently with wa-
ter.3–6 Classical Lewis acids are used in excess since they
form complexes with both the starting materials and prod-
ucts. Therefore, this reaction risks corrosion and increased
environmental impact due to the large amounts of acidic
effluents and solid wastes,7 as well as corrosive gases and
contaminated salts.8 These disadvantages inspired us to
investigate alternative reagents to promote Fries rear-
rangements.
1a
1
Scheme 1 Acid-catalyzed Fries rearrangement of 1
We began by examining the use of MSA and other Lewis
acids (Scheme 1) in the Fries rearrangement of 3-bromo-
phenyl 2-phenylacetate (Scheme 2, Table 1). The Fries re-
arrangement of 1 using commonly used Lewis acids
afforded the desired product in only 11–26% yield despite
lengthy reaction time in these cases (Table 1, entries 1–4).
In contrast, MSA was well suited to perform the rear-
rangement of 1 into 1a regioselectively, and we were able
to isolate a single isomer in higher yields (Table 1, entries
5–12). At various temperatures the Fries rearrangement of
1 provided the desired product in 53–74%, with 70 °C be-
ing preferable leading to complete conversion in three
hours (Table 1, entries 5–7, 9). However, the reaction of 1
at 100 °C for half an hour in MSA afforded 1a in only
62% yield due to degradation of the product (Table 1, en-
try 7). It was observed that the principal byproducts of this
reaction were phenyl acetic acid and 3-bromophenol aris-
ing from hydrolysis of 1. Technical grade MSA is typi-
cally 95% pure containing 2% water. The Fries
rearrangement of 1 at higher water content showed that at
the reaction onset, phenyl acetic acid and 3-bromophenol
were the major products with low yield (Table 1, entry 8).
Therefore, it was found to be very important to use anhy-
drous MSA, as elevated levels of water can hydrolyze 1 to
phenol and phenyl acetic acid. In searching for suitable
desiccant for MSA, methanesulfonic anhydride was found
to dry MSA effectively, and the addition of 0.2 equiva-
lents to the reaction resulted in an in-process water con-
tent of 1014 ppm and significantly improved the reaction
efficiency affording the desired product 1a in 81% yield
(Table 1, entry 10). Surprisingly, attempting to improve
the yield by further desiccating the MSA was not success-
ful. We observed a detrimental effect of excess methane-
sulfonic anhydride on the reaction performance. Addition
of greater than 0.4 equivalents (in-process water content
below 500 ppm) resulted in a decrease in the yield of 1a
and the formation of new undesired byproducts caused by
The use of methanesulfonic acid (MSA) to promote the
Fries rearrangement has been described in limited exam-
ples.4,8–11 In one example the Fries rearrangement of phe-
nyl acetate was mediated by catalytic amounts of MSA
(maximum 28.6%), at temperatures between 160 and
196 °C, leading to around 20–30% conversions. Unfortu-
nately, the lengthy reaction time and the elevated reaction
temperature partially caused degradation of the reaction
mixture.8 When the reaction was carried out at 90 °C with
eight equivalents of MSA, the para isomer was produced
with good conversion and selectively with the same sub-
strate.8 Recently, we found an improved procedure for
Fries rearrangements mediated by MSA using methane-
sulfonic anhydride as an additive. We were interested in
optimizing conditions using MSA because it is gaining in-
creased importance in chemical syntheses as a nonoxidiz-
ing, readily biodegradable strong organic acid with high
thermal stability.12 Herein we describe the use of MSA
treated with methanesulfonic anhydride to promote Fries
SYNLETT 2012, 23, 1927–1930
Advanced online publication: 23.07.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316568; Art ID: ST-2012-S0264-L
© Georg Thieme Verlag Stuttgart · New York