Stetter reaction in room temperature ionic liquids and application to the synthesis of haloperidol

Article abstract of DOI:10.1002/adsc.200404123

Imidazolium-type room temperature ionic liquids (RTILs) have been used for the Stetter reaction, affording the desired 1,4-dicarbonyl compounds in good yields. Thiazolium salts and Et₃N are efficient catalysts for this reaction performed in ionic liquid. The possibility to recycle and reuse the solvent has been demonstrated, although it was not possible to recycle the thiazolium catalyst. This method was used in the total synthesis of haloperidol.

Full text of DOI:10.1002/adsc.200404123

FULL PAPERS
Stetter Reaction in Room Temperature Ionic Liquids and
Application to the Synthesis of Haloperidol
a
b
a, c,
´
´
Siddam Anjaiah, Srivari Chandrasekhar, Rene Gree *
a
`
´
´ ´
ENSCR, Laboratoire de Synthese et Activation de Biomolecules, CNRS UMR 6052, Avenue du General Leclerc,
35700 Rennes Beaulieu, France
Indian Institute of Chemical Technology, Hyderabad – 500007, India
b
c
´
`
`
Present address: Universite de Rennes 1, Laboratoire de Synthese et Electrosynthese Organiques, CNRS UMR 6510,
´ ´
Avenue du General Leclerc, 35042 Rennes Cedex, France
Fax : ( þ33)-223-236-955; e-mail: rene.gree@univ-rennes1.fr
Received: April 29, 2004; Accepted: July 23, 2004
Abstract: Imidazolium-type room temperature ionic been demonstrated, although it was not possible to re-
liquids (RTILs) have been used for the Stetter reac- cycle the thiazolium catalyst. This method was used in
tion, affording the desired 1,4-dicarbonyl compounds the total synthesis of haloperidol.
in good yields. Thiazolium salts and Et3N are efficient
catalysts for this reaction performed in ionic liquid. Keywords: 1,4-dicarbonyls; haloperidol; ionic liquids;
The possibility to recycle and reuse the solvent has organic catalysis; Stetter reaction; thiazolium salts
Introduction
“Room temperature ionic liquids” (RTILs) are the sub-
ject of much current interest as novel reaction media and
one of the possible alternatives to “volatile organic sol-
vents” (VOS).[1] This recent development is mainly due
to their unique physical properties which make them at-
Scheme 1. The Stetter reaction.
tractive solvents for organic synthesis,[2] organometallic
catalysis[3] as well as for biotransformations.[4] Further-
more, the combination of RTILs with supercritical
As catalysts, CNÀ or PBu3[11] can be used but thiazoli-
CO2 offers very exciting new possibilities.[5] It is known um salts in the presence of bases have a much broader
that the nature of the ionic liquid has a strong influence scope. The addition of the catalyst to the aldehyde af-
on the reactivity of dissolved molecules and on the ster- fords a stabilized carbanion which then reacts either
eoselectivity of the reactions performed in such solvents. with the electrophilic olefin to give the expected 1,4-ad-
Furthermore, it has been demonstrated recently that the duct or with a second aldehyde molecule affording the
outcome of reactions can even be controlled by the na- benzoin product. This Stetter reaction has been already
ture of the RTILs.[6] In recent years, many organic reac- widely used in organic synthesis to prepare, for instance,
tions have been successfully performed in imidazolium- cyclopentenones[12] and heterocycles.[13] More recently,
type RTILs. However limitations have been established it has been extended to electrophilic olefins anchored ei-
in the use of basic conditions: this is due to the abstrac- ther on solid support[14] or onto “task specific ionic liq-
tion of the acidic H-2 proton of the imidazolium by solu- uids”.[15] Finally, in the intramolecular version, excellent
ble bases[7] and trapping of the corresponding heterocy- results in terms of asymmetric synthesis have also been
clic carbenes.[8]
reported recently.[16]
As part of our ongoing studies on the use of ionic liq-
The Stetter reaction is performed in protic solvents
uids in synthesis,[9] we became interested in the Stetter like alcohol or in aprotic ones such as DMF, dioxane,
reaction: this is a very simple and useful method to pre- acetonitrile and even without solvent. However, alter-
pare 1,4-dicarbonyl compounds, which are key inter- native solutions appear also to be of much interest and
mediates in organic synthesis.[10] This reaction involves therefore the purpose of this publication is:
the catalyzed addition of aldehydes to electron-deficient
alkenes and is in competition with the formation of ben- – To demonstrate, for the first time, that imidazolium-
zoins (Scheme 1).
type RTILs can be employed with success as solvents
for this Stetter reaction, in spite of their known sensi-
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Siddam Anjaiah et al.
FULL PAPERS
tivity to basic conditions. The desired 1,4-dicarbonyl mized its concentration (Table 1). Without catalyst the
compounds have been isolated usually in good yields reaction afforded already a small amount (15%) of the
and we have further established that it is possible to re- 1,4-addition product 7, together with the benzoin 8
cycle and reuse these solvents, although it is not yet (34%) (entry 1). These compounds are easily separated
possible to recycle the catalyst.
– To study the scope and limitations of this reaction with are in agreement with literature values. The formation
different type of aldehydes and electrophilic alkenes. of 7 was not unexpectedsinceit is known that saltsof var-
by flash chromatography on SiO2 and their spectral data
– To use this method as a key step in the preparation of ious heterocycles, including imidazoliums, can also be
haloperidol, an antipsychotic agent.[17]
used as catalysts.[18] Therefore, the solvent is also able
to react as a catalyst, even if the latter salts are less active
than usual thiazolium salts, and the yields of the desired
product 7 are poor in that case.
Then we made a systematic increase in the quantity of
thiazolium salt 9 from 5 to 20 mol % resulting in a con-
comitant increase in the yield of the 1,4-adduct 7 to 63%
(entries 2 to 4). The use of 40 mol % catalyst did not give
further improvement in the yield (entry 5) and therefore
Results and Discussion
Optimization of the Reaction Conditions for the
Stetter Reaction in Imidazolium-Type RTILs
The condensation of p-fluorobenzaldehyde with methyl we selected 20 mol % for the next experiments. It has
acrylate was selected as a model to optimize the reaction been established that, under classical conditions (cat. 9
conditions, using butylmethylimidazolium tetrafluoro- in DMF), a,b-unsaturated esters are relatively poor sub-
borate [bmim][BF4] as the solvent (Scheme 2).
strates in the Stetter reaction, affording low yields (ca.
The commercially available, and commonly used thia- 30%) of 1,4-adducts. [10] It must be noted that significant-
zolium salt 9 was chosen as a catalyst and we first opti- ly better yields were obtained here by using the ionic liq-
uid as the solvent. Changing the nature of the catalyst to
10 did not improve the yield of 7 (entry 6). The use of a
larger excess of acrylate (10 equivalents) also gave a
similar yield in 7. In [bmim][BF4], the cyanide anion
was a poor catalyst: under the same reaction conditions
it afforded 7 in only 28% yield (entry 7). Then we
checked the nature of the ionic liquid: changing the
counterion to [PF6] (entry 8) or to [NTf2] (entry 9)
gave similar yields in adduct 7. The abstraction of the
H-2 proton of imidazolium salts by bases and trapping
of the corresponding carbenes is known to be responsi-
ble for the difficulties encountered in using this type of
RTIL under basic conditions.[8] Therefore, the 1,2-dime-
thylimidazolium salt [bdmim][BF4] was also studied but
afforded a similar good yield in 7 (entry 10). This result
demonstrates that, in the case of this Stetter reaction cat-
alyzed by thiazolium salts, the presence of the H-2 pro-
Scheme 2. Our model reaction.
ton is nolongera limiting factor. A tentative explanation
Table 1. Optimization of reaction conditions
Exp.
Solvent
Catalyst (%)
Alkene
7 Yield [%]
8 Yield [%]
1
2
3
4
5
6
7
8
9
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
[bmim][NTf2]
[bdmim][BF4]
[bmim][BF4]
[bmim][BF4]
9 (0)
9 (5)
6
6
6
6
6
6
6
6
15
19
53
63
60
57
28
67
62
60
65
61
34
32
29
31
32
30
35
31
32
25
28
27
9 (10)
9 (20)
9 (40)
10 (20)
CNÀ (20)
9 (20)
9 (20)
9 (20)
9 (20)
9 (20)
6
6
10
11
12
2 (R2 ¼H; Z¼COMe)
2 (R2 ¼H, Z¼CN)
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Stetter Reaction in Room Temperature Ionic Liquids
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is that the thiazolium salt reacts faster with the base, af- Extension of the Stetter Reaction in RTILs to Other
fording the corresponding carbene which is the catalyst Aromatic and Aliphatic Aldehydes
in the Stetter reaction and in the benzoin condensation.
Therefore, such a higher reactivity towards the catalyst In a next step we have studied the extension of these re-
would limit the effect of the base added to the imidazo- action conditions to other aldehydes (Table 2).
lium solvent. This is good agreement with literature data
Starting from aromatic aldehydes with different types
on the benzoin condensation.[18] Finally, it was shown of substituents the reaction proceeded also in moderate
that the same conditions could be applied with success to good yields (50–68%) of the desired 1,4-adducts (en-
to other electrophilic alkenes (methyl vinyl ketone, en- tries 1 to 4). In each case, small amounts of benzoin de-
try 11) and acrylonitrile (entry 12). It is known that, un- rivatives were also formed in these reactions. As far as 5-
der classical conditions, the formation of benzoins is re- membered heterocyclic aldehydes are concerned, furfu-
versible and kinetically controlled and therefore, in ral (entry 5) or thiophene carboxaldehyde (entry 6)
DMF, benzoins could be used also as starting materi- gave good yields (60–70%) in corresponding adducts,
al.[10] This is no longer the case in bmimPF6: a reaction, while no reaction was observed in the case of the pyrrole
performed underthe same conditions but using 8instead derivative (entry 7). In contrast, pyridine proved to be
of 5 as starting material, gave no trace of 7 in the crude very reactive since the reaction was completed in
reaction mixture and the starting compound 8 was quan- 3 hours (instead of 10–14 h for benzaldehyde and sub-
titatively recovered.
stituted benzaldehydes) affording the 1,4-adduct in
70% yield (entry 8). Aliphatic aldehydes can also be
used and the catalyst 10 is recommended for the latter
aldehydes.[10] Valeraldehyde was selected as a model
and the desired 1,4-adducts were obtained in good yields
Table 2. Extension to various aldehydes.
Entry
Aldehyde
Alkene
Cat. [%]
Time [h]
10
7 Yield [%]
1
9 (20)
60
2
3
9 (20)
9 (20)
12
12
50
56
4
9 (20)
14
68
5
6
7
9 (20)
9 (20)
9 (20)
12
10
0
60
70
0
70 (1st run)
66 (2nd run)
60 (3rd run)
8
9 (20)
3
9
10
11
10 (20)
10 (20)
10 (20)
10
10
10
67
78
65
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Siddam Anjaiah et al.
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(65–78%) for the three representative alkenes (entries
9–11).
One of the key aspects of the use of RTILs in organic
synthesis is the possibility to recycle and to reuse such
solvents. The highly reactive pyridine-2-carboxaldehyde
appeared as a good substrate to study this recycling
problem. At the end of the first run of the reaction
with methyl acrylate the products were extracted with
ether. The ionic liquid solvent was washed with H2O,
dried under vacuum and then reused for a second run
to give a similar yield in 1,4-adduct. A third cycle was
also performed, with only a slight decrease in yield
(60%, entry 8). However, it must be noted that the cat-
alyst must be added again after each run otherwise the
yield drops dramatically (only 10% yield for 7). This re-
sult may be due to some decomposition of the catalyst
under these reaction conditions but further mechanistic
studies will be necessary in order to clarify this aspect.
The reuse of the solvent to perform the Stetter reac-
tion with another substrate was also demonstrated: after
a first reaction with p-fluorobenzaldehyde, the same
[bmim][PF6] solvent was used to perform a reaction
with pyridinecarboxaldehyde. Careful study by high
field NMR established that only traces (<5%) of the
first 1,4-adduct are present in the crude reaction mixture
of the second reaction. Therefore, it is possible to recycle
and reuse the imidazolium solvents in this Stetter reac-
tion.
Scheme 3. Total synthesis of haloperidol.
Haloperidol is a widely used antipsychotic drug, in
Experimental Section
Some typical procedures for the Stetter reaction in
[bmim][PF6] are given below.
spite of some undesirable side effects.[17]
The 1,4-adduct of p-fluorobenzaldehyde and methyl
acrylate 7, prepared as described previously, was used
as the starting material for a short synthesis of haloper-
idol (Scheme 3). After protection of the carbonyl as a
ketal group affording 11, the ester was reduced to the al-
dehyde 12 in good yield using DIBAL-H at low temper-
ature. A reductive amination process, using the commer-
cially available piperidinol 13, followed by the deprotec-
tion of the ketone afforded the target haloperidol. The
spectral data of 14 are in full agreement with literature
and this compound was obtained in 55% overall yield
from 7 and 30% yield from p-fluorobenzaldehyde.
4-(4-Fluorophenyl)-4-oxobutyric Acid Methyl Ester
(7)
To a stirred suspension of catalyst (2.17 g, 20 mol %) in [bmim]
[PF6] (5 mL) were added Et3N (2.44 g, 24.17 mmol) methyl
acrylate (6.92 g, 80.57 mmol) and p-fluorobenzaldehyde (5 g,
40.28 mmol) at room temperature. The temperature was raised
to 808C and the reaction mixture stirred for 12 h. After com-
pletion of the reaction, as indicated by TLC, the product was
extracted with Et2O (3ꢀ25 mL). The organic phase was dried
and the solvent was removed under reduced pressure. The res-
idue was purified by chromatography on SiO2 to afford 7; yield:
5.07 g (60%) and benzoin 8 (30%). Data for 7: 1H NMR
Conclusion
¼
¼
(400 MHz, CDCl3): d¼2.78 (t, J 6.5 Hz, 2H), 3.31 (t, J
The Stetter reaction can be performed in imidazolium-
type RTILs as solvents, with thiazolium salts and Et3N
as catalysts. In these conditions the 4-oxocarboxylic es-
ters were isolated in good yields, usually higher than
those obtained in classical organic solvents. Further-
more, it was possible to recycle and reuse the ionic liquid
but not the catalyst. This method was employed as a key
step in the total synthesis of haloperidol.
6.5 Hz, 2H), 3.72 (s, 3H), 7.11–7.19 (m, 2H), 8.00–8.07 (m,
2H); 13C NMR (100 MHz, CDCl3): d 28.36, 33.67, 52.25,
116.12 (d, JC,F ¼22 Hz), 131.11 (d, JC,F ¼9 Hz), 133.38 (d,
JC,F ¼3 Hz), 166.22 (d, JC,F ¼255 Hz) 173.69, 196.87.
3-[2-(4-Fluorophenyl)-[1,3]dioxolan-2-yl]propionic
Acid Methyl Ester (11)
To a stirred solution of 7 (5 g, 23.79 mmol) in benzene (60 mL)
were added ethylene glycol (2.95 g, 47.60 mmol) and PTSA
(0.226 g, 5 mol %.) at room temperature, and the reaction mix-
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Stetter Reaction in Room Temperature Ionic Liquids
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ture was refluxed for 20 h, using a Dean–Stark trap. After com-
pletion of the reaction, as indicated by TLC, the reaction mix-
ture was cooled to room temperature and successively washed
with saturated aqueous NaHCO3 solution, brine and dried over
MgSO4. It was concentrated under reduced pressure, and the
residue was purified by chromatography on SiO2 to afford ketal
11; yield: 5.10 g (83%); 1H NMR (400 MHz, CDCl3): d¼2.21 (t,
by evaporation under reduced pressure. The residue was eluted
through a silica gel column using a mobile phase of
(CH2Cl2:MeOH, 9:1) to afford haloperidol (14); yield:
0.291 g (65%); 1H NMR (400 MHz, acetone-d6): d¼1.52–
1.60 (m, 2H), 1.80–1.96 (m, 5H), 2.44–2.49 (m, 5H), 2.69–
2.72 (m, 2H), 7.26–7.31 (m, 4H), 7.41–7.44 (m, 2H), 8.10–
8.14 (m, 2H); 13C NMR (100 MHz, acetone-d6): d¼23.46,
36.96, 39.56, 50.43, 58.79, 71.43, 116.63 (d, JC,F ¼20.7 Hz),
¼
J
7.1 Hz, 2H), 2.40 (t, J¼7.1 Hz, 2H), 3.72 (s, 3H), 3.70–3.77
(m, 2H), 3.95–3.99 (m, 2H), 6.94–7.03 (m, 2H), 7.37–7.45 (m,
2H); 13C NMR (100 MHz, CDCl3): d¼28.94, 35.88, 51.85,
65.03, 109.55, 115.32 (d, JC,F ¼21 Hz), 127.92 (d, JC,F ¼8 Hz),
138.48 (d, JC,F ¼3 Hz), 162.92 (d, JC,F ¼245 Hz), 174.08.
127.03, 127.18, 132.13 (d, JC,F ¼8.7 Hz), 136.56 (d, JC,F ¼
3.3 Hz), 139.94, 154.60, 172.20 (d, JC,F ¼250 Hz), 199.08; MS:
m/e¼376 (Mþ).
Acknowledgements
3-[2-(4-Fluorophenyl)-[1,3]dioxolan-2-yl]-
propionaldehyde (12)
´
We thank P. Guenot (CRMPORennes) for the mass spectral
`
analysis. This work was supported by the Ministere des Affaires
To a stirred solution of ketal 11 (2 g, 7.87 mmol) in CH2Cl2
(40 mL) was added DIBAL-H (1.11 g, 7.87 mmol, 1 M solution
in THF) at À788C and the reaction mixture was stirred for 1 h
at the same temperature. The reaction was quenched by adding
aqueous NH4Cl solution and extracted with CH2Cl2 (2ꢀ
25 mL). The organic layer was dried over MgSO4, concentrated
under reduced pressure, to give aldehyde 12 which was found
`
Etrangeres (fellowship to S. A.) as part of CEFISO/IFCOS.
S. C. thanks the CEFIPRA/IFCPAR (2305–1) for supporting
the visits to Rennes.
References and Notes
to be pure enough for the next step; yield: 1.64 g (93%);
1
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1
ketal; yield: 0.728 g (78%); H NMR (400 MHz, CDCl3): d¼
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2.35–2.47 (m, 4H), 2.75–2.85 (m, 2H), 3.73–3.76 (m, 2H),
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ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1329–1334