Effect of phase transfer chemistry, segmented fluid flow, and sonication on the synthesis of cinnamic esters

Article abstract of DOI:10.1016/j.tet.2010.04.031

Wittig reaction under Phase Transfer conditions was performed in a flow reaction system. Different bases, aldehydes, phosphonium salts, and flow reaction parameters were investigated, in absence of a phase transfert catalyst. An improvement of the reaction outcome (yield and reaction time) was achieved through the immersion of the reactor into an ultrasound bath.

Full text of DOI:10.1016/j.tet.2010.04.031

Tetrahedron 66 (2010) 4032e4039
Contents lists available at ScienceDirect
Tetrahedron
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Effect of phase transfer chemistry, segmented fluid flow, and sonication on the
synthesis of cinnamic esters
*
Mauro Riccaboni , Elena La Porta, Andrea Martorana, Roberta Attanasio
Department of Medicinal Chemistry, NiKem Research Srl, Via Zambeletti 25, 20021 Baranzate, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Wittig reaction under Phase Transfer conditions was performed in a flow reaction system. Different
bases, aldehydes, phosphonium salts, and flow reaction parameters were investigated, in absence of
a phase transfert catalyst. An improvement of the reaction outcome (yield and reaction time) was
achieved through the immersion of the reactor into an ultrasound bath.
Received 29 January 2010
Received in revised form 18 March 2010
Accepted 6 April 2010
Available online 10 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
time, and heat transfer),8,9 there is the possibility of reaching a high
surface-to-volume ratio in reactions involving a fluidic biphasic
Phase-transfer catalyst (PTC) technology is used in the com-
mercial manufacture of more than $10 billion per year of chemicals,
including pharmaceuticals, flavors & fragrances, dyes, additives,
and polymers.1 PTC technology is used in these applications be-
cause it provides many compelling benefits, primarily related to
reducing the cost of manufacture of organic chemicals and pollu-
tion prevention. Among the synthetic advantages that phase
transfer chemistry offers there are the ease of the procedure, the
reduced formation of by-products and the improved selectivity and
reactivity if compared to the same reaction in homogeneous
phase.2,3 Additionally, under the phase transfer conditions the in-
organic bases (NaOH, KOH or K2CO3) can be used in place of more
expensive and dangerous organic bases (t-BuOK, NaH or R2NLi) and
the dipolar aprotic solvents, such as DMF can be avoided.4 However,
in a bi-phasic system the width of the contact surface plays a crucial
role because the reaction either occurs at the interface or the phase
transfer catalyst has a catalytic cycle between the two phases.5,6 For
this reason, the scale-up of the reaction could be difficult and re-
action time could grow longer because of the inefficiency of the
mixing. Moreover, phase transfer catalysts (tetra-alkylammonium
halides or crown ethers, for example) usually employed in PTC to
speed up the reaction, are often toxic,7 expensive and are elimi-
nated with difficulty from the reaction mixture in the work-up and
purification phases.
system. In particular, as reported by Wirth et al.,10 working with a T-
shaped geometry of the inlet junction, a series of organic-aqueous
segments are generated as shown in Figure 1 (figure on the left). As
in a flow reaction system the reactant solutions flow into very long
channels, the total contact surface is enormously increased if
compared to a traditional bi-phasic batch reaction. In addition, the
interaction of the fluids with the channel wall generates an internal
vortex that leads to a continuous refreshing of the interface.
A
A
Ultrasound
B
B
Bath
Figure 1. Segmented flow (on the left) and effect of sonication on segmented flow (on
the right).
A further increase of the interface area can be achieved by the
combination of flow chemistry and sonochemistry. Indeed, im-
mersing the flow reactor in an ultrasound bath, irregular sized
segments, and emulsion are formed (Fig. 1, on the right). In addi-
tion, the propagation and the consequent effects of the sonic waves
are significantly improved when the reaction is performed into
In this context, flow chemistry can be an alternative choice. In
fact, among the advantages that continuous flow organic syntheses
offer over the conventional batch techniques (e.g., precise control of
variables, such as temperature, pressure, concentration, residence
really small channels (diameter: 10e100
flask.
mm) than in a standard
To prove such hypothesis, we employed a model Wittig olefin-
forming reaction. The cinnamic esters and close analogs are
broadly employed in the chemical industries, in particular for the
* Corresponding author. Tel.: þ39 02 35694 7591; fax: þ39 02 35694 7606;
e-mail address: mauro.riccaboni@nikemresearch.com (M. Riccaboni).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.031

M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
4033
production of flavors, synthetic dye, and perfumes.11 Moreover,
the cinnamic moiety occurs in several molecules with a wide
spectrum of biological activities, for example, the 4-methoxy ethyl
cinnamate 3a (Scheme 1) is reported to be a monoamine oxidase
inhibitor.12 Several methods for the synthesis of this class of
compounds have been published so far.13 However, due to the
importance of cinnamic esters and derivatives, the development
of new methodologies for their multi-gram synthesis is still of
great interest.
amount of reagents, concentration and temperature. Thus, the or-
ganic solution of 1a and 2a and the aqueous solution of NaOH were
simultaneously pumped into the flow reactor (Reactor volume
10 mL; reagents flow rate of 1 mL minꢁ1) using a T-inlet junction. As
a result, we obtained an improved yield (78%, entry 2), in a shorter
reaction time (total: 30 min; residence time: 5 min) and without
formation of Z-stereoisomer. Encouraged by the surprising impact
of flow chemistry, we repeated the reaction in the flow system
without the phase transfer catalyst (TBAB). In this case we obtained
a result comparable to the flask system (63% yield, entry 3) but in
a considerably shorter time (total: 30 min; residence time: 5 min)
and avoiding PTC.
2. Results and discussion
In particular, we focused our attention on the reaction between
anisaldehyde 1a and (ethoxycarbonylmethyl)-triphenylphospho-
nium bromide 2a to obtain ethyl 4-methoxy cinnamate 3a
(Scheme 1).
Table 1
Comparison of reaction carried out in batch and using the flow-reactor
Entry
System
Isolated yielda (%)
1
2
3
Flask reactionb
55
78
63
Flow systemc
O
O
Flow system without PTCc
NaOHaq
DCM
Br-
Ph3P+
OEt
a
OEt
H
Product purified by flash chromatography on silica gel.
+
b
c
Reaction carried out as described in Ref. 19.
MeO
O
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
MeO
1a
2a
3a
temperature; organic solvent: DCM; molar ratio: aldehyde/phosponium salt/
NaOH¼1/1/1.1 (with or without 0.5% of TBAB).
Scheme 1. Synthesis of 4-methoxy ethyl cinnamate.
Given these encouraging results, we further investigated the
reaction reported as entry 3 in Table 1; we tried to optimize the
reaction conditions and studied the influence of different param-
eters on the outcome of the reaction. In a first set of experiments,
we studied the influence of temperature, flow rate, and solvent on
the reaction yield (Table 2).
This reaction is broadly reported in the literature; for instance,
Avery et al. claimed a quantitative yield by treating 2a with po-
tassium tert-butoxide in anhydrous diethyl ether under an inert
atmosphere, followed by reaction with 1a (room temperature for
48 h).14 In another example, Frattini et al. achieved 54% conversion
heating 1a and 2a under microwave irradiation at 280 W in DMSO
for 5 min, whereas the same reaction refluxed for 1 h in THF
afforded just 28% conversion.15 El-Batta et al. proved that water is
an effective medium for Wittig reaction over a wide range of sta-
bilized ylides and aldehydes.16 They reported that p-anisaldehyde
reacts slowly with ylides to give 66% of cinnamic ester after 4 h at
20 ꢀC, even though a little formation of undesired Z-regiosomer
was observed (E/Z-ratio: 92:8). At the same time, heating the re-
action to 90 ꢀC for 30 min increased the yield of cinnamic ester to
90% without affecting the E/Z-ratio. The efficiency of water as a re-
action medium compared to the organic solvents is evident in view
of the fact that the same reaction has been reported in refluxing
DCM (4 h, 8%),17 in refluxing benzene (2 days, 73% yield)17 or in
ionic liquid at 60 ꢀC (3 days, 82% yield).18 Nevertheless, the poor
solubility of reagents and products in water can be considered as
a relevant limit of this procedure. Indeed different protocols have to
be set up depending on the particular nature of the aldehydes (e.g.,
solid or liquid). Moreover, the poor solubility of the reagents makes
the scaling-up process complicated.
In this paper we report a protocol that allows achieving ster-
eoselectively compound 3a in 96% yield in five minutes, without
using thermal or microwave heating, anhydrous conditions and
phase transfer catalyst. Moreover, this protocol can be also readily
scaled up with no need of any further optimization or set-up
process.
We first conducted a comparison study between the reaction in
a standard batch process and in a flow system, to evaluate the effect
of the interfacial area on the yield (Table 1). A solution of 1a and 2a
in DCM and a solution of NaOH in water were vigorously stirred in
presence of a catalytic amount (0.5%) of tetra-butylammonium
bromide (TBAB) at room temperature for 24 h.19 This reaction
(entry 1) afforded, after chromatography purification, compound
3a in 55% yield. The same reaction was then run in a flow system
(VapourtecÒ R2eR4 series flow reactor system) using the same
Table 2
Optimization of experimental parameters
Entrya
Temperature (ꢀC)
Reagent flow
rate (mL/min)
Solvent
Isolated
yieldb (%)
1
2
3
4
5
6
7
rt
1
1
1
2
1
1
1
DCM
DCM
DCM
DCM
Toluene
EtOAcc
THFc
63
58
0
40
44
33
49
50
100
rt
rt
rt
c
rt
a
Reactor volume: 10 mL; Molar ratio: aldehyde/phosponium salt/NaOH¼1/1/1.1
(without PTC).
b
c
Product purified by flash chromatography on silica gel.
Presence of 20% of CH3CN is needed to completely dissolve the phosponium salt.
The ambient temperature (63% yield, entry 1) turned out to be
the best compromise of a good yield without degradation of re-
agents and products. In fact, the yield slightly decreased when the
reaction was conducted at 50 ꢀC (58%, entry 2) and completely
dropped at 100 ꢀC (entry 3).
The reaction yield also decreased when the flow rate was in-
creased. In fact, compound 3a was collected in 40% yield conducting
the same reaction as entry 1 with a flow rate of 2 mL minꢁ1 (entry
4). On the other hand, lowering the flow rate led to the formation of
particulate matter in the microchannel of the flow system that
might plug the reactor.
As far as the solvent is concerned, the reaction was repeated
replacing DCM with the typical solvents used in the phase transfer
chemistry, namely Toluene, EtOAc, and THF (entries 5e7). As the
solubility of the phosphonium salt in these solvents is lower than in
DCM, a little amount of acetonitrile had to be added to get clear
solutions. Nevertheless, DCM proved to be the best solvent for this
reaction.

4034
M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
Table 5
Aldehydes investigation
Then, the reaction was further studied varying the stoichio-
metric ratio of the reagents, as summarized in Table 3.
NaOHaq
DCM
Br-
Ph3P+
OEt
Aldehydes
1b-p
Products
3b-p
Table 3
+
Optimization of stoichiometric ratio
O
2a
Entrya
Aldehyde
(equiv)
Phosphonium
salt (equiv)
NaOH
(equiv)
Isolated
yieldb (%)
Entrya
Aldehydes
Productsb
Isolated yieldc (%)
1
2
3
4
5
1
1
2
1
1
1
1
1
2
5
1
10
2
2
5
63
56
43
85
88
1
96
a
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; No PTC was used.
b
Product purified by flash chromatography on silica gel.
2
3
98
98
The best result was obtained working with an excess of phos-
ponium salt and base, as reported in entry 4 (85% yield; aldehyde:
phosponium salt: NaOH¼1:2:2) or in entry 5 (88% yield; aldehyde:
phosponium salt: NaOH¼1:5:5). Nevertheless, this last protocol
entails both a greater waste of reagents and a more complicated
final purification, without a significant improvement in the re-
action yield compared to the conditions of entry 4.
At last we studied the effect of sonication on the reaction carried
out both in batch and in the flow system (Table 4).
4
5
55
Table 4
Effect of sonication on reaction carried out in batch or in the flow-reactor without
using PTC
83d
Entry
System
Time
Sonication
Isolated Yielda (%)
1
2
3
4
Flaskb
Flaskb
Flowc
Flowc
1 h
No
Yes
No
d
1 h
70
63
96
5 mind
5 mind
Yes
6
7
86
37
a
Product purified by flash chromatography on silica gel.
b
Reaction carried out as described in Ref. 19 but without any phase transfer
catalyst.
c
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; molar ratio: aldehyde/phosponium salt/
NaOH¼1/2/2 (without PTC).
d
Residence time.
8
63
89
As expected, no product was formed after one hour when the
reaction was conducted in a flask without sonication (entry 1).
Conversely, the same reaction carried out in an ultrasound bath
(entry 2) led to the desired product in 70% yield, clearly showing
the positive effect of sonication on the reaction rate. As already
reported, the reaction conducted in flow instrument, without PTC
and sonication gave desired product in 63% yield. Finally, with the
aim of verifying if the combination of segmented flow and sono-
chemistry could positively affect the yield, we ran the same re-
action in a flow system, immersing the PTFE tubing reactor in an
ultrasound bath maintained at 25 ꢀC. In this case we achieved
a complete conversion of aldehyde 1a into the desired E-cinnamic
ester 3a (Z-stereoisomer was not formed), which was collected in
96% yield after chromatographic purification. The combination of
flow chemistry and sonochemistry allowed the desired compound
to be formed in excellent yield, in high E-selectivity, without any
phase transfer catalyst and using a continuous process.
8
9
53
10
41e
As a next step, the effectiveness and reproducibility of the op-
timized reaction conditions (Reactor volume: 10 mL; reagents flow
rate: 1 mL minꢁ1; temperature: room temperature; organic sol-
vent: DCM; molar ratio: aldehyde/phosponium salt/NaOH¼1/2/2;
without PTC) were evaluated varying the reagents reported in
Scheme 1.
11
12
75
100
In the first instance, reaction was performed replacing aldehyde
1a with the other aldehydes listed in Table 5.

M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
4035
Table 5 (continued)
Table 6
Bases investigation
Isolated yieldc (%)
Entrya
Aldehydes
Productsb
13
48
Entrya
Base
Isolated yieldb,c (%)
a
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; molar ratio: aldehyde/phosponium salt/
NaOH¼1/2/2 (without PTC).
1
2
3
4
5
NaOH
LiOH
K2CO3
NaHCO3
DMAP
96
d
b
The Z-stereoisomer was not revealed in UPLC-MS analysis.
98
78
78
c
Product purified by flash chromatography on silica gel.
d
E/Z stereoisomers in 6:1 ratio as determined by 1H NMR.
e
Molar ratio: aldehyde/phosponium salt/NaOH¼1/4/4.
a
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; molar ratio: aldehyde/phosponium salt/
NaOH¼1/2/2 (without PTC).
An almost quantitative yield (98%, entry 2) was obtained using
benzaldehyde 1b as the starting material, proving the presence of
an electron-releasing group is not strictly required to have a com-
plete conversion. The same yield was also achieved replacing the
methoxy group with the electron-withdrawing nitro group (entry
3). When aldehyde 1d was used, the corresponding product was
collected in 55% yield (entry 4). It is worth noting that the literature
reports that the p-Me2-N-substituted benzaldehyde does not react
with ylide in water at 20 ꢀC or in refluxing DCM (4 h), whereas it
affords desired product in 78% yield when conducted in MeOH, but
the E/Z-ratio is significantly diminished to 3:1.16 In order to assess
to what extent the steric hindrance affects the yield, the reaction
was performed using the 2-methoxybenzaldehyde 1e (entry 5) and
the product was collected again in a good yield (83% yield), even if
a mixture of E and Z stereoisomers was obtained (E/Z-ratio: 6/1). On
the other hand, using 3-methoxy benzaldehyde 1f (entry 6) as the
staring material, desired compound 3f was achieved in comparable
yield (86%) but without the formation of undesired Z-stereoisomer,
suggesting the ortho substitution affects the regiochemistry of the
reaction. As expected, the Wittig reaction conducted on 4-ace-
tylbenzaldehyde 1g occurred only on aldehyde moiety, even if the
yield was rather modest (37%). Then we extended our study to al-
iphatic aldehydes (entries 8e10) and heteroaromatic aldehydes
(entries 11e13). Compound 3h was achieved in 63% yield while
compound 3i in 89%, likely thanks to the more extended conjuga-
tion. The double Wittig reaction on glutaraldehyde 1m afforded
desired compound 3m in 41% yield. As far as the heteroaromatic
aldehydes are concerned, the reaction yield was modest employing
quinoline-2-carbaldehyde 1p (48%) and isonicotinaldehyde 1n
(75%) but exceptional when using thiophene-2-carbaldehyde
(quantitative), may be because of the different solubility in water of
these aldehydes. It is noteworthy that in all the examples reported
in Table 5 (with the only exception of entry 5) the Z-stereoisomer
was not formed, even using cinnamaldehyde 1i, which is known to
give modest to low E/Z ratios upon exposure to stabilized ylides.16
Then, the influence of different bases on reaction outcome was
evaluated as reported in Table 6.
b
The Z-stereoisomer was not revealed in UPLC-MS analysis.
Product purified by flash chromatography on silica gel.
c
Table 7
NaOH and K2CO3 comparison
Entrya
1
Base
Aldehydes
Isolated yieldb,c (%)
53
NaOH
2
3
K2CO3
NaOH
41
48
4
K2CO3
100
a
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; molar ratio: aldehyde/phosponium salt/
NaOH¼1/2/2 (without PTC).
b
The Z-stereoisomer was not revealed in UPLC-MS analysis.
Product purified by flash chromatography on silica gel.
c
The possibility of using alternative phosphonium salts was fi-
nally investigated, as reported in Table 8.
The Wittig reaction did not occur using lithium hydroxide as the
base. Conversely, the reaction can be conducted using potassium
carbonate without affecting the reaction yield (98%, entry 2). The
use of a milder base, such as sodium bicarbonate or an organic base,
such as DMAP turned out to be well tolerated too (78% yield in both
cases).
We observed that p-anisaldehyde reacts with phosphonium salt
2a and 2b (entry 1 and 2) to give the corresponding compounds in
comparable yields (96% and 95%, respectively). On the contrary,
reaction between p-anisaldehyde and 2c and 2d afforded desired
compounds in lower yields (42% and 48%). This result can be
explained considering that traces of 3-(4-methoxyphenyl)acrylic
acid (entry 3) and 3-(4-methoxyphenyl)acrylamide (entry 4) were
detected in the aqueous phase of these reactions.
At last, we considered the possibility of preparing phosporanes
in situ during the Wittig process, by mixing a DCM solution of Ph3P,
ethyl 2-bromoacetate, and aldehyde with aqueous NaOH (Table 9).
The one-pot protocol afforded compound 3a (entry 1) in lower
yield than the standard protocol (63% and 96%, respectively). In this
In order to understand if K2CO3 could be a valuable alternative to
NaOH, the reactions reported Table 7 were carried out.
We found that when 3,3-dimethylbutanal 1l was used as the al-
dehyde (entries 1 and 2), the reaction yield was slightly decreased
using potassium carbonate (41%) instead of sodium hydroxide (53%).
In significant contrast, using quinoline-2-carbaldehyde 1p (entries 3
and 4), the reaction yield was considerably improved replacing so-
dium hydroxide (48%) with potassium carbonate (100%).

4036
M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
Table 8
other hand, the one-pot procedure provided compounds 3b (entry
Phosphonium salts investigation
2) and 3c (entry 3) in excellent yield (93% and 100%, respectively),
without formation of Z-stereoisomer. The results reported in Table
9 proved that Ph3P, ethyl 2-bromoacetate can be used instead of the
corresponding phosphonium salt. Yet, a deeper optimization of the
one-pot reaction conditions could lead to better results.
Entrya
1
Phosphonium Salt
Productb
Isolated yieldc (%)
96
3. Conclusions
In conclusion, we developed a simple, mild, and fast protocol for
the synthesis of cinnamic ester derivatives by means of Wittig re-
action, combining segmented flow chemistry and sonication. It was
proved that the protocol can be applied to different aldehydes, alkyl
phosponium salts, and bases affording stereoselectively E-cinnamic
esters in moderate to excellent yields, in the absence of any phase
transfer catalyst and in a really short reaction time (5 min residence
time). Moreover, as the flow system works in a continuous way, the
reaction can be easily scaled up to provide virtually any amount of
product, simply running the system for the required time.
The possibility of applying the developed protocol to not sta-
bilized ylides is presently under investigation. In addition, the effect
of combination of flow chemistry and sonochemistry is going to be
studied using other model reactions.
2
3
95
42d
48e
4
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; molar ratio: aldehyde/phosponium salt/
NaOH¼1/2/2 (without PTC).
a
4. Experimental section
4.1. General
b
The Z-stereoisomer was not revealed in UPLC-MS analysis.
c
Product purified by flash chromatography on silica gel.
d
E/Z stereoisomers in 6:1 ratio, as determined by 1H NMR.
e
E/Z stereoisomers in 1.4:1 ratio, as determined by 1H NMR.
Commercially available reagents were used throughout without
any further purification unless otherwise stated. Wittig reactions
under Segmented Flow Condition were performed on commercially
available VapourtecÒ R2eR4 series flow reactor system. The re-
action outcome was supported by TLC and UPLC-MS analysis. An-
alytical thin layer chromatography was carried out using
aluminum-backed plates coated with Merk Kieselgel 60 F254. Plates
were visualized under UV light (at 254 and/or 360 nM). UPLC-MS
were recorded on Waters Alliance, Micromass ZQ and Waters 2996
photodiode array. The product was purified by flash chromatogra-
phy using Merck Geduran Si 60 and the products were character-
Table 9
Phosphonium Salts generated in situ
Entrya
1
Aldehydes
Productb
Isolated yieldc (%)
63d
ized by 1H NMR spectra recorded on
a Bruker ARX300
Spectrometer at 300.13 MHz (1H) using deuterated solvents, such
as DMSO-d6 or CDCl3. The instrument was equipped with a multi-
nuclear inverse probe and temperature controller. Chemical shifts
are expressed in parts of million (ppm,
stants J in units of hertz (Hz).
d units) and coupling con-
2
3
93
4.2. General procedure for Wittig reactions under segmented
flow condition (method A)
100
In the reagent stock bottle ‘A’, aldehyde (1 equiv) and triphe-
nylphosphonium bromide (2 equiv) were dissolved in DCM
(0.01 M). In the stock bottle ‘B’, the base (2 equiv) was dissolved in
water (0.02 M). The automated injection system combined the two
solutions through a T-inlet junction and pumped them at the same
flow rate (1 ml/min) into a 10 ml reactor, immersed in an ultrasonic
bath maintained at 25 ꢀC. The output was collected into a separa-
tion funnel, regulated to continuously remove the organic phase
that was filtered through a phase separator (IsoluteÒ Varian). The
solvent was evaporated under reduced pressure and crude was
purified by flash chromatography on silica gel.
4
66e
a
Reactor volume: 10 mL; reagents flow rate: 1 mL minꢁ1; temperature: room
temperature; organic solvent: DCM; molar ratio: aldehyde/triphenylphosphine/
ethyl 2-bromoacetate/NaOH¼1/1.5/1.5/5 (without PTC).
b
The Z-stereoisomer was not revealed in UPLC-MS analysis.
Product purified by flash chromatography on silica gel.
c
d
The same reaction carried out without sonication afforded the product in 38%
yield after chromatography purification.
e
E/Z stereoisomers in 5:1 ratio, as determined by 1H NMR.
4.2.1. 3-(4-Methoxy-phenyl) acrylic acid ethyl ester (3a). Obtained
case too, the positive effect of sonication was assessed (the one-pot
reaction conducted without sonication afforded compound 3a in
38% yield). As for aldehyde 1o, the one-pot protocol gave com-
pound 3o in lower yield (66% vs 100%) and E/Z-ratio (5:1). On the
from 4-methoxy-benzaldheyde (0.25 mmol, 30.3 mL) and ethox-
ycarbonylmethyl-triphenyl-phosphonium bromide (0.5 mmol,
214.6 mg) dissolved in DCM (25 mL) and aqueous NaOH (0.02 M,
25 mL). Chromatography eluent: petroleum ether/diethyl ether

M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
4037
(95/5) to obtain the title compound as clear oil (49.8 mg; 96.5%
yield). 1H NMR (300 MHz, CDCl3)
2H, J¼7.5); 6.9 (d, 2H, J¼7.5); 6.35 (d, 1H, J¼15); 4.27 (q, 2H, J¼7.5);
3.85 (s, 3H); 1.35 (t, 3H, J¼7.5).
7.14e7.27 (m, 3H); 7.02 (dt, 1H); 5.87 (dt, 1H); 4.20 (q, 2H);
2.70e2.92 (m, 2H); 1.30 (t, 3H).
d
ppm 7.65 (d, 1H, J¼15); 7.5 (d,
4.2.9. (2E,4E)-Ethyl 5-phenylpenta-2,4-dienoate (3i). Obtained from
of cinnamaldehyde (0.1 mmol, 13 mL) and ethoxycarbonylmethyl-
4.2.2. 3-Phenyl-acrilic acid ethyl ester (3b). Obtained from ben-
triphenyl-phosphonium bromide (0.2 mmol, 86 mg) dissolved in
10 mL of DCM and aqueous NaOH (0.02 M,10 mL). Chromatography
eluent: petroleum ether/diethyl ether (9/1). The title compound
was obtained as pale yellow oil (18 mg; 89% yield). 1H NMR
zaldheyde (0.25 mmol, 25.4
mL) and ethoxycarbonylmethyl-tri-
phenyl-phosphonium bromide
(0.5 mmol, 214.6 mg).
Chromatography eluent: petroleum ether/diethyl ether (98/2). The
title compound was collected as a colorless oil (43.1 mg; yield 98%).
(300 MHz, DMSO-d6) d ppm 7.49e7.66 (m, 2H); 7.27e7.48 (m, 4H);
1H NMR (300 MHz, CDCl3)
(m, 3H); 6.45 (d, 1H, J¼15); 4.27 (q, 2H, J¼7.5); 1.35 (t, 3H, J¼7.5).
d
ppm 7.7 (d, 1H, J¼15); 7.55 (m, 2H); 7.4
7.02e7.23 (m, 2H); 6.09 (d, J¼15.3, 1H); 4.16 (q, J¼7.2, 2H); 1.24 (t,
J¼7.0, 3H).
4.2.3. 3-(4-Nitro-phenyl)-acrylic acid ethyl ester (3c). Obtained
from 4-nitrobenzaldheyde (0.25 mmol, 37.7 mg) and ethox-
ycarbonylmethyl-triphenyl-phosphonium bromide (0.5 mmol,
214.6 mg). Chromatography eluent: petroleum ether/diethyl ether
(95/5). The title compound was collected as a white solid (54 mg;
4.2.10. (E)-Ethyl 5,5-dimethylhex-2-enoate (3l). Obtained from 3,3-
dimethylbutanal (0.2 mmol, 26 mL) and ethoxycarbonylmethyl-tri-
phenyl-phosphonium bromide (172 mg, 0.40 mmol) dissolved in
20 mL of DCM and aqueous NaOH hydroxide (0.02 M, 20 mL).
Chromatography eluent: petroleum ether/diethyl ether (9/1). The
final compound was obtained as a colorless oil (14 mg; 52.9% yield).
98% yield). 1H NMR (300 MHz, CDCl3)
d
ppm 8.26 (d, 2H, J¼7.5);
7.68 (m, 3H); 6.55 (d, 1H, J¼15); 4.3 (q, 2H, J¼7.5); 1.35 (t, 3H, J¼7.5).
1H NMR (300 MHz, CDCl3)
(dt, J¼15.5, 1.5, 1H); 4.21 (q, J¼7.0, 2H); 2.10 (dd, J¼7.9, 1.2, 2H); 1.31
(t, J¼7.0, 3H); 0.96 (s, 9H).
d
ppm 7.00 (dt, J¼15.5, 7.92, 1H); 5.82
4.2.4. 3-(4-Dimethylammino-phenyl) acrilic acid ethyl ester (3d).
Obtained from 4-dimethylamino-benzaldheyde (0.25 mmol,
37.2 mg) and ethoxycarbonylmethyl-triphenyl-phosphonium bro-
mide (0.5 mmol, 214.6 mg). Chromatography eluent: DCM. The title
compound was collected as a white solid (30.3 mg; 55.2% yield). 1H
4.2.11. (2E,7E)-Diethyl nona-2,7-dienedioate (3m). Obtained from
glutaraldehyde (0.1 mmol, 10.0 mg) and (2-ethoxy-2-oxoethyl)tri-
phenylphosphonium bromide (0.40 mmol, 172 mg) dissolved in
10 mL of DCM and aqueous NaOH (0.04 M,10 mL). Chromatography
eluent: DCM/MeOH (95/5). The title compound was obtained as
a colorless oil (9.8 mg; yield 41.2%). 1H NMR (300 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
ppm 7.68 (d, 1H, J¼15); 7.61 (m, 1H); 7.27
(d, 2H); 6.60 (d, 2H, J¼15); 6.47 (d, 1H, J¼7.5); 6.39 (d, 1H, J¼7.5);
4.26 (q, 2H); 3.03 (s, 6H); 1.34 (t, 3H).
d
ppm 6.95 (dt, J¼15.6, 7.0, 2H); 5.85 (dt, J¼15.6, 1.6, 2H); 4.21 (q,
4.2.5. 3-(2-Methoxy-phenyl)-acrylic acid ethyl ester (3e). Obtained
from 2-methoxy-benzaldheyde (0.25 mmol, 30.3 mL) and ethox-
J¼7.1, 4H); 2.25 (m, J¼7.3, 7.3, 7.1, 1.5, 4H); 1.66 (quin, J¼7.4, 2H);
1.31 (t, J¼7.0, 6H).
ycarbonylmethyl-triphenyl-phosphonium bromide (0.50 mmol,
215 mg). Chromatography eluent: petroleum ether/diethyl ether
(95/5). The title compound was collected as colorless oil (43 mg;
4.2.12. 3-Pyridin-4-yl-acrylic-acid ethyl ester (3n). Obtained from
pyridine-4-carbaldheyde (0.25 mmol, 23.8 mL) and ethox-
85% yield). 1H NMR (300 MHz, CDCl3)
d
ppm 8.05 (m, 1H); 7.56 (m,
ycarbonylmethyl-triphenyl-phosphonium bromide (0.50 mmol,
215 mg). Chromatography eluent: petroleum ether/diethyl ether
(95/5). The title compound was collected as a white solid (33.3 mg;
1H); 7.07 (m, 1H); 6.89 (m, 1H); 4.39 (d, 1H); 4.24 (q, 2H); 3.84 (s,
3H); 1.23 (t, 3H).
75% yield). 1H NMR (300 MHz, CDCl3)
d ppm 8.59e8.86 (m, 2H);
4.2.6. (E)-Ethyl 3-(3-methoxyphenyl)acrylate (3f). Obtained from 3-
7.66 (d, 1H); 7.57e7.67 (m, 2H); 6.71 (d, 1H); 4.34 (q, 2H); 1.38 (t,
methoxy-benzaldheyde
(0.1 mmol,
12
mL)
and
ethox-
3H).
ycarbonylmethyl-triphenyl-phosphonium bromide (0.2 mmol,
86 mg) dissolved in 10 mL of dichloromethane and aqueous NaOH
(0.02 M, 10 mL). Chromatography eluent: petroleum ether/diethyl
ether (9/1). The title compound was collected as an oil (17.7 mg,
4.2.13. (E)-Ethyl 3-(thiophen-2yl) acrylate (3o). Obtained from
thiophene-2-carbaldehyde
(0.1 mmol,
9.17
mL),
ethox-
ycarbonylmethyl-triphenyl-phosphonium bromide (0.2 mmol,
86 mg), and aqueous NaOH (0.02 M, 10 mL). Chromatography elu-
ent: petroleum ether/diethyl ether (95/5). The title compound was
collected as yellow oil (18 mg; quantitative yield). 1H NMR
86.1% yield). 1H NMR (300 MHz, DMSO-d6)
d
ppm 7.62 (d, J¼16.1,
1H); 7.33 (t, J¼7.6, 1H); 7.23e7.31 (m, 2H); 6.99 (ddd, J¼7.8, 2.6, 1.3,
1H); 6.66 (d, J¼15.8, 1H); 4.20 (q, J¼7.0, 2H); 3.80 (s, 3H); 1.27 (t,
J¼7.0, 3H).
(300 MHz, DMSO-d6)
0.9, 1H); 7.56 (d, 1H); 7.15 (dd, J¼5, 3.5, 1H); 6.26 (d, J¼15.5, 1H);
4.18 (q, J¼7.2, 2H); 1.25 (t, J¼7.0, 3H).
d
ppm 7.80 (dt, J¼15.5, 0.6, 1H); 7.73 (dt, J¼5,
4.2.7. (E)-Ethyl 3-(4-acetylphenyl)acrylate (3g). Obtained from 4-
acetylbenzaldehyde
(0.2 mmol,
29.6 mg)
and
ethox-
ycarbonylmethyl-triphenyl-phosphonium bromide (0.80 mmol,
344 mg) dissolved in 20 mL of DCM and aqueous NaOH (0.04 M,
20 mL). Chromatography eluent: DCM/MeOH (95/5). Desired
compound was collected as pale yellow oil (16 mg; 37% yield). 1H
4.2.14. (E)-Ethyl 3-(quinolin-2-yl)acrylate (3p). Obtained from
quinoline-2-carbaldehyde (0.10 mmol, 15.7 mg) and (2-ethoxy-2-
oxoethyl)triphenylphosphonium bromide (0.20 mmol, 86 mg).
Chromatography eluent: dichloromethane/diethyl ether (7/3). The
title compound was obtained as a brown solid (11 mg; 48.4% yield).
NMR (300 MHz, DMSO-d6) d ppm 7.93e8.07 (m, 2H); 7.81e7.93 (m,
2H); 7.71 (d, J¼15.8, 1H); 6.77 (d, J¼16.1, 1H); 4.22 (q, J¼7.0, 2H);
1H NMR (300 MHz, DMSO-d6)
d
ppm 8.44 (d, J¼8.5, 1H); 8.05 (dd,
2.60 (s, 3H); 1.27 (t, J¼7.0, 3H).
J¼8.5, 0.9, 1H); 8.01 (dd, J¼8.2, 1.2, 1H); 8.00 (d, J¼8.5, 1H); 7.81
(ddd, J¼8.5, 7.0, 1.7, 1H); 7.79 (d, J¼16.1, 1H); 7.65 (ddd, J¼8.2, 7.0,
1.2, 1H); 7.09 (d, J¼16.1, 1H); 4.25 (q, J¼7.0, 2H); 1.30 (t, J¼7.0, 3H).
4.2.8. 5-Phenyl-2-pent-enoic acid ethyl ester (3h). Obtained from 3-
phenyl-propionaldheyde (0.25 mmol, 30.2 mL) and ethox-
ycarbonylmethyl-triphenyl-phosphonium bromide (0.5 mmol,
215 mg). Chromatography eluent: petroleum ether/diethyl ether
(95/5). The title compound was obtained as an oil (32.8 mg; 63.4%
4.2.15. 3-(4-Methoxy-phenyl) acrylic acid ethyl ester (3a) using
K2CO3 as the base. Obtained from 4-methoxy-benzaldheyde
(0.25 mmol, 30.3
mL), ethoxycarbonylmethyl-triphenyl-phospho-
yield). 1H NMR (300 MHz, CDCl3)
d ppm 7.28e727 (m, 2H);
nium bromide (0.5 mmol, 215 mg) dissolved in DCM (25 mL) and

4038
M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
aqueous K2CO3 (0.02 M, 25 mL). Chromatography eluent: petro-
leum ether/diethyl ether (95/5). The title compound was obtained
as colorless oil (49.8 mg; 98% yield). 1H NMR (300 MHz, CDCl3)
9H). Z-regioisomer: 1H NMR (300 MHz, DMSO-d6)
d ppm 7.64 (m,
2H); 6.95 (m, 2H); 6.82 (d, J¼12.9, 1H); 5.76 (d, J¼12.9, 1H); 3.79 (s,
3H); 1.43 (s, 9H).
d
ppm 7.65 (d, 1H, J¼15); 7.5 (d, 2H, J¼7.5); 6.9 (d, 2H, J¼7.5); 6.35
(d, 1H, J¼15); 4.27 (q, 2H, J¼7.5); 3.85 (s, 3H); 1.35 (t, 3H, J¼7.5).
4.2.22. 3-(4-Methoxy-phenyl)-acrylonitril (3s). Obtained from 4-
methoxy-benzaldheyde (0.2 mmol, 24 mL), cyanomethyl-tri-
4.2.16. (E)-3-(4-Methoxy-phenyl) acrylic acid ethyl ester (3a) using
NaHCO3 as the base. Obtained from 4-methoxy-benzaldheyde
(0.1 mmol, 12 mL), ethoxycarbonylmethyl-triphenyl-phosphonium
phenyl-phosphonium bromide (0.4 mmol, 152 mg) and
aquoeus NaOH (0.02 M, 20 mL). Chromatography eluent: pe-
troleum ether/diethyl ether (95/5). The title compound was
collected as white solid of were obtained as final product
bromide (0.2 mmol, 86 mg) dissolved in DCM (10 mL) and aqueous
NaHCO3 (0.02 M, 10 mL). Chromatography eluent: petroleum ether/
diethyl ether (8/2). The title compound was obtained as colorless oil
(15.3 mg; 48.5% yield). 1H NMR (300 MHz, CDCl3)
d ppm 7.42
(m, 2H); 7.36 (d, J¼16.4, 1H); 6.96 (m, 2H); 5.73 (d, J¼16.4,
(16 mg; 78% yield). 1H NMR (300 MHz, DMSO-d6)
d
ppm 7.64e7.74
1H); 3.87 (s, 3H).
(m, 2H), 7.60 (d, J¼16.1, 1H); 6.80e7.08 (m, 2H); 6.47 (d, J¼15.8, 1H);
4.18 (q, J¼7.2, 2H); 3.80 (s, 3H); 1.26 (t, J¼7.2, 3H).
4.3. General procedure for one-pot Wittig reactions under
segmented flow condition (method B)
4.2.17. (E)-3-(4-Methoxy-phenyl) acrylic acid ethyl ester (3a) using
DMAP as the base. Obtained from 4-methoxy-benzaldheyde
In the reagent stock bottle ‘A’, aldehyde (1 equiv), triphenyl-
(0.25 mmol, 30.3
m
L) and ethoxycarbonylmethyl-triphenyl-phos-
phosphine (1.5 equiv) and a-bromoester (1.5 equiv) were dis-
phonium bromide (0.5 mmol, 214.6 mg) dissolved in DCM (25 mL)
and aqueous DMAP (0.02 M, 25 mL). Chromatography eluent:
petroleum ether/diethyl ether (95/5). The title compound was
obtained as colorless oil (49.8 mg 78% yield). 1H NMR (300 MHz,
solved in DCM (0.1 M). In the stock bottle ‘B’, the base (5 equiv)
was dissolved in water (0.5 M). The automated injection system
combined the two solutions through a T-inlet junction and
pumped them at the same flow rate (1 ml/min) into a 10 ml re-
actor, immersed in an ultrasonic bath maintained at 25 ꢀC. The
outcome was collected into a separation funnel, regulated to
continuously remove the organic phase that was filtered through
a phase separator (IsoluteÒ Varian). The solvent was evaporated
under reduced pressure and crude was purified by flash chro-
matography on silica gel.
CDCl3)
d
ppm 7.65 (d, 1H, J¼15); 7.5 (d, 2H, J¼7.5); 6.9 (d, 2H,
J¼7.5); 6.35 (d, 1H, J¼15); 4.27 (q, 2H, J¼7.5); 3.85 (s, 3H); 1.35 (t,
3H, J¼7.5).
4.2.18. (E)-Ethyl 5,5-dimethylhex-2-enoate (3l) using K2CO3 as base.
The procedure is the same as described for (3a) but using potassium
carbonate (0.40 mmol, 56 mg) dissolved in 20 mL of H2O. Chro-
matography eluent: petroleum ether/diethyl ether (9/1). The title
compound was collected as colorless oil (14 mg; 41.1% yield). 1H
4.3.1. 3-(4-Methoxy-phenyl) acrylic acid ethyl ester (3a). Obtained
from 4-methoxybenzaldehyde (1 mmol, 121
phine (1.50 mmol, 393 mg), and ethyl 2-bromoacetate (1.50 mmol,
166 L) dissolved in DCM (10 mL) and aqueous NaOH (0.5 M,
mL), triphenylphos-
NMR (300 MHz, CDCl3)
J¼15.5, 1.5, 1H); 4.21 (q, J¼7.2, 2H); 2.10 (dd, J¼7.9, 1.5, 2H); 1.31 (t,
J¼7.0, 3H); 0.96 (s, 9H).
d
ppm 7.00 (dt, J¼15.5, 7.9, 1H); 5.82 (dt,
m
10 mL). Chromatography eluent: petroleum ether/diethyl ether
(85/15 to 8/2) to obtain the title compound as pale yellow oil
(78.6 mg, 38.1% yield).
The same reaction carriedout puttingthereactorin a sonicbath at
room temperature afforded 130 mg (63.1% yield) of the title com-
pound afterchromatography purification.1H NMR (300 MHz, DMSO-
4.2.19. (E)-Ethyl 3-(quinolin-2-yl)acrylate (3p) using K2CO3 as base.
The procedure is the same as described for (3a) but using quino-
line-2-carbaldehyde (0.1 mmol, 15.7 mg), (2-ethoxy-2-oxoethyl)
triphenylphosphonium bromide (0.2 mmol, 86 mg) and of potas-
sium carbonate (27.6 mg, 0.20 mmol). Chromatography eluent:
dichloromethane/diethyl ether (7/3). The title compound was
obtained as a brown solid (22.7 mg; quantitative yield). 1H NMR
d6)
d
ppm 7.64e7.72 (m, 2H); 7.60 (d, J¼16.1, 1H); 6.87e7.08 (m, 2H);
6.47 (d, J¼16.1, 1H); 4.18 (q, J¼7.0, 2H); 3.80 (s, 3H); 1.25 (t, J¼7.0, 3H).
(300 MHz, DMSO-d6)
d
ppm 8.44 (d, J¼8.5, 1H); 7.96e8.11 (m, 3H);
4.3.2. (E)-Ethyl cinnamate (3b). Obtained from benzaldehyde
7.78e7.86 (m, 1H); 7.80 (d, J¼16.1, 1H); 7.65 (ddd, J¼8.1, 6.9, 1.2, 1H);
(0.1 mmol, 10
ethyl 2-bromoacetate (0.15 mmol, 17.0
m
L), triphenylphosphine (0.15 mmol, 39.3 mg) and
L) dissolved in DCM
7.09 (d, J¼16.1, 1H); 4.25 (q, J¼7.0, 2H); 1.30 (t, J¼7.0, 3H).
m
(10 mL) and aqueous NaOH (0.5 M, 10 mL). Chromatography elu-
ent: petroleum ether/diethyl ether (8/2). The title compound was
collected as colorless oil (16.3 mg, 93% yield). 1H NMR (300 MHz,
4.2.20. (E)-Methyl 3-(4-methoxyphenyl)acrylate (3q). Obtained
from 4-methoxy-benzaldheyde (0.25 mmol, 25.4 mL) and methox-
ycarbonylmethyl-triphenyl-phosphonium bromide (0.5 mmol,
215 mg). Chromatography eluent: petroleum ether/diethyl ether
(98/2). The title compound was collected as colorless oil (45.6 mg;
DMSO-d6)
d
ppm 7.69e7.76 (m, 2H); 7.65 (d, J¼16.1, 1H);
7.34e7.48 (m, 3H); 6.63 (d, J¼16.1, 1H); 4.20 (q, J¼7.2, 2H); 1.27 (t,
J¼7.2, 3H).
yield 95%). 1H NMR (300 MHz, CDCl3)
d
ppm 7.65 (d, 1H, J¼15); 7.5
(d, 2H, J¼7.5); 6.9 (d, 2H, J¼7.5); 6.35 (d, 1H, J¼15); 3.88 (t, 3H); 3.84
4.3.3. (E)-Ethyl 3-(4-nitrophenyl)acrylate (3c). Obtained from 4-
nitrobenzaldehyde
(1.5 mmol, 393 mg), and ethyl 2-bromoacetate (1.5 mmol, 166
(s, 3H).
(1 mmol,
151 mg),
triphenylphosphine
L)
m
4.2.21. (E), (Z)-tert-Butyl 3-(4-methoxyphenyl) acrylate (3r).
Obtained from 4-methoxy-benzaldheyde (0.1 mmol, 12 mL), (2-tert-
dissolved in DCM (1 mL) and aqueous NaOH (0.5 M, 10 mL). Chro-
matography eluent: petroleum ether/diethyl ether (8/2). The title
compound was collected as colorless oil (113 mg; 51% yield). 1H
butoxy-2-oxoethyl) triphenylphosphonium chloride (0.2 mmol,
83 mg) and aqueous NaOH (0.02 M, 10 mL). Chromatography elu-
ent: petroleum ether/diethyl ether (9/1). (E)-tert-Butyl 3-
(4methoxyphenyl) acrylate was collected as a colorless oil (10 mg;
42.7% yield) and (Z)-tert-butyl 3-(4methoxyphenyl) acrylate was
collected as a colorless oil (1.7 mg; 7% yield). E-regiosiomer: 1H
NMR (300 MHz, DMSO-d6) d ppm 8.16e8.34 (m, 2H), 7.98e8.09 (m,
2H); 7.77 (d, J¼16.1, 1H); 6.86 (d, J¼15.8, 1H); 4.23 (q, J¼7.1, 2H);
1.28 (t, J¼7.0, 3H).
4.3.4. (E), (Z)-Ethyl 3-(thiophen-2-yl)acrylate (3o). Obtained from
NMR (300 MHz, DMSO-d6)
1H); 6.76e7.09 (m, 2H); 6.36 (d, J¼16.1,1H); 3.80 (s, 3H); 1.48 (s,
d
ppm 7.57e7.70 (m, 2H); 7.50 (d, J¼16.1,
thiophene-2-carbaldehyde (0.1 mmol, 9.2
(39.3 mg, 0.15 mmol), and ethyl 2-bromoacetate (0.150 mmol,
mL), triphenylphosphine

M. Riccaboni et al. / Tetrahedron 66 (2010) 4032e4039
5. Wachsen, K.; Himmler, O.; Cornils, B. Catal. Today 1998, 42, 333e339.
4039
17 mL) dissolved in DCM (10 mL) and aqueous NaOH (0.5 M, 10 mL).
6. Adams, D. J.; Dyson, P. J.; Tavener, S. J. Chemistry in Alternative Reaction Media;
Wiley: Chichester, UK, 2004.
7. For example, as reported on the SigmaeAldrich Catalog, benzyl-
Chromatography eluent: petroleum ether/diethyl ether (8/2).
(E)-Ethyl 3-(thiophen-2-yl)acrylate (yield 65, 8%, 12 mg) and
2.7 mg of (Z)-ethyl 3-(thiophen-2-yl)acrylate (yield 14.82%) were
obtained as final compounds.
tributylammonium chloride is classified
R 22e34; tetrabutylphosphonium
chloride is classified R 22-24-34; 18-Crown-6 is classified R 22-36/37/38; di-
cyclohexano-18-crown-6 is classified R 23/24/25-36/37/38.
8. Ducry, L.; Roberge, D. M. Angew. Chem., Int. Ed. 2005, 44, 7972e7975.
9. Yoshida, J.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J. Angew. Chem., Int. Ed. 2005,
44, 2413e2416.
10. Ahemed-Omer, B.; Barrow, D.; Wirth, T. Chem. Eng. J. 2008, 135S, S280eS283.
11. Budavari, S. Merck Index, 13th ed.; Merck: Rahway, NJ, USA, 2001.
12. Noro, T.; Miyase, T.; Kuroyanagi, M.; Ueno, A.; Fukushima, S. Chem. Pharm. Bull.
1983, 31, 2708e2711.
E-regioisomer: 1H NMR (300 MHz, DMSO-d6)
d ppm 7.80 (d,
J¼15.8, 1H); 7.70e7.76 (m, 1H); 7.47e7.59 (m, 1H); 7.15 (dd, J¼5, 3.5,
1H), 6.26 (d, J¼15.8, 1H), 4.18 (q, J¼7.1, 2H); 1.25 (t, J¼7.0, 3H). Z-
regioisomer: 1H NMR (300 MHz, DMSO-d6)
d ppm 7.44e7.81 (m,
2H); 7.29 (d, J¼12.3, 1H); 7.13 (dd, J¼5.1, 3.7, 1H); 5.77 (d, J¼12.6,
1H); 4.18 (q, J¼7.0, 2H); 1.25 (t, J¼7.0, 3H).
13. See for example: (a) Bowden, A. J. Am. Chem. Soc. 1940, 62, 2422e2426; (b)
Vieregge, H. Rec. Trav. Chem. Pays-Bas 1966, 85, 929e951; (c) Reuchardt, C.
Chem. Ber. 1967, 100, 1144e1164; (d) Yamane, T. Tetrahedron 1973, 29,
955e962; (e) Lu, X.; Fang, H.; Ni, Z. J. Organomet. Chem. 1989, 373, 77e84; (f)
Villeras, J.; Rambaud, M.; Graff, M. Tetrahedron Lett. 1985, 26, 53e56; (g)
Brown, T.; Blakemore, R.; Durant, G.; Emmet, J.; Gannelin, C. Eur. J. Med.
Chem. 1988, 23, 53e62; (h) Fujimura, O.; Honma, T. Tetrahedron Lett. 1998,
39, 625e626; (i) Calo, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J. Org.
Chem. 2003, 68, 2929e2933; (j) Ahmed-Omer, B.; Barrow, D. A.; Wirth, T.
Tetrahedron Lett. 2009, 50, 3353e3355; (k) Schwalbe, T.; Autze, V.; Hohmann,
M.; Stirner, W. Org. Process Res. Dev. 2004, 8, 440e454.
Acknowledgements
The authors gratefully acknowledge Dr. Luca Raveglia for helpful
discussion on the project and Dr. Sergio Menegon for NMR char-
acterization of products.
References and notes
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