Selective methoxy ether cleavage of 2,6-dimethoxyphenol followed by a selective acylation

Article abstract of DOI:10.1016/j.tetlet.2011.10.140

A Friedel-Crafts reaction of 2,6-dimethoxyphenol in the presence of aluminum chloride and propanoyl or butanoyl chloride, respectively, lead, at elevated temperatures, to a selective cleavage of one of the methoxy groups followed by a selective acylation

Full text of DOI:10.1016/j.tetlet.2011.10.140

Tetrahedron Letters 53 (2012) 11–14
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective methoxy ether cleavage of 2,6-dimethoxyphenol followed
by a selective acylation
Enoch A. Adogla, Romy F.J. Janser, Samuel S. Fairbanks, Caitlyn M. Vortolomei, Ranjith K. Meka,
⇑
Ingo Janser
Laboratory of Organic Synthesis, Catalysis & Biochemistry (LOSCB), Department of Chemistry, New Mexico Institute of Mining and Technology,
801 Leroy Place, Socorro, NM 87801, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Revised 25 October 2011
Accepted 26 October 2011
Available online 31 October 2011
A Friedel–Crafts reaction of 2,6-dimethoxyphenol in the presence of aluminum chloride and propanoyl or
butanoyl chloride, respectively, lead, at elevated temperatures, to a selective cleavage of one of the meth-
oxy groups followed by a selective acylation of the meta position with respect to the phenolic hydroxyl
group. Under the same reaction conditions 2-methoxyphenol does not get demethylated; a mechanism to
account for these findings is proposed. This reaction gives access to a variety of ortho-acylated catechols.
Substituted catechols are widely used in supramolecular chemistry and are precursors of pesticides,
flavors, and fragrances. Additionally, catechol moieties are found in various natural products.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts
Fries rearrangement
Selective methoxy cleavage
Selective acylation
Ethacrynic acid
Substituted catechols
The Friedel–Crafts alkylation and acylation of aromatic systems,
commonly known as the Friedel–Crafts reaction, was developed by
Friedel and Craft in 1877.1 This reaction is still a very important
tool in synthetic organic chemistry. In our laboratory, we are using
this reaction to synthesize analogs of ethacrynic acid (EA) (Fig. 1).
Ethacrynic acid is a loop diuretic which is used to treat high blood
pressure and edema.2,3 Some of our analogs possess a significant
potency to inhibit the migration of several cancer cell lines.4,5
As the starting materials for the syntheses of the EA analogs, we
used various substituted phenols or phenol itself. In the first step,
these compounds were acylated by a Friedel–Crafts reaction in
the presence of aluminum chloride (AlCl3) as the Lewis acid catalyst
and the corresponding acyl chloride in carbon disulfide (CS2) as the
solvent. If the reaction was carried out below room temperature,
the major products obtained from the acylation reaction were es-
ters, formed via O-acylation of the phenolic oxygen of the phenol
derivatives. In order to obtain the C-acylated products (ortho or para
to the hydroxyl group), the reaction has to be carried out at higher
temperatures. At these elevated temperatures, the Fries rearrange-
ment takes place in which the phenyl ester rearranges to the hydro-
xy aryl ketone.6,7 This protocol worked very well for all of the
phenol derivatives we used, except for 2,6-dimethoxyphenol 1
(Scheme 1). To our surprise, the Friedel–Crafts acylation with this
compound did not yield the expected para-acylated hydroxy aryl
ketone. Instead, it lead to a selective cleavage of one of the methoxy
groups with a subsequent acylation of the position meta to the hy-
droxyl group, to form 1-(2,3-dihydroxy-4-methoxyphenyl)propan-
1-one 6 or 1-(2,3-dihydroxy-4-methoxy-phenyl)butan-1-one 7,
respectively, as the major product (Scheme 1). In order to further
investigate the product formation, we performed the reaction at
various temperatures. When the reaction was carried out at 0 °C
for 12 h, the major product obtained from the reaction was 2,6-
dimethoxyphenyl propionate 2 or 2,6-dimethoxyphenyl butyrate
3, respectively (Scheme 1). Carrying out the reaction at room tem-
perature for 12 h, mainly lead to the formation of the para-acylated
products 1-(4-hydroxy-3,5-dimethoxyphenyl)propan-1-one 4 and
1-(4-hydroxy-3,5-dimethoxyphenyl)butan-1-one 5, respectively.
However, if the reaction was performed at elevated temperatures
(approximately 46 °C), a selective cleavage of one of the methoxy
groups followed by a selective acylation of the meta position oc-
curred to form 1-(2,3-dihydroxy-4-methoxyphenyl)propan-1-one
Cl
Cl
COOH
O
⇑
Corresponding author. Tel.: +1 575 835 6948; fax: +1 575 835 5364.
E-mail address: ijanser@nmt.edu (I. Janser).
Figure 1. Structure of ethacrynic acid (EA).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.140

12
E. A. Adogla et al. / Tetrahedron Letters 53 (2012) 11–14
O
O
O
R
OMe
Cl
R
MeO
MeO
2 equiv. AlCl3, CS2
0ºC, 12 h
2: R = C2H5 (77%) + traces of 4
3:
5
R = C3H7 (75%) + traces of
O
OH
OH
Cl
R
MeO
OMe
OMe
2 equiv. AlCl3, CS2
r. t., 12 h
1
R
O
4: R = C2H5 (56%) + 22% of 2
5:
3
R = C3H7 (49%) + 25% of
O
OH
Cl
R
2 equiv. AlCl3, CS2
reflux, 12 h
HO
R
OMe
6: R = C2H5 (56%) + 18% of 4
7: R = C3H7 (48%) + 23% of 5
R = C2H5, C3H7
O
Scheme 1. Friedel–Crafts reaction of 2,6-dimethoxyphenol 1 with an acyl chloride at different temperatures and the corresponding yields.
3 equiv. AlCl3
no reaction
CS2, reflux, 24h
R
δ+
Cl
Cl
Cl
OH
O
OH
O
O
Al
δ+
MeO
OMe
OMe
O
Cl
R
Me
AlCl3, CS2
R = C2H5 or C3H7
O
1
8
F
3 equiv.
Cl
CS2, reflux, 24h
R
no reaction
Cl
Al
Cl
O
Cl
OMe
R = C2H5, C3H7
OH
O
OH
O
R
OMe
OMe
R
Scheme 2.
+
G
O
R
Cl
Cl
R
δ+
ortho -product
para -product
δ+ Cl
Al
Cl
O
OH
O
O
Cl
δ+
Al
δ+
Scheme 4. Proposed mechanism for the reaction of 2-methoxyphenol
propanoyl or butanoyl chloride, respectively.
8 with
MeO
OMe
MeO
O
Cl
Cl
R
Me
AlCl3, CS2
1
A
R = C2H5 or C3H7
R
R
δ+
δ+
R
R
Cl2Al
δ+ Cl
δ+ Cl
Cl2Al
O
O
O
O
δ+
δ+
AlCl2
δ+
O
O
Cl
O
O
Cl
AlCl2
Al
Al
δ+
δ+
MeO
O
MeO
O
MeO
O
Cl
O
Cl
Me
Me
Me
Cl-
- MeCl
- H+
C
B
Cl2Al
Cl2Al
sterical hindrance
more accesible side
O
O
δ+
δ+
MeO
MeO
O
MeO
O
R
AlCl2 H+/H2O
AlCl2
Figure 2.
O
O
D
E
R
2,6-dimethoxyphenol 1 in CS2 in the presence of 3 equiv of AlCl3
but in the absence of acyl chloride. After 24 h, the only compound
we could isolate was the starting material (Scheme 2). Addition-
ally, we performed the reaction in the presence of 3 equiv of butan-
oyl chloride or 3 equiv of propanoyl chloride, respectively, but in
the absence of AlCl3. After 24 h of reflux in CS2, we obtained the
same result; only the starting material could be isolated. An early
conclusion is that the selective cleavage only occurs in the pres-
ence of both AlCl3 and the respective acyl chloride.
OH
OH
6: R = C2H5
7:
O
R = C3H7
R
Scheme 3. Proposed mechanism for the reaction of 2,6-dimethoxyphenol 1 with
propanoyl or butanoyl chloride, respectively.
6 or 1-(2,3-dihydroxy-4-methoxyphenyl)butan-1-one 7, respec-
tively (Scheme 1).
To investigate the selective cleavage of one of the methoxy
groups more in-depth, we wanted to determine whether alumi-
num chloride (AlCl3) or the respective acyl chloride or a combina-
tion of both is responsible for the ether cleavage. Thus, we refluxed
Additional investigations were carried out with 2-methoxyphe-
nol 8 and 3-methoxyphenol, respectively. Both phenol derivatives
were reacted with propanoyl chloride and butanoyl chloride under
the same reaction conditions as described above and for both
compounds no ether cleavage was obtained. These results were
insofar surprising since due to the structural similarity of

E. A. Adogla et al. / Tetrahedron Letters 53 (2012) 11–14
13
2-methoxyphenol 8 and 2,6-dimethoxyphenol 1, it was expected
that 2-methoxyphenol 8 will also be demethylated in the Fri-
edel–Crafts acylation reaction.
phenyl ring meta to the phenolic oxygen atom to form complex
E. Due to the coordination of the acylium carbocation to the alumi-
num, this electrophilic attack leads, due to sterical reasons, exclu-
sively to the meta-acylated phenol derivatives 6 or 7, respectively,
which can be obtained after an aqueous work-up (Scheme 3).
The first step of the proposed mechanism of the reaction of 2-
methoxyphenol 8 with an acyl chloride is also the formation of
an ester via O-acylation of the hydroxyl group of the phenol deriv-
ative (not shown in Scheme 4). The next step includes a complex-
ation of aluminum chloride to the carbonyl oxygen of the ester and
to the oxygen of the methoxy group, as shown in Scheme 4, to form
complex F. This complex undergoes an intramolecular Fries rear-
rangement and the free acylium carbocation attacks either the
ortho- or para-position with respect to the phenolic oxygen of 2-
methoxyphenol 8 to form the ortho- or the para-product, respec-
tively (Scheme 4).
An extensive literature search revealed that various Lewis acids
such as aluminum trihalides or boron trihalides have been used as
ether-cleaving agents,8–11 in particular AlCl3 and BCl3 can be
used to selectively cleave aromatic methoxy groups adjacent to a
carbonyl function without affecting other methoxy groups present
in the molecule. Haraldsson et al. have reported the selective cleav-
age of aromatic benzyl ethers with magnesium bromide via a
neighboring group effect.14 In 1979, Paul et al. reported the selec-
tive cleavage of 2,3,4,6-tetramethoxybenzaldehyde with alumi-
num chloride at position 2 (ortho to the carbonyl function).15 To
the best of our knowledge, there has been no report on the selec-
tive ether cleavage of ortho methoxy phenols with additional acyl-
ation of the position para to the hydroxyl group of the substituted
phenol.
12
13
The above proposed mechanism for the formation of compounds
6 and 7 (Scheme 3) explains why 2,6-dimethoxyphenol 1 under-
goes a selective methoxy cleavage, whereas this is not observed
for 2-methoxyphenol 8. Another feasible mechanism to account
for our findings is that aluminum chloride only binds to the car-
bonyl oxygen of the ester and to the oxygen of the methoxy group
of both compounds, 2,6-dimethoxyphenol 1 and 2-methoxyphenol
8. In this case, the open side ortho to the phenolic oxygen of 2-
methoxyphenol 8 would make the carbonyl carbon of the ester,
compared to 2,6-dimethoxyphenol 1, more sterically accessible
(Fig. 2). Therefore, we propose that immediately after the activation
of the corresponding compound (complexation) with AlCl3, alumi-
num chloride migrates to the phenolic oxygen atom (Scheme 4),
thereby generating a free acylium carbocation. This rearrangement
is much faster than the loss of a ClÀ, therefore, no demethylation is
observed for 2-methoxyphenol 8. Since the ortho side of 2,6-dime-
thoxyphenol 1 is blocked, the migration of aluminum chloride is
slow compared to the abstraction of a ClÀ and its subsequent attack
on the carbon of the methoxy group which would lead to the ob-
served demethylation of 2,6-dimethoxyphenol 1.
In order to underpin our proposed mechanism, we performed
the Friedel–Crafts acylation with 3,5-dimethoxyphenol 9 under
the same reaction conditions as described above (Scheme 5). We
carried out the reaction at 0 °C, at room temperature, and at ele-
vated temperatures. The results are shown in Scheme 5.
At 0 °C and at room temperature the formation of the ester 10 or
11, respectively, predominates and at higher temperatures the para-
acylated product (1-(4-hydroxy-2,6-dimethoxyphenyl)propan-
1-one 12, or 1-(4-hydroxy-2,6-dimethoxyphenyl)butan-1-one) 13
In the following, we propose a mechanism for the reaction of
2,6-dimethoxyphenol 1 with propanoyl or butanoyl chloride,
respectively (Scheme 3). This mechanism shall account for our
findings that one of the methoxy groups of 2,6-dimethoxyphenol
1 gets demethylated in these reactions, whereas this cannot be ob-
served for 2-methoxyphenol 8 (Scheme 4).
The first step of the proposed mechanism is the formation of an
ester via O-acylation of the hydroxyl group of the phenol derivative
(not shown in Scheme 3). The next step includes a complexation of
aluminum chloride to the carbonyl oxygen of the ester and to the
oxygen of the methoxy group as shown in Scheme 3; additionally a
second molecule of aluminum chloride chelates into the other side
between the phenolic oxygen and the oxygen of the methoxy
group, to form complex A. The loss of a chloride anion from the
aluminum chloride forms complex B and produces a nucleophile
(ClÀ), which, even if poor, is capable of attacking the carbon of
the methoxy group, thereby cleaving the ether. We believe that
this cleavage is possible due to the double complexation of
2,6-dimethoxyphenol 1 to aluminum chloride which makes this
compound highly electron deficient and thus very reactive toward
the ClÀ attack on the carbon of the methoxy group. On the other
hand, this activation through a ‘double complex’ is not possible
for 2-methoxyphenol 8 (Scheme 4). Simultaneously, the ester is
cleaved (similar to the Fries rearrangement) to generate an acylium
carbocation which is coordinated to the aluminum (complex C).
Due to the possible free rotation about the O–Al single bond,
complex D is formed simply by rotating about the O–Al bond
and now the acylium carbocation can attack the carbon of the
O
O
O
O
R
Cl
R
10:
R = C2H5 (78%)
2 equiv. AlCl3, CS2
0ºC, 12 h
11: R = C3H7 (77%)
MeO
OMe
O
O
OH
R
Cl
R
10: R = C2H5 (55%) + 15% of 12
11: 13
2 equiv. AlCl3, CS2
r. t., 12 h
R = C3H7 (56%) + 18% of
MeO
OMe
MeO
MeO
OMe
O
9
OH
Cl
R
12:
10
R = C2H5 (79%) + 8% of
13: R = C3H7 (73%) + 12% of 11
OMe
2 equiv. AlCl3, CS2
reflux, 12 h
R = C2H5, C3H7
O
R
Scheme 5. Friedel–Crafts reaction of 3,5-dimethoxyphenol 9 with an acyl chloride at different temperatures and the corresponding yields.

14
E. A. Adogla et al. / Tetrahedron Letters 53 (2012) 11–14
was formed as the major product. No product from a selective cleav-
age of one of the methoxy groups was obtained which is not surpris-
ing since an activation of 3,5-dimethoxyphenol 9 by AlCl3 is not
possible in the way it is described above for 2,6-dimethoxyphenol 1.
In summary, the work presented here demonstrates that in the
presence of an acyl chloride (e.g., propanoyl chloride or butanoyl
chloride, respectively), and a Lewis acid catalyst (AlCl3), 2,6-dime-
thoxyphenol 1 undergoes a selective methoxy cleavage with a sub-
sequent acylation of the position meta to the phenolic oxygen
atom. A mechanism to account for the observed results has been
proposed and underpinned by various experiments. Further inves-
tigations with other methoxy substituted phenols are currently
underway in our laboratory.
Acknowledgments
The financial support of the US National Institutes of Health
(P20 RR016480) under the INBRE program of the National Center
for Research Resources (NCRR) is greatly appreciated.
References and notes
1. Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1450.
2. Zhao, G.; Yu, T.; Wang, R.; Wang, X.; Jing, Y. Bioorg. Med. Chem. 2005, 13, 4056.
3. Zhao, G.; Liu, C.; Wang, R.; Song, D.; Wang, X.; Lou, H.; Jing, Y. Bioorg. Med.
Chem. 2007, 15, 2701.
4. Janser, R. F. J.; Meka, R. K.; Bryant, Z. E.; Adogla, E. A.; Vogel, E. K.; Wharton, J. L.;
Tilley, C. M.; Kaminski, C. N.; Ferrey, S. L.; Van slambrouck, S.; Steelant, W. F. A.;
Janser, I. Bioorg. Med. Chem. Lett. 2010, 20, 1848.
General procedure: 16 2,6-dimethoxyphenol 1 (154 mg, 1.0 mmol,
1.0 equiv) was added to carbon disulfide at room temperature. Pow-
dered aluminum chloride (267 mg, 2.0 mmol, 2.0 equiv) was added
in batches. The mixture was allowed to stir for 10 min at room tem-
perature before the corresponding acyl chloride (1.2 mmol,
1.2 equiv) was added dropwise. The reaction mixture was refluxed
for 12 h and after cooling to room temperature, carbon disulfide
was decanted. The residue was added to a mixture of ice (10.0 g)
and concentrated hydrochloric acid (approximately 1 mL to obtain
pH 1) which yielded an oily fraction. The fraction was extracted
three times with ether (10 mL) and the combined organic layers
were washed with 5% sodium bicarbonate solution (10 mL) and
dried over sodium sulfate. The obtained yellow liquid was purified
through column chromatography using ethyl acetate/hexane (1:5)
as the eluent.
5. Bryant, Z. E.; Janser, R. F. J.; Jabarkhail, M.; Candelaria-Lyons, M. S.; Romero, B.
B.; Van slambrouck, S.; Steelant, W. F. A.; Janser, I. Bioorg. Med. Chem. Lett. 2011,
21, 912.
6. Fries, K.; Finck, G. Chem. Ber. 1908, 41, 4271.
7. Fries, K.; Pfaffendorf, W. Chem. Ber. 1910, 43, 212.
8. Reese, C. B.; Haslam, E. In Protective Groups in Organic Chemistry; McOmie, J. F.
W., Ed.; Plenum Press: London, 1973; p 95.
9. Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249.
10. Boto, A.; Hernandez, D.; Hernandez, R.; Suarez, E. Org. Lett. 2004, 6, 3785.
11. Boto, A.; Hernandez, D.; Hernandez, R.; Suarez, E. J. Org. Chem. 2006, 71, 1938.
12. Paul, E. G.; Wang, P. S. C. J. Org. Chem. 1979, 44, 2307.
13. Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.; Morton, R. B.; Parton,
B.; Price, A. W.; Somvichien, N. Tetrahedron Lett. 1966, 4153.
14. Baldwin, J. E.; Haraldsson, G. G. Acta Chem Scand 1986, B 40, 400.
15. Paul, E. G.; Wang, P. S.-C. J. Org. Chem. 1979, 44, 2307.
16. Analytical data for 1-(2,3-dihydroxy-4-methoxyphenyl)propan-1-one (6). 1H
NMR (400 MHz, CDCl3): d = 12.34 (s, 1H), 7.60 (d, J = 9.1 Hz, 1H), 6.54 (d,
J = 9.1 Hz, 1H), 4.64 (s, 2H), 3.97 (s, 3H), 2.98 (q, J = 7.1 Hz, 2H), 1.23 (t,
J = 7.1 Hz, 3H).