Polymer-assisted solution-phase synthesis under combined ultrasound and microwave irradiation: Preparation of α,β-unsaturated esters and carboxylic acids, key intermediates of novel sigma ligands

Article abstract of DOI:10.1080/00397910902738112

The optimal conditions to prepare α,β-unsaturated methyl esters via Wittig reaction combining polymer-assisted solution-phase synthesis (PASPS) methodology and simultaneous ultrasound and microwave irradiation were established. The effects of temperature, solvent, and irradiation time were discussed. Results clearly indicated the superiority of combined ultrasound and microwave-assisted procedure over microwave-assisted methodology. Moreover, an efficient PASPS procedure to prepare α,β-unsaturated carboxylic acids via tandem Wittig olefination and hydrolysis reaction was developed under combined ultrasound and microwave irradiation. Generally, a good conversion of aldehydes to acids was observed. The optimized protocols allowed us to quickly prepare a small collection of either α,β-unsaturated esters or carboxylic acids, key intermediates for the drug-discovery process of new sigma ligands. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902738112

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Polymer-Assisted Solution-
Phase Synthesis Under
Combined Ultrasound and
Microwave Irradiation:
Preparation of α,β-Unsaturated
Esters and Carboxylic Acids,
Key Intermediates of Novel
Sigma Ligands
D. Rossi a , M. Urbano a , A. Carnevale Baraglia a , M.
Serra a , F. Bergamelli b , M. Iannelli b , O. Azzolina a
& S. Collina a
a Department of Pharmaceutical Chemistry ,
University of Pavia , Pavia, Italy
b Milestone , Bergamo, Italy
Published online: 12 Aug 2009.
To cite this article: D. Rossi , M. Urbano , A. Carnevale Baraglia , M. Serra ,
F. Bergamelli , M. Iannelli , O. Azzolina & S. Collina (2009) Polymer-Assisted
Solution-Phase Synthesis Under Combined Ultrasound and Microwave Irradiation:
Preparation of α,β-Unsaturated Esters and Carboxylic Acids, Key Intermediates
of Novel Sigma Ligands, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:18, 3254-3262, DOI:
10.1080/00397910902738112

To link to this article: http://dx.doi.org/10.1080/00397910902738112
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Synthetic Communications1, 39: 3254–3262, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902738112
Polymer-Assisted Solution-Phase Synthesis
Under Combined Ultrasound and Microwave
Irradiation: Preparation of a,b-Unsaturated
Esters and Carboxylic Acids, Key Intermediates
of Novel Sigma Ligands
D. Rossi,1 M. Urbano,1 A. Carnevale Baraglia,1 M. Serra,1
F. Bergamelli,2 M. Iannelli,2 O. Azzolina,1 and S. Collina1
1Department of Pharmaceutical Chemistry,
University of Pavia, Pavia, Italy
2Milestone, Bergamo, Italy
Abstract: The optimal conditions to prepare a,b-unsaturated methyl esters via
Wittig reaction combining polymer-assisted solution-phase synthesis (PASPS)
methodology and simultaneous ultrasound and microwave irradiation were estab-
lished. The effects of temperature, solvent, and irradiation time were discussed.
Results clearly indicated the superiority of combined ultrasound and microwave-
assisted procedure over microwave-assisted methodology. Moreover, an efficient
PASPS procedure to prepare a,b-unsaturated carboxylic acids via tandem Wittig
olefination and hydrolysis reaction was developed under combined ultrasound
and microwave irradiation. Generally, a good conversion of aldehydes to acids
was observed. The optimized protocols allowed us to quickly prepare a small
collection of either a,b-unsaturated esters or carboxylic acids, key intermediates
for the drug-discovery process of new sigma ligands.
Keywords: Microwave, PASPS, sigma ligand intermediates, ultrasound,
a,b-unsaturated carboxylic acids, Wittig reaction
Received September 11, 2008.
Address correspondence to S. Collina, Dipartimento di Chimica Farmaceutica,
ꢀ
Universita di Pavia, Viale Taramelli 12, 27100, Pavia, Italy. E-mail: simona.
collina@unipv.it
3254

PASPS with Ultrasound and Microwaves
INTRODUCTION
3255
Over the past years, polymer-supported reagents emerged as an important
tool for synthetic organic chemists. They have been used both to facilitate
reactions (polymer-supported reagents) and to clean up reaction mixtures
(polymer-supported scavengers). The enormous potential and the wide
range of reactions that can be covered using such polymer-bound agents
has been well documented.[1] In the meantime, microwave-assisted chemistry
has been extensively applied in organic synthesis to improve reaction yields
and to dramatically reduce reaction time. Performing chemical reactions in
dedicated microwave equipment has now become standard operation in
many laboratories and has also been widely embraced by industrial
research.[2] It is also well documented that ultrasonic irradiation can enhance
chemical reaction yields.[3] Moreover, many organic reactions are greatly
accelerated by the combined application of ultrasound and microwave
irradiation (US-MW) if compared to either microwave (MW) irradiation
or power ultrasound (US) alone.[4] Recently, the combination of US and
MW irradiation can be easily realized using a dedicated instrument.
In this article, the preparation of a,b-unsaturated methyl esters and
the corresponding a,b-unsaturated carboxylic acids (Fig. 1a) using a
combination of polymer-assisted chemistry and simultaneous US-MW
irradiation is described. Target compounds are key intermediates for
the preparation of a small library of novel selective sigma ligands, based
on the arylvinylamide scaffold (Fig. 1b).[5]
Recently, an efficient and easy-to-use protocol based on the combi-
nation of polymer-assisted solution-phase synthesis (PASPS) and MW
dielectric heating for the preparation of a,b-unsaturated methyl esters
via Wittig reaction has been described by us.[6] The optimized procedure,
tested on 20 different aldehydes, gave rise to a conversion percentage
equal or greater than 70% with the exception of some substrates.[6]
In this article, the development of a Wittig olefination protocol under
combined US-MW irradiation employing polymer-bound triphenylpho-
sphine (TPPP) is discussed. Moreover, an efficient US-MW-assisted
Figure 1. General structure of target compounds (a), and key intermediates for
the synthesis of new sigma ligands based on the arylvinylamide scaffold (b).

3256
D. Rossi et al.
tandem procedure, comprising Wittig olefination of aldehydes followed
by hydrolysis of the ester intermediates and suitable for the synthesis
of a,b-unsaturated carboxylic acids, is developed and optimized.
Although the use of TPPP under MW irradiation has been already
tested,[6,7] to the best of our knowledge the effects of simultaneous
MW-US irradiation on either the Wittig reaction or TPPP efficiency have
never been investigated. The optimized procedure provided the desired
products with good conversion percentage and led us to quickly prepare
a small collection of a,b-unsaturated carboxylic acids without isolation of
the methyl ester intermediates.
EXPERIMENTAL
Reagents, solvents, and starting materials were purchased from standard
sources.
1H NMR spectra were recorded on a Bruker Advance 400-MHz
spectrometer using CDCl3 as solvent and tetramethylsilane (TMS) as
internal standard.
All experiments were carried out in a MicroSynth=Sonic (Milestone)
MW-US apparatus, with a double magnetron multimode unit equipped
with a patented pyramidal-shaped rotating diffuser. A homogeneous
microwave distribution in the cavity and delivery of up to 1000 W of
power was ensured. The instrument was controlled with a touch screen
terminal running the EasyControl software. Working under temperature
control, microwave power is adjusted to maintain an even heating profile
over the entire time period through a proportional-integral-derivative
(PID) algorithm, operating under temperature control. Temperature
was internally checked by a fiber-optic probe inserted into the reaction
mixture. The UV accessory consisted of an electronic generator (20 KHz)
coupled with a suitable transducer and a Pyrex1 horn developed by
Danacamerini (Turin, Italy).
General Procedure for Combined US-MW- and TPPP-Assisted
Synthesis of 1b–8b via Wittig Reaction
Diethylene glycol (10 mL) was added to a mixture of aldehyde (1a–8a,
1 mmol), methyl bromoacetate (4 equiv), AcONa (4 equiv), and TPPP
(2 equiv) in a 50-mL, two-necked, round-bottomed flask. The mixture
was subjected to simultaneous MW (100 W) and US (40 W) irradiation
at 130ꢀC for 10 or 20 min under temperature control. Workup: the mix-
ture was filtered on a pad of Celite1 and washed thoroughly with metha-
nol. After concentration under vacuum, the filtrate was diluted with ethyl

PASPS with Ultrasound and Microwaves
3257
acetate, washed with 1 N HCl, dried over anhydrous sodium sulfate, and
evaporated to dryness.
General Procedure for US-MW-Assisted Tandem Wittig–Hydrolysis
Synthesis of 1c–8c
The Wittig reaction was conducted as described (reaction time 20 min).
After filtration, water (5 mL) and lithium hydroxide (LiOH) (5 eq) were
added to the reaction mixture, and simultaneous MW (100 W) and US
(40 W) irradiation was applied (15 min, 90ꢀC temperature control).
Workup: the reaction mixture was acidified with 2 N HCl and extracted
with ethyl acetate. The combined organic phase was washed with water,
dried over anhydrous sodium sulfate, and evaporated under reduced
pressure. The crude product was finally purified using Bond Elute NH2
cartridge, eluting with 2 N HCl in MeOH. The organic phase was dried
in vacuo, yielding the desired acid compounds.
RESULTS AND DISCUSSION
At first, the Wittig reaction was tested on aldehydes 1a–7a (Scheme 1a)
under simultaneous MW-US irradiation in the presence of TPPP. By
Scheme 1. (a) Combined US-MW- and TPPP-assisted Wittig reaction: methyl
bromoacetate, AcONa, TPPP, diethylene glycol, 130ꢀC, 100 W (MW), 40 W
(US), 10 or 20 min; (b) US-MW-assisted Wittig olefination–hydrolysis reaction:
1) combined MW-US- and TPPP-assisted Wittig reaction; 2) LiOH, DEG=water
water mixture (2=1 v=v), 90ꢀC, 100 W (MW), 40 W (US), 15 min.

3258
D. Rossi et al.
applying our already developed MW-assisted protocol, compounds
1a–7a were only partially converted into the corresponding methyl esters,
as stated in Table 1 (entries 1–7).[6]
The reaction setup was optimized on 5a using methyl bromoacetate,
sodium acetate (AcONa), and TPPP, according to our already developed
MAOS protocol, under simultaneous US-MW irradiation. All the experi-
ments were performed under temperature control, setting MW and US
power at 100 and 40 W respectively. The effects of temperature, solvent,
and irradiation time were examined to maximize the conversion into the
corresponding a,b-unsaturated methyl ester 5b. To take full advantage of
both microwave dielectric heating and US-induced cavitation, a suitable
reaction medium has to be considered to maximize the energy transfer. In
fact, cavitation phenomena and the associated energy transfer mainly
take place when US are transferred to a liquid phase in laminar condi-
tions.[8] Both temperature and viscosity of the solvent play an important
role in this matter. In detail, the employment of high-viscosity media at
temperatures far from their boiling points guarantees a laminar motion.
On the other hand, microwave irradiation is mainly effective with polar
reaction media. Considering these points, higher-boiling-point solvents
[i.e., diethylene glycol (DEG) and N,N-dimethylformamide (DMF)],
which are polar enough to efficiently absorb MW irradiation and viscous
enough to guarantee laminar conditions during stirring, were used
instead of methanol (employed in our MAOS protocol).
As shown in Table 2, the reaction was first carried out in DEG at
110ꢀC, 130ꢀC, and 150ꢀC (entries 1, 2, and 3, respectively) by applying
simultaneous MW-US irradiation for 20 min. Reaction efficiency was
1
evaluated on the crude product by H NMR, according to our previous
paper.[6] Experimental results clearly indicated that the combined
US-MW procedure is more effective than the MW-assisted one alone
Table 1. Wittig reaction of 1a–8a using microwave heating and TPP polymer
Entry
Ar
Compound
Conversiona (%)
1
2
3
4
5
6
7
8
4-(OH)C6H4
4-(CH3)2NC6H4
3,4-(OCH3)2C6H3
2-(OC2H5)-3-(OCH3)C6H3
2,4-(OCH3)2C6H3
3-[C8H6N-1-H]
1b
2b
3b
4b
5b
6b
7b
8b
45.4
16.8
60.3
67.2
34.1
17.5
30.6
70.4
E-C6H5CH¼CH
3-(C6H5CH2O)C6H4
1
aDetermined on crude products by 400-MHz H NMR.

PASPS with Ultrasound and Microwaves
3259
Table 2. Wittig reaction of 1a–8a using simultaneous MW-US irradiation and
TPP polymer
Entry
Ar
Compound Time (min) Conversiona (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2,4-(OCH3)2C6H3
2,4-(OCH3)2C6H3
2,4-(OCH3)2C6H3
2,4-(OCH3)2C6H3
2,4-(OCH3)2C6H3
2,4-(OCH3)2C6H3
2,4-(OCH3)2C6H3
4-(OH)C6H4
4-(OH)C6H4
4-(CH3)2NC6H4
4-(CH3)2NC6H4
3,4-(OCH3)2C6H3
3,4-(OCH3)2C6H3
2-(OC2H5)-3-(OCH3)C6H3
2-(OC2H5)-3-(OCH3)C6H3
3-[C8H6N-1-H]
5b
5b
5b
5b
5b
5b
5b
1b
1b
2b
2b
3b
3b
4b
4b
6b
6b
7b
7b
8b
8b
20
20
20
20
20
10
30
10
20
10
20
10
20
10
20
10
20
10
20
10
20
56.1b
70.2
71.3c
15.3b,d
10.7d
60.1
71.6
70.3
70.0
25.4
30.5
62.8
72.1
75.8
85.1
<10%
<10%
67.4
73.0
93.6
3-[C8H6N-1-H]
E-C6H5CH ¼ CH
E-C6H5CH ¼ CH
3-(C6H5CH2O)C6H4
3-(C6H5CH2O)C6H4
98.6
1
aDetermined on crude products by 400-MHz H NMR.
b110ꢀC.
c150ꢀC.
dDMF.
(conversion ¼ 70.2% and 34.1%, respectively), as further proved by a
control experiment performed by applying our MAOS protocol using
DEG instead of methanol (conversion ¼ 35.7%).
As reported in Table 2, an increase of temperature from 110 to 130ꢀC
gave rise to an improvement in the conversion percentage, while no sig-
nificant difference was observed when the temperature was further
increased to 150ꢀC; moreover, the use of dimethylformamide (DMF),
either at 110ꢀC or 130ꢀC (entries 4 and 5, respectively), led to a dramatic
reduction in the conversion percentage. Regarding the reaction time, the
decrease from 20 to 10 min slightly reduced the conversion (entries 2, 6),
whereas the extension of the run time to 30 min did not give any signifi-
cant benefit in term of conversion (entry 7).
Based on these considerations, the optimized experimental condi-
tions (DEG, 130ꢀC, 20 min) were applied for the preparation of methyl

3260
D. Rossi et al.
esters 1b–4b, 6b, and 7b. Because of the slight differences in the
conversion observed for 5a that cut down the reaction time from 20 to
10 min, a run time of 10 min was also tested on all substrates. Interest-
ingly, results reported in Table 2 showed that desired a,b-unsaturated
methyl esters were obtained with conversion greater than 70%, with the
only exception of 2b (entries 10 and 11) and 6b (entries 16 and 17). Any-
way, greater conversions were still achieved when irradiation was applied
for 20 min. Comparable results were obtained within 10 min only for
compound 1b (entries 8 and 9). Thus, the superiority of combined
US-MW-assisted reaction over MW-assisted methodology was clearly
proved (only the Wittig olefination of 6a was not improved). Particularly,
simultaneous US-MW irradiation was highly advantageous for the pre-
paration of 1b, 5b, and 7b. Based on the good conversion percentages
obtained, TPPP can be efficiently used for the Wittig olefination of
aldehydes under combined US-MW irradiation.
The optimized US-MW-assisted protocol was also applied to
aldehyde 8a (Scheme 1a), which gave rise to a conversion of 70% under
MW irradiation alone. Interestingly, as shown in Table 2, under US-MW
the Wittig olefination of 8a was driven to completion, confirming the
superiority of the combined approach over the MW-assisted methodol-
ogy alone.
As a further step, a US-MW-assisted procedure via tandem Wittig
and hydrolysis reaction for the synthesis of 1c–8c (Scheme 1b) was devel-
oped. Preliminary experiments were carried out on 7a and 8a, applying
the optimized Wittig protocol and employing tetramethylammonium
hydroxide (TMNOH) for the hydrolysis step, according to our already
developed MAOS protocol,[5] a DEG=water mixture (2=1 v=v) was used
as solvent. Simultaneous US-MW irradiation (power of 100 W and
40 W, respectively, with temperature control) was applied for 15 min at
90ꢀC. Each experiment was performed in duplicate, either with or with-
out filtration of the TPPP after the first step of the reaction sequence.
Results are reported in Table 3 (entries 1–4). The poor conversion
prompted us to switch from TMNOH to LiOH (entries 5–8). Interest-
ingly, for both substrates the hydrolysis reaction using LiOH was driven
to completion when TPPP was filtered off, whereas poor conversion was
still observed when the TPPP filtration was not carried out.
The procedure involving TPPP filtration was then extended to all the
aldehydes to prepare the desired a,b-unsaturated carboxylic acids 1c–8c
(entries 9–14). Satisfactory levels of esters–acids conversion were achieved,
with the only exception of 6c (entry 14). Particularly, the best results were
observed for 3c–5c, 7c, and 8c, for which the hydrolysis reaction was
quantitative. Finally, a convenient reaction workup was refined for the
isolation of the desired compounds. After a liquid–liquid extraction

PASPS with Ultrasound and Microwaves
3261
Table 3. Hydrolysis efficiency: Tandem Wittig and hydrolysis reaction 1a–8a
Entry
Ar
Compound
Conversiona (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
E-C6H5CH ¼ CH
E-C6H5CH ¼ CH
3-(C6H5CH2O)C6H4
3-(C6H5CH2O)C6H4
E-C6H5CH ¼ CH
E-C6H5CH ¼ CH
3-(C6H5CH2O)C6H4
3-(C6H5CH2O)C6H4
4-(OH)C6H4
7c
7c
8c
8c
7c
7c
8c
8c
1c
2c
3c
4c
5c
6c
20.5b
27.2b,c
35.9b
22.9b,c
>99
20.5c
98.2
19.2c
77.7
50
>99
>99
>99
<5%
4-(CH3)2NC6H4
3,4-(OCH3)2C6H3
2-(OC2H5)-3-(OCH3)C6H3
2,4-(OCH3)2C6H3
3-[C8H6N-1-H]
1
aDetermined on crude products by 400-MHz H NMR.
bTMNOH.
cHydrolysis step performed without preliminary TPPP filtration.
aimed at removing the DEG, the catch-and-release solid phase extraction
(SPE) technique (Bond Elute NH2 cartridge) afforded compounds 1c–5c,
7c, and 8c in good purity with yields ranging from 65% to 97%, with the
only exception of compounds 1c and 2c (yields 47% and 15%, respec-
tively). Generally, a good conversion of aldehydes–acids was observed;
when poor yields were observed, the limiting step of the reaction sequence
was the Wittig reaction.
In conclusion, the optimal conditions for the US-MW-assisted Wittig
olefination of various aldehydes in the presence of TPPP were estab-
lished. In addition, a simple and efficient procedure for preparing a,b-
unsaturated carboxylic acids from aldehydes via tandem Wittig and
hydrolysis reaction under simultaneous US-MW irradiation was developed.
The optimized protocols allowed us to quickly prepare a small collec-
tion of either a,b-unsaturated esters or carboxylic acids, key intermedi-
ates for the drug discovery process of new sigma ligands.
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