An investigation into the use of silica-supported bases within EOF-based flow reactors

Article abstract of DOI:10.1016/j.tet.2004.07.006

Using a series of silica-supported bases, we demonstrate the synthesis of eight condensation products within an EOF-based flow reactor; in all cases, high yields (>99%) and product purity are obtained. By incorporating a series of silica-supported bases i

Full text of DOI:10.1016/j.tet.2004.07.006

Tetrahedron 60 (2004) 8421–8427
An investigation into the use of silica-supported bases within
EOF-based flow reactors
*
Charlotte Wiles, Paul Watts and Stephen J. Haswell
Department of Chemistry, Faculty of Science and the Environment, The University of Hull, Cottingham Road, Hull, HU6 7RX, UK
Received 6 April 2004; revised 8 June 2004; accepted 1 July 2004
Abstract—Using a series of silica-supported bases, we demonstrate the synthesis of eight condensation products within an EOF-based flow
reactor; in all cases, high yields (O99%) and product purity are obtained.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
phase synthesis, the use of solid-supported reagents means
that excess reagent can be employed in order to drive the
reaction to completion, while the reagent can be easily
removed from the reaction mixture. With the obvious
similarities to solid-phase synthetic methodology, polymers
have found widespread use in the preparation of solid-
supported reagents;6,7 other materials however include
zeolites,8 clays9 and silicas.10 Unlike certain polymers,
silica exhibits no swelling in organic solvents and is
thermally, chemically and mechanically stable; conse-
quently, its use as a support is becoming more widespread.
Due to the non-porous nature of the support, functionalisa-
tion is limited to the surface and as a result, reaction rate is
not limited by reagent diffusion whilst enabling controlled,
reproducible loading. In order to prevent any undesirable
adsorption of materials onto the silica, any unfunctionalised
silanol groups are end-capped. With this in mind, we were
interested in investigating the incorporation of silica-
supported reagents for continuous synthesis in a minia-
turised flow reactor.
Increased demand for the rapid preparation of small
molecule libraries has led to renewed interest in the
development of clean and efficient techniques for the
synthesis of organic compounds. With this in mind, the
miniaturisation of reaction technology is of particular
interest to the pharmaceutical industry, where long term
objectives include the desire to perform multiple functions
such as synthesis, detection, screening and biological
evaluation within a single integrated device, resulting in
an overall reduction in the time taken to discover new lead
compounds and put them into production.1 To date,
numerous compounds have been successfully synthesised
within micro fabricated devices with many groups demon-
strating advantages over traditional batch techniques such as
greater reaction control, leading to increased conversions,
selectivities and reduced reaction times.2 Although many
groups have begun the task of transferring synthetic
methodology from batch to micro reactors, few have
addressed the problems associated with product purification
in continuous systems.3 In order to tackle these problems,
we were interested in the use of solid-supported reagents.4
1.2. Knoevenagel condensation
The Knoevenagel reaction is defined as the condensation of
an aldehyde or ketone with compounds that possesses an
active methylene group. The reaction is brought about using
organic bases such as primary or secondary amines.11 The
active methylene groups employed include nitro, cyano and
acyl groups and in most cases, two groups are required in
order to provide sufficient activation. As Scheme 1
illustrates, the primary product formed is the unsaturated
product although, in some cases, further reaction may take
place with a second molecule of the activated methylene
compound resulting in a Michael addition to afford the bis
product. With careful selection of the starting materials,
enantioselective12 and diastereoselective13 condensation
1.1. Solid-supported reagents
Compared to solid-phase techniques,5 where reaction
intermediates are immobilised and cannot be fully charac-
terised until cleaved from the support, the use of solid-
supported reagents means that reaction products remain in
solution, enabling reaction progress to be monitored. As the
technique couples the advantages of both solid and solution-
Keywords: Silica supported base; Knoevenagel reaction; Flow reactor.
* Corresponding author. Tel.: C44-1482-465471; fax: C44-1482-
466416.; e-mail: p.watts@hull.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.006

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C. Wiles et al. / Tetrahedron 60 (2004) 8421–8427
Scheme 1. General scheme illustrating the reaction of activated methylenes and aldehydes with a functionalised silica gel 1.
products may be obtained. The main disadvantage associ-
ated with the Knoevenagel condensation is that the reactions
do not proceed to completion and require purification to
remove the organic base and its salt. Many alternatives
exist, including acid catalysed condensations,14 dry grind,15
the use of microwave irradiation,16 zeolites,17 aluminium
oxides18 and the use of amino functionalised polymers19 and
silica gels.20
Prior to investigating the incorporation of a silica-supported
base within a flow reactor, using the preparation of 2-cyano-
3-phenyl acrylic acid ethyl ester 2 as a model reaction, the
rate of reaction was compared to a solution phase base at
room temperature. As Figure 2 illustrates, compared to
piperazine 3, the rate of conversion is markedly reduced
when 3-(1-piperazino)propyl-functionalised silica gel 1 is
employed.
It was therefore proposed that by incorporation of a series of
supported bases into a micro-fabricated device, that product
purity could be increased while simultaneously maintaining
the advantages associated with miniaturisation. Firstly, in
order to compare the use of supported reagents within a flow
reactor with traditional batch techniques, the reactions were
initially performed in batch using both silica-supported and
solution phase bases.
2. Results and discussion
As Scheme 1 illustrates, treatment of an activated methylene
with a base 1 in the presence of an aldehyde, results in the
preparation of an unsaturated product (Fig. 1).
Figure 2. Graph illustrating the rate of conversion when employing
solution-phase organic bases compared with solid-phase bases.
Having demonstrated the successful synthesis of 2-cyano-3-
phenyl acrylic acid ethyl ester 2 using 3-(1-piperazino)prop-
yl-functionalised silica gel 1, the next step was to
investigate reagent longevity. As Figure 3 illustrates,
recycling the reagent results in a significant decrease in
conversion to 2-cyano-3-phenyl acrylic acid ethyl ester 2.
As the reaction is base catalysed and the reagent is end-
capped to prevent fouling, the increase in reaction time was
attributed to a loss of reagent as a result of recycling. In
order to confirm this, the reaction was again investigated
Figure 3. Graph illustrating the effect of recycling a solid supported reagent
on the rate of conversion.
Figure 1. Synthetic targets for preparation in a miniaturised device.

C. Wiles et al. / Tetrahedron 60 (2004) 8421–8427
8423
Figure 6. Schematic illustrating the principle of electroosmotic flow.
double layer. Application of an electric field causes the
double layer to move towards the most negative electrode,
inducing bulk flow within the microchannel.
To perform a reaction, the starting materials are passed over
a silica-supported reagent using EOF, reacted for a specified
time, collected in the product reservoir and analysed using a
chromatographic technique. As Figure 5 illustrates, 5 mg of
3-(1-piperazino)propyl-functionalised silica gel 1 (4.75!
10K3 mmol) was packed into a borosilicate glass capillary
(500 mm!3 cm) and in order to prevent loss of the reagent,
micro porous silica frits were placed at either end.22 The
capillary was then primed with MeCN to remove any air,
ensuring the formation of a complete circuit, and the
capillary attached to two glass reservoirs. The reagents were
manipulated through the device via the application of a
voltage to the platinum electrodes placed in the reagent
reservoirs. As Figure 7 illustrates, a 1:1 mixture of
benzaldehyde 4 and ethylcyanoacetate 5 (40 ml, 1.0 M) in
MeCN was placed in reservoir A and MeCN in reservoir B
(40 ml). Application of 333 and 0 V cmK1 resulted in the
mobilisation of the reaction mixture through the packed bed
Figure 4. Graph illustrating the effect of base amount on the rate of
conversion.
using varying amounts of 3-(1-piperazino)propyl-functio-
nalised silica gel 1 (0.05–0.0125 mmol). As Figure 4
illustrates, as the quantity of base employed is decreased,
the reaction time required increases, confirming the
reduction in reaction rate is due to reagent loss. Having
demonstrated the ability to recycle 3-(1-piperazino)propyl-
functionalised silica gel 1, the next step was to demonstrate
its use in a micro fabricated device.
In order to evaluate the use of silica-supported reagents
within an EOF-based system, a miniaturised flow reactor
was investigated (Fig. 5). This approach not only enabled
the reagents to be packed with ease but also provided a
relatively inexpensive, versatile system. Although examples
of pressure-driven systems have been reported within the
literature, owing to its simplicity, the technique of
electroosmotic flow (EOF) is demonstrated. The technique
is advantageous as it is simple to use, requires no
mechanical parts, enables reproducible pulse-free flow and
most importantly, with respect to packed systems, generates
minimal back-pressure.21 As Figure 6 illustrates, when an
ionisable surface such as glass, quartz or Teflon, comes in
contact with a suitable solvent system, the surface is
neutralised with a diffuse layer of positive ions from the
bulk liquid. A proportion of the counterions are adsorbed
onto the surface, resulting in the formation of an immobile
layer, and the remaining positive ions form a transient
at a flow rate of 0.5 ml minK1
.
After 20 min, the reaction products were collected in
reservoir B, diluted with MeCN and analysed by GC-MS,
whereby 98.3% conversion to 2-cyano-3-phenyl acrylic acid
ethyl ester 2 was obtained with respect to residual
benzaldehyde 4 (Fig. 8). Consequently, in order to
demonstrate the use of the aforementioned device for the
continuous synthesis of 2-cyano-3-phenyl acrylic acid ethyl
ester 2, the reactor was run continually over a period of
4.75 h (14 runs), whereby 0.025 g (0.124 mmol, 98.9%) of
product 2 was prepared. As Table 1 illustrates, reproducible
conversions of greater than 98% were obtained demonstrat-
ing device stability and reagent longevity. After analysis by
GC-MS, the reaction products were collected and concen-
trated in vacuo, the crude product was then analysed by
NMR. As Figure 9 illustrates, NMR confirms the successful
Figure 7. Schematic of the preparation of 2-cyano-3-phenyl acrylic acid
ethyl ester 2 in an EOF-based miniaturised device.
Figure 5. Schematic of the reaction set-up used for the evaluation of solid-
supported reagents.

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C. Wiles et al. / Tetrahedron 60 (2004) 8421–8427
Table 1. Table illustrating device reproducibility over 4.7 h
Run No.
Conversion (%)
1
2
3
4
5
6
7
8
98.3
98.5
98.3
98.3
98.4
99.2
99.1
99.1
100.0
99.6
99.3
100.0
100.0
99.2
9
10
11
12
13
14
MeanZ99.1%, % RSDZ0.65
synthesis of 2-cyano-3-phenyl acrylic acid ethyl ester 2 in
high purity within a micro fabricated device without the
need for further purification. Having demonstrated the
ability to synthesise 2-cyano-3-phenyl acrylic acid ethyl
ester 2, the technique was repeated using 4-bromobenzal-
dehyde 6, 3,5-dimethoxybenzaldehyde 7, 4-benzyloxyben-
zaldehyde 8, to afford the respective condensation products
9, 10 and 11 in 99.5, 94.7 and 95.1% conversion
respectively (Table 2).
Having successfully demonstrated the preparation of an
array of condensation products, the technique was extended
to the synthesis of 2-benzylidene malononitrile 12. Using
the aforementioned methodology, a 1:1 mixture of mal-
ononitrile 13 and benzaldehyde 4 (40 ml, 1.0 M) in MeCN
was placed in reservoir A and MeCN in reservoir B (40 ml).
As malononitrile 13 exhibits a greater electroosmotic
mobility cf. ethylcyanoacetate 5, the applied field was
Figure 8. Chromatogram illustrating the synthesis of 2-cyano-3-phenyl
acrylic acid ethyl ester 2 within a micro reactor (98.3% conversion).
Figure 9. 13C NMR of 2-cyano-3-phenyl acrylic acid ethyl ester 2 synthesised using a micro fabricated device.

C. Wiles et al. / Tetrahedron 60 (2004) 8421–8427
8425
Table 2. Summary of the conversions obtained in a micro fabricated device
using 3-(1-piperazino)propyl-functionalised silica gel 1
Table 3. Comparison of the conversions obtained for the synthesis of 2-
cyano-3-phenyl acrylic acid ethyl ester 2 using silica-supported bases 1, 17,
18 and 19
Product No.
Applied Field
(V cmK1
Flow Rate
(ml minK1
)
Conversiona
(%)
Base
Applied field
(V cmK1
Flow rate
(ml minK1
)
Conversiona
(%)
)
)
2
9
333
333
333
333
167
167
167
167
0.5
0.3
0.3
0.5
1.0
0.5
0.7
1.0
99.1
99.5
94.7
95.1
96.9
96.3
97.8
99.7
1
333
333
333
333
0.5
0.35
.35
99.1
99.4
100.0
99.3
10
11
12
14
15
16
17
18
19
0.80
a
R10 replicates were performed for each compound.
Using four silica-supported bases, 3-(1-piperazino)propyl-
functionalised silica gel 1, 3-(dimethylamino)propyl-func-
tionalised silica gel 17, 3-aminopropyl-functionalised silica
gel 18 and 3-(1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-
a]pyrimidino)propyl-functionalised silica gel 19, enabled
the synthesis of an array of condensation products in
excellent conversions when the device was operated at flow
rates of !1.0 ml minK1. This technique is therefore suitable
for the rapid synthesis of small quantities of compound for
biological screening or the preparation of larger quantities
by scaling-out.24 The ability to prepare pure compounds in
sufficient quantities to obtain structural information is also
advantageous as it negates the need to prepare synthetic
standards, whilst demonstrating the preparation of com-
pounds of analytical purity. Compared to standard batch
techniques employing solid supported reagents, the use of a
continuous flow reactor is advantageous as reagents can be
recycled without any loss upon filtration, resulting in more
consistent conversions over extended periods of operation
(Table 1 cf. Fig. 3). Localised concentration gradients
enable reactions to be driven to completion without the need
to employ large quantities of reagent, that is, 5 mg (4.75!
10K4 mmol) in a micro reactor enables conversions in
excess of 95% to be attained in minutes compared with
O95 h in batch (Fig. 4, 0.0125 mmol).
a
R10 replicates were performed for each compound.
reduced in order to obtain comparable flow rates. Appli-
cation of 167 and 0 V cmK1 resulted in the mobilisation of
the reaction mixture through the packed bed, at a flow rate
of 1.0 ml minK1, resulting in 96.9% conversion to 2-
benzylidene malononitrile 12. This was subsequently
repeated using 4-bromobenzaldehyde 6, 3,5-dimethoxybenz-
aldehyde 7, 4-benzyloxybenzaldehyde 8, to afford 2-(4-
bromobenzylidene)-malononitrile 14 (96.9%), 2-(3,5-
dimethoxybenzylidene)-malononitrile 15 (96.3%) and
2-(4-benzyloxybenzylidene)-malononitrile 16 (97.3%)
respectively (Table 2). Again, H and 13C NMR spectra
1
were obtained for all compounds synthesised within the
device demonstrating excellent product purity. In all cases,
no by-product formation was observed by GC-MS or NMR
spectroscopy. The technique was subsequently repeated
using the reagents; 3-(dimethylamino)propyl-functionalised
silica gel 17 (1.50 mmol N gK1), 3-aminopropyl-functiona-
lised silica gel 18 (1.00 mmol N gK1) and 3-(1,3,4,6,7,8-
hexahydro-2H-pyrimido[1,2-a]-pyrimidino)-propyl-func-
tionalised silica gel 19 (2.4 mmol N gK1) (Fig. 10) whereby
99.4, 100 and 99.3% conversion to 2-cyano-3-phenyl
acrylic acid ethyl ester 2 were obtained.
Previous work by Macquarrie et al.,23 demonstrated the use
of a 3-aminopropyl-functionalised silica surface in a heated,
pressure-driven, aluminium micro reactor. Operating the
device at 98 8C enabled 70% conversion of a 1:1
ethylcyanoacetate 5 and benzaldehyde 4 to 2-cyano-3-
phenyl acrylic acid ethyl ester 2. Compared to the work
described herein, this approach is disadvantageous as
solvent-free techniques are only suitable for the preparation
of low viscosity compounds. Also, the elevated reaction
temperatures employed, compromises device simplicity.
This investigation therefore focussed on the preparation of
an array of condensation products at room temperature,
within an EOF-based micro fabricated device (Table 3).
3. Conclusions
In conclusion, we have demonstrated the successful
incorporation of a series of silica-supported bases within
an EOF-based micro-fabricated device, enabling the
synthesis and characterisation of eight condensation pro-
ducts. Using the methodology described herein, further
studies are currently underway within our laboratories to
extend both the type of reagent and support employed,
enabling more complex syntheses to be demonstrated.
4. Experimental
4.1. Materials and methods
All materials (analytical grade) were purchased from
Aldrich and were used without purification. All NMR
spectra were recorded as solutions in deuteriochloroform
(CDCl3) using tetramethylsilane (TMS) as an internal
standard. The spectra were recorded on a Joel GX400
spectrometer and the chemical shifts are given in parts per
million (ppm) with coupling constants given in Hertz (Hz).
The following abbreviations are used to report NMR data;
sZsinglet, dZdoublet, tZtriplet, br sZbroad singlet, mZ
Figure 10. Schematic of 3-(dimethylamino)propyl-functionalised silica gel
17, 3-aminopropyl-functionalised silica gel 18 and 3-(1,3,4,6,7,8-hexahy-
dro-2H-pyrimido[1,2-a]pyrimidino)propyl-functionalised silica gel 19.

8426
C. Wiles et al. / Tetrahedron 60 (2004) 8421–8427
multiplet and C0Zquaternary carbon. Gas chromatography-
mass spectrometry (GC-MS) was performed using a Varian
GC (CP-3800) coupled to a Varian MS (2000) with a CP-Sil
8 (30 m) column (Phenomenex) and ultra high purity helium
(99.999% Energas) carrier gas. Samples were analysed
using one of the following methods; Method A: injector
temperature 250 8C, helium flow rate 1.0 ml minK1, oven
temperature 60 8C for 1.0 min and then ramped to 270 8C at
35 8C minK1, with a 3.0 min filament delay or; Method B:
4.3.1. 2-Cyano-3-phenyl acrylic acid ester 225. (0.0253 g,
98.9%) as a white solid; dH 1.41 (3H, t, JZ7.0 Hz,
CH2CH3), 4.39 (2H, q, JZ7.0 Hz, CH2CH3), 7.53 (3H, m,
Ar), 7.99 (2H, m, Ar) and 8.26 (1H, s, CH); dC 14.2 (CH3),
62.8 (CH2), 103.1 (C0CN), 115.5 (CN), 129.3 (2!CH),
131.0 (2!CH), 131.5 (C0), 133.3 (CH), 155.1 (CH) and
162.5 (CO); m/z (EI) 202 (MCC1, 70%), 201 (100), 172
(80), 156 (90), 128 (75), 102 (55), 77 (50) and 51 (50); GC-
MS retention time (Method A) RTZ6.63 min.
injector temperature 250 8C, helium flow rate 1.0 ml minK1
,
oven temperature 60 8C for 1.0 min and then ramped to
4.3.2. 3-(4-Bromophenyl)-2-cyano acrylic acid ethyl ester
926. (0.0118 g, 99.5%) as a white solid; dH 1.40 (3H, t, JZ
7.3 Hz, CH2CH3), 4.39 (2H, q, JZ7.3 Hz, CH2CH3), 7.65
(2H, d, JZ8.7 Hz, Ar), 7.86 (2H, d, JZ8.7 Hz, Ar) and 8.19
(1H, s, CH); dC 14.2 (CH3), 62.9 (CH2), 103.7 (C0CN),
115.3 (CN), 128.3 (C0Br), 130.3 (C0), 132.3 (2!CH), 132.7
(2!CH), 153.6 (CH) and 162.3 (CO); 281 (MCC1, 90%),
280 (45), 279 (100), 251 (25), 200 (20), 154 (10), 127 (25),
100 (20) and 76 (20); GC-MS retention time (Method B)
RTZ10.84 min.
270 8C at 20 8C minK1, with a 3.0 min filament delay.
4.2. Batch reactions
4.2.1. General procedure for the solution-phase synthesis
of Knoevenagel condensation products in batch. Piper-
azine 3 (0.09 g, 0.1 mmol) was added to a stirred solution of
activated methylene (1.0 mmol) and aldehyde (1.0 mmol) in
anhydrous MeCN (10 ml mmolK1). After stirring overnight,
the reaction mixture was concentrated in vacuo prior to the
addition of dilute HCl (50 ml, 0.1 M) and the reaction
products extracted into DCM (3!50 ml). The combined
extracts were dried (MgSO4) and concentrated in vacuo,
subsequent recrystallisation from DCM/hexane afforded the
respective condensation product.
4.3.3. 3-(3,5-Dimethoxyphenyl)-2-cyano acrylic acid
ethyl ester 1027. (0.0109 g, 99.5%) as a white solid; dH
1.40 (3H, t, JZ7.0 Hz, CH2CH3), 3.85 (6H, s, 2!OCH3),
4.39 (2H, q, JZ7.0 Hz, CH2CH3), 6.65 (1H, m, Ar), 7.15
(2H, m, Ar) and 8.17 (1H, s, CH); dC 14.2 (CH3), 55.7 (2!
OCH3), 62.8 (CH2), 103.4 (C0CN), 106.2 (CH), 108.6 (2!
CH), 115.6 (CN), 133.1 (C0), 155.2 (CH), 161.1 (2!C0)
and 162.5 (CO); 262 (MCC1, 20%), 261 (100), 189 (55),
161 (25) and 77 (10); GC-MS retention time (Method A)
RTZ8.06 min.
4.2.2. General procedure for the solid-phase synthesis of
Knoevenagel condensation products in batch. 3-(1-
Piperazino)propyl-functionalised
silica
gel
1
(1.9 mmol N gK1, 200–400 mesh) (0.10 g, 0.1 mmol) was
added to a stirred solution of activated methylene
(1.0 mmol) and aldehyde (1.0 mmol) in anhydrous MeCN
(10 ml mmolK1). After stirring overnight, the reaction
mixture was filtered and the filtrate concentrated in vacuo
to afford the respective condensation product.
4.3.4. 3-(4-Benzyloxyphenyl)-2-cyano acrylic acid ethyl
ester 11. (0.0211 g, 99.1%) as a cream solid (Found C,
74.51; H, 5.77; N, 4.62. C19H17O3N requires C, 74.25; H,
5.58; N, 4.56%); dH 1.39 (3H, t, JZ7.3 Hz, CH2CH3), 4.37
(2H, q, JZ7.3 Hz, CH2CH3), 5.15, (2H, s, CH2), 7.00 (2H,
d, JZ8.7 Hz, Ar), 7.40 (5H, m, Ar), 7.99 (2H, d, JZ8.7 Hz,
Ar) and 8.17 (1H, s, CH); dC 14.2 (CH3), 62.5 (CH2), 70.4
(C0CH2), 99.5 (C0), 115.6 (2!CH), 124.6 (CN), 127.5 (2!
CH), 128.4 (CH), 128.8 (2!CH), 133.7 (2!CH), 135.8
(C0), 154.4, (CH), 162.9 (OC0) and 163.1 (CO); 308 (MCC
1, 5%), 307 (20), 91 (100) and 65 (20); GC-MS retention
time (Method B) RTZ12.35 min.
4.3. Micro-scale methodology
The reactions described herein were carried out using a
single capillary device, as illustrated in Figure 5, with
capillary dimensions of 500 mm i.d.!3.0 cm. To hold the
supported reagent in place, micro porous silica frits were
placed at either end of the capillary.22 To mobilise reagents
by EOF, platinum electrodes (0.5 mm o.d.!2.5 cm) were
placed within the reagent reservoirs and voltages applied
using a Paragon 3B high-voltage power supply (HVPS),
capable of applying 0–1000 V to four pairs of outputs
(Kingfield Electronics). Automation of the HVPS was
achieved using an in-house LabVIEWe program. To enable
the results obtained to be attained using devices of different
dimensions, voltages are reported as applied fields (V cmK1),
that is, voltage/capillary length. To monitor the progress of
the reaction, experiments were conducted over a period of
20 min, after which, the product reservoir was analysed by
GC-MS, whereby comparison of the amount of product with
respect to residual aldehyde enabled the percentage
conversion to be determined. In order to obtain NMR data
on the compounds synthesised in the flow system, the
reactors were operated continuously for 3–5 h, after which
the reaction products were concentrated in vacuo and the
crude compound analysed.
4.3.5. 2-Benzylidene-malononitrile 1225. (0.0154 g, 100%)
as a pale yellow solid; dH 7.55 (2H, m, Ar), 7.64 (1H, m,
Ar), 7.79 (1H, s, CH) and 7.91 (2H, m, Ar); dC 83.0 (C0),
112.6 (CN), 113.7 (CN), 129.7 (2!CH), 130.8 (2!CH),
131.0 (C0), 134.7 (CH) and 159.9 (CH); 155 (MCC1,
20%), 154 (100), 127 (20) and 76 (10); GC-MS retention
time (Method A) RTZ5.84 min.
4.3.6. 2-(4-Bromobenzylidene)-malononitrile 1428.
(0.0349 g, 99.9%) as a pale yellow solid; dH 7.69 (2H, d,
JZ8.4 Hz, Ar), 7.72 (1H, s, CH) and 7.77 (2H, d, JZ
8.4 Hz, Ar); dC 83.6 (C0), 112.3 (CN), 113.5 (CN), 129.7
(C0Br), 130.0 (C0), 131.8 (2!CH), 133.1 (2!CH) and
158.4 (CH); 235 (MCC1, 70%), 234 (100), 233 (95), 232
(90), 153 (25) and 77 (10); GC-MS retention time (Method
B) RTZ9.65 min.
4.3.7. 2-(3,5-Dimethoxybenzylidene)-malononitrile 1525.

C. Wiles et al. / Tetrahedron 60 (2004) 8421–8427
8427
7. Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis 1997,
1217.
(0.0240 g, 99.2%) as a yellow solid; dH 3.84 (6H, s, OCH3),
6.70 (1H, m, Ar), 7.03 (2H, m, Ar) and 7.69 (1H, s, CH); dC
55.7 (2!OCH3), 83.2 (C0), 107.3 (CH), 108.3 (2!CH),
112.7 (CN), 113.7 (CN), 132.4 (C0), 160.1 (CH) and 161.3
(2!C0OCH3); 215 (MCC1, 25%), 214 (100), 186 (55),
171 (20), 155 (20), 142 (15), 114 (10) and 76 (10); GC-MS
retention time (Method A) RTZ7.50 min.
8. Sen, S. E.; Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55,
12657.
9. Varma, R. S. Tetrahedron 2002, 58, 1235.
10. Singh, R. P.; Subbarao, H. N.; Dev, S. Tetrahedron 1980, 37,
846.
11. Jones, G. Org. React. 1967, 15, 204 and references therein.
12. Togni, A.; Pastor, S. D. J. Org. Chem. 1990, 55, 1649.
13. Trost, B. M.; Florez, J.; Jebaratnam, D. J. J. Am. Chem. Soc.
1987, 109, 613.
4.3.8. 2-(4-Benzyloxybenzylidene)-malononitrile 1629.
(0.0235 g, 99.6%) as a pale yellow solid; dH 5.17 (2H, s,
CH2), 7.08 (2H, d, JZ9.0 Hz, Ar), 7.39 (5H, m, Ar), 7.64
(1H, s, CH) and 7.90 (2H, d, JZ9.0 Hz, CH); dC 70.6 (CH2),
78.8 (C0), 113.3 (CN), 114.4 (CN), 116.0 (2!CH), 124.2
(C0), 127.5 (2!CH), 128.6 (CH), 128.9 (2!CH), 133.5
(2!CH), 135.5 (C0), 158.8 (CH) and 163.9 (OC0); 261
(MCC1, 5%), 260 (5), 114 (10) and 91 (100); GC-MS
retention time (Method B) RTZ11.97 min.
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Full financial support provided by the EPSRC (Grant No.
GR/S34106/01) is gratefully acknowledged. Mike Bailey
(University of Hull) is also acknowledged for assistance in
the device fabrication.
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