Strong-acids-promoted protiodeacylation of sterically nonhindered alkyl aryl ketones

Article abstract of DOI:10.1055/s-2007-982576

In the presence of strong acids in aqueous and anhydrous media alkyl aryl ketones bearing a strong electron-releasing group in the aromatic ring undergo protiodeacylation. In a reaction with triflic acid in aromatic solvents, the transfer of the liberated acyl group to aromatic solvent molecules is observed. The effects of the nature and the position of the activating group and the strength of the acid and the solvent, on the course of this ipso-substitution were investigated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982576

LETTER
1699
Strong-Acids-Promoted Protiodeacylation of Sterically Nonhindered Alkyl
Aryl Ketones
Protiodeacylation of
S
t
a
erically N
o
t
nhinde
j
red Alk
a
yl
A
ryl ket
ž
ones Koželj, Andrej Petrič*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana 1000, Slovenia
Fax +386(1)2419220; E-mail: Andrej.Petric@fkkt.uni-lj.si
Received 30 April 2007
Dedicated to the memory of Dr. Nelson J. Leonard
comparison to the analogous monocyclic compounds.5d
The reversibility of reactions under standard Friedel–
Crafts acylation conditions has been documented only
sporadically.7a In contrast, the zeolite-catalyzed migration
Abstract: In the presence of strong acids in aqueous and anhydrous
media alkyl aryl ketones bearing a strong electron-releasing group
in the aromatic ring undergo protiodeacylation. In a reaction with
triflic acid in aromatic solvents, the transfer of the liberated acyl
group to aromatic solvent molecules is observed. The effects of the of the acetyl group from position 1 to position 6 in 1-(2-
nature and the position of the activating group and the strength of
the acid and the solvent, on the course of this ipso-substitution were
investigated.
methoxy-1-naphthyl)ethanone has been more thoroughly
studied because the 2,6-isomer is an important precursor
in naproxene synthesis.7b,c
Key words: protiodeacylation, transacylation, ketones, retro-
Friedel–Crafts reaction, ipso-electrophilic-aromatic substitution
O
H
HBraq or TfOHaq
toluene, reflux
R
R1O
The synthesis of novel molecular probes for medical
research using {1-[6-(dimethylamino)-2-naphthyl]ethyl-
idene}malononitrile1a–c (DDNP) as the lead compound
often involves strongly acidic or basic media. We have
previously reported on an unusual base-promoted cleav-
age of alkyl aryl ketones.1d Herein we report on a rather
unexpected cleavage of these ketones with strong acids.
The ipso substitutions of a substituent, bound to an aro-
matic ring by a carbon–metal, carbon–boron, carbon–sili-
con, carbon–halogen, carbon–sulfur, or carbon–nitrogen
bond, are becoming important tools in the tool chest of
synthetic organic chemistry.2 The analogous replacement
of alkyl or acyl substituents by hydrogen is a far less fre-
quently observed and synthetically utilized reaction. The
transformation of benzoylmesitylene with hot phosphoric
acid into a mixture of mesitylene and benzoic acid is the
first such documented deacylation reaction.3a A subse-
quent investigation led to the conclusion that the structural
requirements that govern this type of transformation are
the presence of bulky groups adjacent to the acyl group
and the presence of electron-releasing substituents in the
ring. If these two requirements are met, the protonation at
the acyl-bearing carbon is facilitated and the deacylation
reaction is assisted by steric acceleration.3–5 The relatively
large, negative Hammett r value (r = –4.6) reveals the im-
portance of the protonation step in these reactions.5c It has
been observed that for a successful deacylation at least
one of the positions ortho to the acyl group must be occu-
pied by an alkyl group.3–6 In 1-naphthyl ketone derivatives
steric interactions with hydrogen at the peri position (8-
position) bring about deacylation-rate enhancement in
HO
Scheme 1 The deacylation of alkyl aryl ketones with aqueous acids
In contrast to the above observations, we have found that
steric hindrance around the departing acyl group is not a
necessary requirement for successful deacylation. A
methoxy (or a hydroxyl) group in a conjugated position to
the leaving acyl group offers sufficient activation for a
successful deacylation with HBr (Scheme 1). The results
are summarized in Table 1.
The first step in the reaction sequence in the cases of
methoxy derivatives was most likely demethylation; this
produced the corresponding hydroxyl derivative, which
underwent subsequent deacylation. The transformation
failed if the activating group was attached to a position in
the ring that does not enable a direct conjugation with the
departing acyl group, e.g., with m-methoxyacetophenone
(entry 2). However, in the cases with the activating group
at the ortho position to the acyl group (entries 3 and 10)
the requirement for direct conjugation is met, the reaction
with HBr failed; this can be explained by the formation of
a strong intramolecular hydrogen bond between the
carbonyl oxygen and the hydroxyl group in the ortho
position, which renders the compound less reactive. The
presence of the hydrogen bond is also indicated by a large
chemical shift of the hydroxyl proton signal (larger than
1
10 ppm) in the H NMR spectrum. An activating group
that is not a resonance donor, e.g., an alkyl group, offered
a too weak activation and the deacylation reaction failed
(entry 11). Although an amino group is a better electron-
releasing group than hydroxyl,2 it is more basic and thus
protonated in acidic media to a much greater extent.
Protonation blocks the activating effect of the amino
group in the investigated reaction (entries 12 and 13).
SYNLETT 2007, No. 11, pp 1699–1702
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982576; Art ID: G10207ST
© Georg Thieme Verlag Stuttgart · New York

1700
M. Koželj, A. Petrič
Table 1 The Deacylation of Alkyl Aryl Ketones with Aqueous HBr8
Entry
1
Ketone
Product
Yield (%)
1-(4-Methoxyphenyl)ethanone
1-(3-Methoxyphenyl)ethanone
1-(2-Methoxyphenyl)ethanone
1-(4-Methoxyphenyl)propan-1-one
(4-Methoxyphenyl)(phenyl)methanone
1-(4-Hydroxyphenyl)ethanone
1-(6-Methoxy-2-naphthyl)ethanone
1-(6-Methoxy-2-naphthyl)propan-1-one
1-(6-Hydroxy-2-naphthyl)ethanone
1-(1-Hydroxy-2-naphthyl)ethanone
1-(4-Methylphenyl)ethanone
Phenol
85
0
2
(Phenol)a
3
(Phenol)a
0
4
Phenol
70
43
80
70
53
68
0
5
Phenol
6
Phenol
7
2-Naphthol
8
2-Naphthol
9
2-Naphthol
10
11
12
13
14
1-Naphthol
(Toluene)a
0
1-(4-Aminophenyl)ethanone
(Aniline)a
0
1-(6-Dimethylamino-2-naphthyl)ethanone
6-Methoxy-3,4-dihydronaphthalen-1(2H)-one
(2-Dimethylaminonaphthalene)a
8-Hydroxy-3,4-dihydronaphthalen-1(2H)-one
0
11
a Expected main product.
Unlike HBr, triflic acid in an aqueous medium success- we chose cyclic alkyl aryl ketone 6-methoxy-3,4-di-
fully catalyzes the deacylation of compounds bearing the hydronaphthalen-1(2H)-one as the substrate for the
activating group, not only in para but also in ortho or meta deacylation reaction (Table 1, entry 14; Scheme 2).
positions. The results are shown in Table 2.
We expected to isolate a product that would contain both
The lower yield of phenol formed from 1-(2-methoxy- the aromatic and the acyl parts of the substrate, thus
phenyl)ethanone (entry 2) is indicative of the relatively revealing the fate of the acyl group. But instead of 4-(3-
strong stabilization effect of the intramolecular hydrogen hydroxyphenyl)butanoic acid, or its probable precursor
bonding in the hydroxyl intermediate.
acid bromide, we isolated 8-hydroxy-3,4-dihydronaph-
thalen-1(2H)-one.10
In the above reactions the fate of the aromatic ring part of
the substrates was determined on the basis of the isolated The plausible reaction steps explaining this transforma-
products. However, the fate of the acyl parts of the tion are demethylation, fission of the bond between the
molecules could not be determined. Irrespective of the aromatic ring and the carbonyl group, and subsequent in-
actual reactive form in which the acyl group left the tramolecular acylation. The driving force is most probably
protonated intermediate,5c,6,9a it was most probably con- the formation of a strong intramolecular hydrogen bond
verted to a carboxylic acid. We did not attempt to detect between the 8-hydroxyl and 1-carbonyl groups.
acetic or propionic acids in the reaction mixtures contain-
ing a large excess of aqueous HBr or triflic acid. Instead,
ions preferentially react with water, giving free carboxylic
In aqueous media the elusive reactive species like acylium
acids.5,6 In anhydrous acidic media, however, this cannot
happen and the reactive electrophilic species must react
with other nucleophiles present in the reaction mixture. A
Table 2 The Deacylation of Alkyl Aryl Ketones with Aqueous Tri-
flic Acid8
reaction with the conjugate base of the utilized anhydrous
Entry Ketone
Product
Yield
(%)
H
1
2
3
4
5
1-(4-Methoxyphenyl)ethanone
Phenol
86
67
46
72
68
O
O
O
COX
1-(3-Methoxyphenyl)ethanone
1-(2-Methoxyphenyl)ethanone
1-(6-Methoxy-2-naphthyl)ethanone
1-(6-Hydroxy-2-naphthyl)ethanone
Phenol
Phenol
MeO
HO
2-Naphthol
2-Naphthol
Scheme 2 Intramolecular transacylation
Synlett 2007, No. 11, 1699–1702 © Thieme Stuttgart · New York

LETTER
Protiodeacylation of Sterically Nonhindered Alkyl Aryl Ketones
1701
acid would be a logical choice, but the product formed to the reaction temperature in the boiling solvent being too
would be a very reactive, mixed anhydride. If an aromatic low.11 Transacylation also failed if chlorobenzene was
compound is used as a solvent, although weakly nucleo- used as the solvent. This result is attributed to the de-
philic, it can react with the acylium ion or an acid deriva- activating effect of the chlorine atom, which makes
tive to produce stable products. Transacylation reactions chlorobenzene too weak a nucleophile for a successful
of this kind were observed if sterically hindered acyl- reaction with the electrophile formed in the reaction
pentamethylbenzenes were treated with acids in anisole. mixture. Tetraline can be formally considered as an
Acylanisoles were formed as the consequence of the acyl alkylbenzene, but the reaction performed in its presence
group transfer.6b,9a
resulted in a tarry material from which we could not
isolate and characterize any pure material.
These results prove that not only the steric effects, but also
the electronic effects of the substituents in the aromatic
ring can provide enough activation for a successful pro-
tiodeacylation reaction. Hydroxyl or alcoxy groups pro-
vide a balanced activating donor effect and weak basicity.
In nitrogen-based functional groups the basic character is
too pronounced and in acidic media protonation disables
the activating electron-donating effect. Although alkyl
groups usually accelerate the electrophilic aromatic sub-
stitution through their positive inductive effect or hyper-
conjugation, in protiodeacylation the electron-donating
properties alone do not provide enough activation for a
successful reaction. The electron-donating properties
must combine with the steric effect, e.g., a methyl group
in the ortho position, to promote protiodeacylation in
alkyl aryl ketones. If the transformation is performed with
a strong acid in an anhydrous aromatic solvent, the
cleaved-off acyl group is transferred to the solvent mole-
cule. These findings complement the present knowledge
on Friedel–Crafts and related reactions.2 Protons must be
considered as viable electrophiles in reactions of the
aromatic compounds in strong acids, in aqueous and non-
aqueous media. At the same time, the fact that not only
proton groups, but also other groups, can act as the leaving
group in electrophilic aromatic substitutions, must be
taken in account.
O
O
H
TfOHanhyd
toluene, reflux
R
R
+
R1O
R1O
Me
Scheme 3 The deacylation of alkyl aryl ketones with anhydrous
acid
At first glance our results, summarized in Table 3, contra-
dict these findings. In our experiments the acyl group was
transferred from the methoxy-/hydroxy- to the alkyl-sub-
stituted aromatic ring, which is the opposite direction to
that observed previously. In both cases the formation of
the acylium ion or its reactive derivative can be envisaged,
although the driving forces of the deacylations were
different. In the case of acylpentamethyl benzenes the
intermediate acylium ion reacted readily in a kinetically
controlled reaction with anisole, the only viable aromatic
compound in the reaction mixture, forming acyl anisole.
The latter can in principle re-enter the deacylation reac-
tion, but because of the large excess of anisole in compar-
ison to the competing pentamethyl benzene formed in the
first step, it is most likely that the acylanisole remains as
the major isolated product. In our experiments performed
with anhydrous triflic acid we presumed that acylium
triflate was formed as the reactive acylium derivative
(Scheme 3);9b,11 it then further reacted preferentially in a
thermodynamically controlled reaction with alkylben-
zenes. The acyl-group transfer was successful if toluene
Acknowledgment
or xylene were used as the solvent. If benzene was used, The work was supported by the Ministry of Higher Education,
Science and Technology of the Republic of Slovenia and the
only traces of products were detected, which we attributed
Slovenian Research Agency (P1-0230-0103 and J1-6693-0103).
Table 3 Anhydrous Triflic Acid Promoted Transacylation12
No
1
Ketone
Solvent
Products
1-(4-Methoxyphenyl)ethanone
(4-Methoxyphenyl)(phenyl)methanone
1-(6-Hydroxy-2-naphthyl)ethanone
1-(4-Methoxyphenyl)ethanone
1-(4-Methoxyphenyl)ethanone
1-(4-Methoxyphenyl)ethanone
1-(4-Methoxyphenyl)ethanone
Toluene
36% 1-(4-Methylphenyl)ethanone (and other isomers), anisole
50% (4-Methylphenyl)(phenyl)methanone, phenol
36% 1-(4-Methylphenyl)ethanone, 2-naphthol
Traces of anisole
2
Toluene
3
Toluene
4
Benzene
Xylene
5
Ca. 30% isomeric 1-(dimethylphenyl)ethanones
Tar
6
Tetraline
Chlorobenzene
7
No changes
Synlett 2007, No. 11, 1699–1702 © Thieme Stuttgart · New York

1702
M. Koželj, A. Petrič
(8) General Procedure for the Reaction with Aqueous Acid
A ketone (100 mg) was dissolved in the appropriate
cosolvent (toluene, xylene, 3 mL); an acid (3 mL of 48% or
62% HBr in H2O or 1 mL of 50% TfOH in H2O) was added,
and refluxed for 48 h. The reaction mixture was cooled,
diluted with H2O (20 mL) and extracted with CH2Cl2 (4 × 5
mL); the combined organic phases were washed with a sat.
aq solution of NaHCO3, dried over anhyd Na2SO4, and
evaporated. The products were identified by 1H NMR
spectroscopy and GC-MS.
References and Notes
(1) (a) Shogi-Jadid, K.; Small, G. W.; Agdeppa, E. D.; Kepe, V.;
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2002, 24. (b) Liu, J.; Kepe, V.; Žabjek, A.; Petrič, A.;
Padgett, H. C.; Satyamurthy, N.; Barrio, J. R. Mol. Imaging
Biol. 2007, 9, 6. (c) Škofic, P.; Dambrot, C.; Koželj, M.;
Golobič, A.; Barrio, J. R.; Petrič, A. Acta Chim. Slov. 2005,
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(10) 1H NMR: d = 2.09 (q, 2 H, J = 6.2 Hz, 3-CH2), 2.67 (t, 2 H,
J = 6.2 Hz, 5-CH2), 2.90 (t, 2 H, J = 6.1 Hz, 2-CH2), 6.70
(dd, 1 H, J1 = 8.4 Hz, J2 = 0.9 Hz, 5-H), 6.79 (d, 1 H, J1 = 8.4
Hz, 7-H), 7.35 (t, 1 H, J = 8.4 Hz, 6-H), 12.43 (s, 1 H, 8-OH).
GC-MS: [M+] = 162; [M] = 162.185 g/mol; spectrum is
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(12) General Procedure for the Reaction with Anhydrous
Acid
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A ketone (100 mg) was dissolved in dry aromatic solvent
(5 mL), TfOH (0.2 mL) was added, and the mixture was
refluxed under argon. After 72 h the mixture was cooled,
diluted with H2O (15 mL), and the organic layer was
separated. The water layer was extracted with CH2Cl2
(2 × 10 mL); combined organic phases were washed with a
sat. aq solution of NaHCO3, dried over anhyd Na2SO4, and
evaporated. The mixture of compounds was analyzed by
means of GC-MS.
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