Friedel-crafts acylation reactions using esters

Article abstract of DOI:10.1002/ejoc.201201181

Intermolecular and intramolecular Friedel-Crafts acylation reactions of various aliphatic and aromatic esters at room temperature with the use of very simple reagents and activating groups in are described. The products were obtained in good yield (60-85 %). The detailed mechanistic pathway was studied by DFT calculations and supported by experimental evidence. Copyright

Full text of DOI:10.1002/ejoc.201201181

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201181
Friedel–Crafts Acylation Reactions Using Esters
Subhash P. Chavan,*[a] Sumanta Garai,[a] Achintya Kumar Dutta,[b] and Sourav Pal[b]
Keywords: Acylation / C–C coupling / Cyclization / Esters / Synthetic methods
Intermolecular and intramolecular Friedel–Crafts acylation
reactions of various aliphatic and aromatic esters at room
temperature with the use of very simple reagents and activa-
ting groups in are described. The products were obtained in
good yield (60–85%). The detailed mechanistic pathway was
studied by DFT calculations and supported by experimental
evidence.
inter- and intramolecular acylation reactions of esters that
involve the use of harsh reagents such as poly(phosphoric
acid) and triflic acid, but they are not of general use.[8,9]
Our quest for a suitable ester that could be used as an
acylating agent encouraged us to search for an activating
group that could activate the ester for Friedel–Crafts acyl-
ation reactions. Generally, anhydrides are known to react
faster and act as better electrophiles than esters. There are
some isolated reports on the Friedel–Crafts acylation reac-
tion of α-acetoxybutendioic anhydride (2a). Pevarello
et al.[10] and Mi et al.[11] reported the Friedel–Crafts acyl-
ation of 2a with 1,2-dichlorobenzene and benzene, respec-
tively, under reflux conditions. In both of these reactions,
the anhydride carbonyl group participated in the acylation
reaction in the presence of an ester carbonyl group to form
the corresponding α-hydroxy keto acid. Interestingly, when
we treated 2a with different aromatic compounds, we were
surprised to note that the anhydride group acted as an acti-
vating group; the acylation reaction took place at the less
electrophilic ester carbonyl group in very short time at
Introduction
Inter- and intramolecular Friedel–Crafts acylation of
aromatic rings is one of the most fundamental, important,
and useful C–C bond-forming reactions in organic and in-
dustrial chemistry for the synthesis of aromatic ketones and
important synthetic intermediates.[1] Conventionally un-
stable and sensitive acylating reagents such as acid chlor-
ides[2] and anhydrides[3] have been employed as acylating
agents with suitable Lewis acids by following appropriate
protocols. Acids[4] have also been shown to undergo Frie-
del–Crafts acylation reactions under harsh conditions.
Hence, the development of stable, ready-to-use, and easy-
to-handle reagents is very important for Friedel–Crafts
acylation reactions.
Esters are more stable, less expensive, easily purified, and
easier to handle than conventional acylating agents. Hence,
esters would be ideal choice if they could be used as substi-
tutes of conventional acylating agents, but because of their
low reactivity, their utilization in Friedel–Crafts reactions
remains a challenging problem.
Recently, Baba et al.[5] reported indium tribromide cata-
lyzed Friedel–Crafts acylation reactions with esters, but
there are some drawbacks to their protocol. Their method-
ology is restricted to a narrow range of substrates (only tert-
butyl esters participated in the reaction), and it requires the
use of costly reagents. Derivatives of Meldrum’s acid[6] and
enol esters[7] have also been used in Friedel–Crafts acylation
reactions. There are some isolated reports of Friedel–Crafts
[a] CSIR-NCL (National Chemical Laboratory), Division of
Organic Chemistry,
Dr. Homi Bhabha Road, Pune, Maharashtra, India 411008
Fax: +91-20-5892629
E-mail: sp.chavan@ncl.res.in
Homepage: http://www.ncl.org.in/ocd/files/staff/SPC_Group/
homePage.html
[b] Physical Chemistry Division
CSIR-NCL (National Chemical Laboratory)
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201181.
Figure 1. Friedel–Crafts acylation reaction of α-acetoxybutendioic
anhydride.
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S. P. Chavan, S. Garai, A. K. Dutta, S. Pal
SHORT COMMUNICATION
room temperature (Figure 1). We also observed that tartaric Table 2. Acylation of 2-methylanisole with different acylating
agents.
anhydride, the methyl and ethyl esters of malic acid, and
tartaric acid also acted as activation groups.
Results and Discussion
To the best of our knowledge, there is no report on the
direct Friedel–Crafts acylation reaction with the use of acti-
vated esters in the presence of AlCl3. Herein, we wish to
report our findings on the facile Friedel–Crafts acylation
reactions of esters that occur at room temperature in very
short times to produce products in good yields with high
regioselectivity.
Thus, as a test case, the intermolecular acylation of elec-
tron-rich 2-methylanisole (1a) with 2,5-dioxotetrahydrofu-
ran-3-yl acetate (2a) was studied in search of effective rea-
gents and reaction conditions. Accordingly, Friedel–Crafts
acylation of 1a with 2a in the presence of AlCl3 at room
temperature furnished aromatic ketone 3a in 74% yield.
When BF3·OEt2[12] and triflic acid[13] were used as reagents,
the yield was 60 and 50%, respectively (Table 1, entries 2
and 3).
Table 1. Effect of reagents on the acylation of 2-methylanisole.
Entry
Reagent
Time [min]
Yield [%]
1
2
3
4
5
6
AlCl3
BF3·OEt2
CF3SO3H
ZnCl2
ZnO
FeCl3
10
720
1200
overnight
overnight
120
72
60
50
SM[a] was recovered
SM[a] was recovered
SM[a] decomposed
[a] Starting material.
We next examined other catalysts that have been reported
to catalyze Friedel–Crafts acylation reactions of activated
aromatic compounds with acid chlorides, anhydrides and
acids. However, with the use of an activated ester, the start-
ing material was surprisingly recovered when ZnCl2 and
ZnO[14] were used as reagents, whereas the starting material
[15]
decomposed when FeCl3 was used (Table 1, entries 4–6).
After establishing the optimum reaction conditions, we
studied various types of esters to examine the scope of the
reaction (Table 2).The influence of the activating group and
the side chain of the ester on the acylation efficiency were
examined by using AlCl3 with 1a at room temperature as
the standard reaction conditions (Table 2). An increase in
the number of carbon atoms in the acid part of the ester,
that is, acetate ester 2a, propionate ester 2b, benzoate ester
2c, acryloyl ester 2d, and allyl ester 2e, had no adverse effect
on the efficiency of the reactions, as the corresponding
ketones were furnished in similar yields (72–74%; Table 2,
entries 1–5). We also varied the activating group to study
[a] Some esters were prepared by a literature procedure, whereas
others are commercially available. [b] Only isomerized product was
its effect on the efficiency of the reaction. Accordingly, isolated.
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Friedel–Crafts Acylation Reaction Using Esters
when the activating group was changed from malic anhy- Table 4. Intramolecular Friedel–Crafts acylation reaction.
dride to the ethyl or methyl ester of malic acid or tartaric
acid, hardly any effect on the yield and reaction time was
observed (69–75%, 10–20 min; Table 2, entries 6–10), and
acylation proceeded smoothly with the ester when an imide
(i.e., 2k) was the activating group (Table 2, entry 11).
This protocol can also be applied to different aromatic
rings, which give the corresponding ketones in very short
times and in good yields at room temperature. Heterocyclic
compounds and polycyclic compounds also participated in
this Friedel–Crafts acylation reaction and gave moderate
yields (Table 3).
Table 3. Acylation of different aromatic compounds with the same
acylating agents.
A plausible reaction pathway for the inter- and intramo-
lecular Friedel–Crafts acylation reactions of esters is illus-
trated in Scheme 1. Activation of the carbonyl group of the
ester occurs by chelation of the Lewis acid to the adjacent
carbonyl group of the anhydride (intermediate A) to form
a seven-membered ring. As a result of the chelation, ionic
intermediate B is formed. The carbonyl carbon atom bears
a positive charge in this intermediate, and it is thus acti-
vated to participate in the acylation reaction (Scheme 1).
Scheme 1. Proposed mechanism for the AlCl3 catalyzed Friedel–
Crafts acylation of ester.
Comprehensive theoretical calculations were performed
[a] Other 50% is acid.[11] [b] Based on recovery of the starting mate-
rial.
to rationalize these unusual and unexpected experimental
observations and presumptions regarding the formation of
activated adduct B, which results in chemoselective acyl-
The efficient and simple reaction conditions led us to in- ation. We first optimized our proposed adduct (Figure 2,
vestigate intramolecular Friedel–Crafts acylation reactions. intermediate B) with the DFT-B3LYP method and the 6-
Our methodology was equally efficient in the preparation 31G*++ basis set with the PCM model to incorporate sol-
of 1-tetralone, 1-indanone, and a seven-membered ring vent effects, preceded by calculation of the Fukui func-
(Table 4).
tions.[16]
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S. P. Chavan, S. Garai, A. K. Dutta, S. Pal
SHORT COMMUNICATION
materials were recovered when the reaction was performed
with substrates 2m–o. We also synthesized activated ester 2p
bearing a ketone, which underwent facile acylation with 1a
(Scheme 2). This result supports our observations that the
presence of an α-carbonyl functionality may activate the es-
ter by complexation with AlCl3.
Figure 2. Activated adduct for the acylation reaction.
From the atom-condensed Fukui function of the acti-
vated adduct we observed that the electrophilic Fukui func-
tion (fa+) at position C-5 has the highest index, which sug-
gests that the ester carbonyl carbon center is more prone to
act as an electrophilic center than the anhydride carbonyl
carbon center (Table 5).
Table 5. Condensed electrophilic Fukui functional (fa+) for the ad-
duct.
Carbon no.
C1
C2
C3
C4
C5
C6
+
fa
0.0247 0.019
0.009
0.009
0.242
0.053
Scheme 2. Studies on the Friedel–Crafts acylation reaction path-
way.
Our presumptions were further confirmed by transition-
state calculations. Transition state TS1 for the unexpected
ester carbonyl centered product is 36.67 kcal/mol more
stable than transition state TS2, which is for the expected
anhydride carbonyl centered product. This results in the
preferential formation of the former and confirms our in-
ference from Fukui function analysis (Figure 3).
Advantages of our acylation methodology were demon-
strated by the synthesis of 1-tetralone 3p,[17] which is a pre-
cursor to heritol and heritonin, from highly stable ester 1l
(Scheme 3). The transformation from the acid was earlier
reported by our group by using trifluoroacetic anhydride
and CF3CO2H. The additional advantage of our protocol
over the existing method is that there is no need to generate/
handle unstable, hazardous, and moisture-sensitive acid
chlorides. The esters can be prepared and stored over ex-
tended periods of time and can be used straight from the
shelf for the reactions; thus, our protocol is very user
friendly.
Figure 3. Energy profile diagram for unexpected and expected
products.
To gain mechanistic insight, further experiments were
carried out. We synthesized tetrahydrofuran acetate ester 2l
lacking a carbonyl group. Accordingly, when substrate 2l
was subjected to the reaction with 1a under the optimized
reaction conditions, the starting materials were recovered,
even after stirring for 24 h at room temperature as well as
under reflux conditions. To ascertain whether the presence
Scheme 3. Direct synthesis of 1-tetralone intermediate 3p (precur-
sor to heritol and heritonin).
Conclusions
We have developed simple and efficient Friedel–Crafts
of the oxygen atom of the lactone or ester activates the es- acylation reactions by using various aliphatic and aromatic
ter, we synthesized compounds 2m–o. However, starting esters. This methodology was also extended to intramolecu-
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Friedel–Crafts Acylation Reaction Using Esters
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lar Friedel–Crafts acylation reactions to synthesize 1-in-
danone, 1-tetralone, and seven-membered ring derivatives
in good yields. Our methodology has several advantages:
(1) Simple reaction conditions and simple reagents are used.
(2) Stable esters that can be stored at room temperature for
long periods of time are used. (3) The activating groups are
simple, commercially available, and cheap, and they can
also be prepared easily in the laboratory. (4) The reaction
proceeds with equal efficiency for inter- and intramolecular
Friedel–Crafts acylation reactions. (5) High yields and high
selectivities are obtained. (6) It can be used for both ali-
phatic and aromatic esters. (7) It can be scaled up easily
(see the Supporting Information). We believe this protocol,
owing to its robustness, simplicity, and efficiency, should
find widespread usage amongst practicing synthetic organic
chemists.
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Experimental Section
General Procedure for the Friedel–Crafts Acylation Reaction: To a
cold (0 °C), magnetically stirred solution of aromatic compound
(1 equiv.) and the corresponding anhydride or ester (1.2 equiv.) in
anhydrous DCM was added anhydrous crystalline aluminum chlor-
ide (4 equiv.[18]) in one portion under an atmosphere of nitrogen.
The resulting mixture was warmed to room temperature, and the
red-orange reaction mixture was stirred at room temperature until
completion of the reaction. The reaction mixture was then poured
into ice-cooled 10% aqueous HCl, and the aqueous layer was ex-
tracted with DCM. The combined organic extract was dried with
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
reaction mixture was purified by flash silica gel column chromatog-
raphy (SiO2; petroleum ether/ethyl acetate).
Supporting Information (see footnote on the first page of this arti-
cle): Instrumentation and chemicals, experimental procedures,
characterization data, theoretical studies, and copies of the NMR
spectra.
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Acknowledgments
S. G. thanks the Council of Scientific and Industrial Research
(CSIR), and S. P. C. acknowledges the Council of Scientific and
Industrial Research – National Chemical Laboratory (CSIR-
NCL), Pune, for financial support.
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Received: September 3, 2012
Published Online: November 6, 2012
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