Friedel-Crafts reactions in ionic liquids: The counter-ion effect on the dealkylation and acylation of methyl dehydroabietate

Article abstract of DOI:10.1016/j.tetlet.2004.03.185

Ionic liquids with different counter-ion and alkyl substitutes were tested as solvents in the dealkylation and acylation of methyl dehydroabietate, a useful and inexpensive building block for the synthesis of higher diterpenes derivatives. Ionic liquids with halogen counter-ions are very active in both reactions with high rate constant and conversion, avoiding the use of the conventional solvents (benzene and carbon disulfide) in these reactions. In the dealkylation reaction, the change of counter-ion from halogens to tetrafluoroborate had a dramatic effect on the stereoselectivity, showing the importance of the counter-ion in the course of the reactions.

Full text of DOI:10.1016/j.tetlet.2004.03.185

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4375–4377
Friedel–Crafts reactions in ionic liquids: the counter-ion effect on
the dealkylation and acylation of methyl dehydroabietate
*
Carlos Baleiz ~a o, Nat ꢀe rcia Pires, B ꢀa rbara Gigante and Maria Jo ~a o Marcelo Curto
INETI––Departamento de Tecnologia das Ind ꢀu strias Qu ꢀı micas, Estrada do Paßco do Lumiar, 22, 1649-038 Lisboa, Portugal
Received 9 February 2004; revised 29 March 2004; accepted 30 March 2004
Abstract—Ionic liquids with different counter-ion and alkyl substitutes were tested as solvents in the dealkylation and acylation of
methyl dehydroabietate, a useful and inexpensive building block for the synthesis of higher diterpenes derivatives. Ionic liquids with
halogen counter-ions are very active in both reactions with high rate constant and conversion, avoiding the use of the conventional
solvents (benzene and carbon disulfide) in these reactions. In the dealkylation reaction, the change of counter-ion from halogens to
tetrafluoroborate had a dramatic effect on the stereoselectivity, showing the importance of the counter-ion in the course of the
reactions.
Ó 2004Elsevier Ltd. All rights reserved.
The use of ionic liquids (IL) as alternative green solvents
in organic synthesis has been the focus of a large volume
of the dealkylation concerted with epimerizing/nonepi-
merizing conditions of methyl dehydroabietate (1) using
those new solvents (Scheme 1). The effect of different
lengths of the alkyl chains and counter-ions on reaction
rate, conversion and selectivity was investigated. The
study was extended to the acylation reaction (Scheme 2)
and its performance compared with similar reactions in
‘conventional’ organic solvents.
1–3
of work. The ultra-low volatibility of IL provides an
obvious advantage over volatile organic solvents and
their almost infinite flexibility in structure and anionic
character enables to adjust their properties to suit the
requirements of a particular process. Since the pioneer-
4;5
ing work of Wilkes and co-workers, reporting IL
based on dialkylimidazolium cations, Friedel–Crafts
alkylations or acylations have been the most studied
16
Dealkylation of methyl dehydroabietate 1 has been
carried out with AlCl in benzene or toluene at room
6
;7
reactions.
3
temperature to give a mixture of isomers, methyl trans-
deisopropyldehydroabietate 2 (ca. 30%) and methyl cis-
deisopropyldehydroabietate 3 (ca. 70%). The deisoprop-
ylation process consists of two reverse Friedel–Crafts
reactions, one a hydrogen replacement of the isopropyl
Our interest in the search for environmental friendly
8
–12
procedures
ologies for the synthesis of higher diterpenes derivatives
lead us to use appropriate new method-
13–15
from resin acids,
in this particular case on the study
1
1
6
5
1
C
2
17
2
0
11 13
1
4
1
A
4
9
B
6
+
-
2
3
10
8
7
[C -mim] X / AlCl / PhMe
n 3
5
+
r.t., N2
1
9
CO CH
CO CH
2
3
2
3
CO CH
2
3
1
8
21
1
2
3
Scheme 1.
Keywords: Ionic liquids; Friedel–Crafts; Counter-ion effect; Methyl dehydroabietate.
*
Corresponding author. Tel.: +351-217165141; fax: +351-217168100; e-mail: barbara.gigante@ineti.pt
0
040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.185

4376
C. Baleiz ~a o et al. / Tetrahedron Letters 45 (2004) 4375–4377
O
this halogenoaluminate complex to promote the cleav-
age/reformation of ring B due to steric hindrance. In the
case of halogen counter-ions, the increase in acidity
introduced by the halogens (Cl < Br < I) is opposed by
the size of the halogen ions.
+
-
[
C -mim] X / AlCl / CH COCl
n 3 3
r.t., N2
CO CH
CO CH
2
3
2
3
These results and our interest in obtaining either one or
the other of the isomers, led us to study the effect of the
bulkier air and moisture stable tetrafluoroborate [BF4]
1
4
Scheme 2.
6
or hexafluorophosphate [PF ] 3-methyl-1-pentylimi-
dazolium ionic liquids, that were used, up to now in
Friedel–Crafts reactions with metal trifluoromethane-
sulfonates.
group and the other the cleavage of ring B, and one
standard Friedel–Crafts reaction for the reformation of
ring B. During the latter reaction, the intermediate
carbonium ion has two steric modes of interaction with
the benzene ring, so it is not surprising that bond for-
mation occurs on the other side of ring A, thus creating
the isomer 3. Thus, using a bulkier and constrained solid
catalyst (HY zeolite), in toluene at reflux, 2 (ca. 90%)
18
In the present study, for these two ionic liquids, no
reaction was observed when the proportion of reagents
was the same as with the heptahalodialuminate (III)
systems. However, increasing the amount of solvent/
catalyst complex ionic liquid a higher conversion (90%)
and selectivity for 2 (85%) were obtained with tetraflu-
oroborate 3-methyl-1-pentylimidazolium ionic liquid in
longer reaction time (15 h).
8
was selectively produced. In this later case no isomer 3
was formed, since no cleavage of ring B occurs.
As steric hindrance plays an important role in Friedel–
1
7
Crafts reactions, the dealkylation of 1 was carried out
with a solvent/catalyst acidic complex ionic liquid, 1-
alkyl-3-methylimidazolium heptahalodialuminate (III)
These systems were also applied to the Friedel–Crafts
acetylation of methyl dehydroabietate 1 (Scheme 2). No
19
carbon disulfide was used and the reactions were very
fast, resulting in short reaction times (15 min) and high
conversions (>80%) and regioselectivities (>95 %) in the
case of methyl 12-acetyl-dehydroabietate 4 using differ-
ent halogenoaluminate (III) ionic liquids, except when
the counter ion was chloride. As for the dealkylation
reaction, the complexes air and moisture stable tetra-
n 2 6
[C mim]Al Cl X with different counter ions and/or dif-
ferent 1-alkyl chain lengths (n ¼ 3, 5, 7), in the presence
of an excess of toluene (twice the mole fraction of 1) as
isopropyl acceptor.
8
C H
n 2n+1
X -
N
N
+
4 6
fluoroborate [BF ] and hexafluorophosphate [PF ] 3-
methyl-1-pentylimidazolium ionic liquids also proved to
be inactive except when the catalytic complex
[C mim]BF /AlCl (1:2) was used in a larger amount (7-
5 4 3
fold).
X - = Cl , Br , I , BF -, PF -
[
-
-
-
4
6
+
Cn-mim] , n = 3,5,7
The results obtained (Table 1) showed that no signifi-
cant difference was introduced by the alkyl chain length
used. All heptahalodialuminate complexes are highly
active at room temperature with high conversion (90–
98%), either with bromide or chloride as counter-ion,
giving a proportion of isomers as described in the lit-
erature for the traditional reaction with aluminium
chloride in benzene, but in shorter reactions times. The
marked difference in the stereoselectivity observed for
In conclusion, the results obtained (Tables 1 and 2)
show that both dealkylation and acetylation of methyl
dehydroabietate 1 can be improved in terms of reaction
rate by the use of appropriate ionic liquids as solvents,
and thus avoiding the conventional organic solvents
usually employed in these reactions (benzene and carbon
disulfide). In the case of dealkylation, it is possible to
direct the cleavage/reformation of ring B to high yields
16
5
[C mim]I can be interpreted as due to the difficulty of
a
3
Table 1. Dealkylation of methyl dehydroabietate 1 using AlCl as catalyst and toluene with different ionic liquids as solvents
Entry
Solvent
Time (h)
Conversion (%)
2:3 (%)
b
1
2
3
Benzene
3
100
98
98
96
90
87
0
27:73
28:72
29:71
28:72
27:73
52:48
––
[C
[C
3
5
7
5
5
5
5
5
5
mim]Br
mim]Br
mim]Br
mim]Cl
mim]I
0.5
0.5
0.5
0.5
0.5
48
4
5
6
7
8
9
1
[C
[C
[C
[C
[C
[C
[C
mim]PF
6
mim]BF
4
48
0
––
c
c
mim]PF
mim]BF
6
48
15
0
90
––
85:15
0
4
a
b
c
The reaction as carried out in the presence of AlCl
Ref. 16; 1/benzene/AlCl
¼ 1/352/5.
/ionic liquid/AlCl
/toluene ¼ 1/7/14/4.
3
and toluene. 1/ionic liquid/AlCl
3
/toluene ¼ 1/2/4/4.
3
1
3

C. Baleiz ~a o et al. / Tetrahedron Letters 45 (2004) 4375–4377
4377
Table 2. Acylation of methyl dehydroabietate 1 with acetyl chloride
a
In a reaction where no aliquots were removed, 4 was
extracted with diethyl ether with high mass balance
(>90%). Recrystallization from methanol afforded
methyl 12-acetyldehydroabietate 4 (98 mg, 85%).
3
using AlCl as catalyst with different ionic liquids as solvents
Entry Solvent
Time (h)
Conversion (%) 4 (%)
b
1
2
3
4
5
6
7
8
9
1
CS
2
4100
0.25
0.25
0.25
0.25
0.25
48
86
[C
[C
3
mim]Br
mim]Br
mim]Br
mim]Cl
mim]I
95
96
90
80
97
0
96
97
95
98
98
––
––
––
94
5
7
5
5
5
5
5
5
[C
[C
[C
[C
[C
[C
[C
Acknowledgements
mim]PF
6
Financial support to C. Baleiz ~a o from Fundaßc ~a o para a
Ci ^e ncia e Tecnologia, Portugal (PRAXIS XXI/BD/
21375/99) is gratefully acknowledged.
mim]BF
4
48
0
c
c
mim]PF
mim]BF
6
48
0
87
0
4
0.5
a
The reaction as carried out in the presence of acetyl chloride and
AlCl . 1/ionic liquid/AlCl
/acetyl chloride ¼ 1/2/4/4.
Ref. 19; 1/CS /AlCl
/acetyl chloride ¼ 1/52/3/3.
/ionic liquid/AlCl
/acetyl chloride ¼ 1/7/14/4.
3
3
b
c
2
3
1
3
References and notes
of stereoisomers, 2 or 3, which can be obtained as main
products using either [mpim]BF4or [mpim]halogen,
respectively.
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3
1
1.Experimental
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J. Org. Chem. 1986, 51, 480–483.
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7
. Sheldon, R. Chem. Commun. 2001, 2399–2407.
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ionic liquid (0.64mmol), toluene (136 lL, 1.28 mmol)
and AlCl (171 mg, 1.28 mmol). Once the mixture was
3
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homogeneous, 1 (100 mg, 0.32 mmol) was added. The
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column SGE, 12 m, 0.25 lm film thickness) using stan-
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^
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447.
dards obtained in accordance with the literature.
3
Aliquots were quenched with water, extracted with
diethyl ether and dried over anhydrous MgSO before
1
1
1
1
1. Baleiz ~a o, C.; Gigante, B.; Garcia, H.; Corma, A. Green
Chem. 2002, 4, 272–274.
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4
analysis. In reactions where no aliquots were removed,
the product was extracted with a high mass balance
(
>80%) and the compounds were isolated by crystalli-
zation from diethyl ether/methanol to yield methyl
trans-deisopropyldehydroabietate 2 (15–62%) or methyl
cis-deisopropyldehydroabietate 3 (10–68%).
2001, 57, 1793–1799.
4. Gigante, B.; Silva, A. M.; Marcelo-Curto, M. J.; Sav-
luchinske Feio, S.; Roseiro, J.; Reis, L. V. Planta Med.
2
002, 68, 680–684, and references cited therein.
1
5. Gigante, B.; Santos, C.; Silva, A. M.; Curto, M. J. M.;
Nascimento, M. S. J.; Pinto, E.; Pedro, M.; Cerqueira, F.;
Pinto, M. M.; Duarte, M. P.; Laires, A.; Rueff, J.;
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Chem. 2003, 11, 1631–1638.
1
.2. General procedure for acylation of 1
To the homogeneous mixture of the ionic liquid
0.64mmol) and AlCl (171 mg, 1.28 mmol), 1 (100 mg,
.32 mmol) and acetyl chloride (91.3 lL, 1.28 mmol)
were added and left stirring at room temperature.
Aliquots were quenched with water, extracted with
(
0
3
1
1
6. Tahara, A.; Akita, H. Chem. Pharm. Bull. 1975, 23, 1976–1983.
7. Olah, G. A. In Friedel–Crafts and Related Reactions;
Interscience, 1963; p 871.
1
19. Cambie, R. C.; Franich, R. A. Aust. J. Chem. 1971, 24,
8. Ross, J.; Xiao, J. Green Chem. 2002, 4, 129–133.
diethyl ether and dried over anhydrous MgSO before
4
19
analysis by GLC using standards previously obtained.
117–134.