Acid-catalysed synthesis and deprotection of dimethyl acetals in a miniaturised electroosmotic flow reactor

Article abstract of DOI:10.1016/j.tet.2005.03.082

Through incorporating a series of polymer-supported acid catalysts into a miniaturised EOF-based flow reactor, we demonstrate a clean and efficient technique for the protection of aldehydes as their respective dimethyl acetal. In addition, we also report the acid catalysed deacetalisation of 11 dimethyl acetals to their respective aldehyde. In all cases, the compounds described are obtained in high yield (>95%) and excellent purity (>99%) without the need for further product purification.

Full text of DOI:10.1016/j.tet.2005.03.082

Tetrahedron 61 (2005) 5209–5217
Acid-catalysed synthesis and deprotection of dimethyl acetals in a
miniaturised electroosmotic flow reactor
*
Charlotte Wiles, Paul Watts and Stephen J. Haswell
Department of Chemistry, The University of Hull, Cottingham Road, Hull, HU6 7RX, UK
Received 28 February 2005; accepted 23 March 2005
Available online 13 April 2005
Abstract—Through incorporating a series of polymer-supported acid catalysts into a miniaturised EOF-based flow reactor, we demonstrate a
clean and efficient technique for the protection of aldehydes as their respective dimethyl acetal. In addition, we also report the acid catalysed
deacetalisation of 11 dimethyl acetals to their respective aldehyde. In all cases, the compounds described are obtained in high yield (O95%)
and excellent purity (O99%) without the need for further product purification.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
performing reactions in continuous flow reactors, such as
the one described herein, the support material undergoes
minimal physical degradation, resulting in extended reagent
lifetime and system reproducibility.5–7
As a result of increasing environmental pressure, the
chemical industry as a whole are exploring many routes to
improve both the cleanliness and efficiency of many
synthetic processes. One such approach is the application
of micro reaction technology, which enables reactions to be
performed more rapidly, efficiently and selectively than
traditional batch-scale reactions. Although many groups
have demonstrated the advantages of synthesising small
organic compounds in micro fabricated devices, few have
addressed the problems associated with purification of
reaction products prepared using continuous flow systems.1
In order to address this, we recently investigated the use of
silica-supported catalysts in a micro fabricated device
whereby analytically pure products were synthesised.2
Automation of this technique would therefore, enable the
high-throughput synthesis of analytically pure compounds,
suitable for the fine chemical industry or combinatorial
applications. With these factors in mind, we propose that by
incorporating a series of solid-supported acid catalysts into
miniaturised flow reactors, problems such as corrosion of
reactor vessels, generation of acidic waste and the inability
to recover/recycle the catalyst can be addressed. In order to
demonstrate the advantages associated with the proposed
technique, the acid catalysed synthesis of dimethyl acetals
and their deprotection was investigated.
Compared to solid-phase techniques,3 where reaction
intermediates and products cannot be fully characterised
until they are cleaved from the support, the use of solid-
supported reagents is advantageous as reaction products
remain in solution thus enabling the reaction to be
monitored with time.4 Additionally, as the supported
reagent can be easily removed from the reaction mixture,
excess amounts can be employed in order to drive the
reaction to completion. Although solid-supported reagents
have many advantages over their solution phase counter-
parts, one main limitation is the support degradation that
occurs as a result of stirring or shaking. Therefore by
1.1. Acid catalysed acetalisation
Acetals are one of the most common carbonyl protecting
groups, prepared by the treatment of aldehydes (or ketones)
with alcohols (or orthoformates) in the presence of an acid
catalyst (Scheme 1). Although triflic acid and p-toluene-
sulfonic acid are generally used, other catalysts include
ferric chloride,8 ammonium nitrate9 rhodium(III) com-
plexes10 and ethanolic hydrogen chloride.11 In addition,
numerous examples of solid-supported acid catalysts have
been applied to the synthesis of acetals, these include,
Amberlite resin,12 Amberlyst-15 (dry),13 polymer-sup-
ported lanthanides,14 and Nafion-H.15,16 As Scheme 1
illustrates, hydrolysis of an acetal with an aqueous acid,
affords the respective carbonyl compound. Consequently, as
Keywords: Acetals; Micro reactor; Deprotection.
*
Corresponding author. Tel.: C44 1482 465471; fax: C44 1482 466416;
e-mail: p.watts@hull.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.082

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C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
Scheme 1. Schematic illustrating the acid catalysed acetalisation of an aldehyde.
neither the forward or reverse reaction is base catalysed,
acetals are frequently employed as protecting groups.
1.4. Principle of electroosmotic flow
When an ionisable surface such as glass,18 quartz19 or
teflon,20 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 an immobile layer and
the remaining ions form a transient double layer (Fig. 2).
Application of an electric field causes the double layer to
move towards the oppositely charged electrode, inducing
bulk flow within the channel/capillary.
1.2. How are reactions performed?
To conduct a reaction, the starting materials are passed over
a solid-supported reagent or catalyst and the reaction
products are collected at the outlet (Fig. 1). The reaction
mixture is then analysed by GC–MS whereby conversion of
starting material to product is determined. If any residual
starting material is observed the reaction is repeated, this
time passing the reagents over the support at a slower flow
rate, thus having the effect of increasing the reagents
residence time within the reactor. When successfully
optimised, the devices are operated continuously in order
to prepare sufficient quantity of product for analysis by
NMR spectroscopy and if required, elemental analysis.
Using this approach, work-up is extremely simple, consist-
ing of concentrating the reaction product in vacuo followed
by analysis. By optimising the flow rate, and hence
residence time within the reactor, it is possible to obtain
complete conversion of starting materials to product in a
single pass through the device (Scheme 3).
Figure 2. Schematic illustrating the principle of electroosmotic flow for a
negatively charged glass surface.
As electrokinetic flow is a surface phenomenon, the
physical properties of the fluid have a direct bearing on
the flow rates observed (Eq. 1), consequently the technique
is typically employed for polar, low viscosity solvent
systems. In addition, in order to preserve the diffuse double
layer, the solutions must be OpH 2. Below this, no EOF is
observed as an immobile layer replaces the diffuse positive
ions. Consequently, performing reactions that require acidic
reagents can be problematic, in order circumvent this
problem we recently demonstrated an alternative approach
to the synthesis of esters21 and McCreedy et al.22 reported
Figure 1. Schematic illustrating the use of solid-supported catalysts in a
continuous flow reactor.
1.3. Pumping mechanism
Although examples of pressure-driven micro fluidic systems
have featured widely in the literature,17 owing to its
simplicity, the evaluation of polymer-supported acid
catalysts was carried out using electroosmotic flow (EOF).
The advantages of using this approach are, it is simple to
use, requires no mechanical parts, enables reproducible
pulse-free flow, generates minimal back-pressure, can alter
both the direction and magnitude of flow and can be easily
automated. Of the many positive features associated with
the use of EOF, in this case, the generation of minimal
backpressure and reproducible flow are the most important.
Equation 1. Determination of electroosmotic flow (EOF) velocity.24

C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
5211
the use of a sulphated zirconia catalyst for the dehydration
of alcohols. More recently, Crocker et al.23 reported the use
of amine functionalised electrokinetic micro pumps for the
mobilisation of acidic solutions (0.1% TFA in H2O/MeCN)
whereby nl minK1 flow rates were obtained. Therefore, by
incorporating polymer-supported acids into micro fabri-
cated devices, we are able to conduct reactions that
otherwise could not be performed efficiently within EOF-
based devices.
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 4 illustrates, benzaldehyde 3 and
trimethylorthoformate 4 (40 ml, 1.0 and 2.0 M, respectively)
in MeCN was placed in reservoir A and MeCN in reservoir
B (40 ml). Application of 333 and 0 V cmK1 respectively,
resulted in the mobilisation of the reaction mixture at a flow
rate of 1.75 ml minK1. After 10 min, the reaction products
were collected from reservoir B, diluted with MeCN, and
analysed by GC–MS, whereby 100% conversion to
dimethoxymethyl benzene 2 was obtained with respect to
residual benzaldehyde 3. In order to demonstrate both
system reproducibility and the continuous synthesis of
dimethoxymethyl benzene 2, the reaction was repeated a
further 14 times (2.5 h), whereby conversions of O99.6%
were obtained (Table 1). After analysis by GC–MS, all
reaction products were collected and concentrated in vacuo,
to afford dimethoxymethyl benzene 2 as a pale yellow oil
(0.025 g, 96.6%). In order to confirm product purity, the
crude reaction mixture was analysed by NMR spectroscopy,
whereby no residual aldehyde was observed.
2. Results and discussion
2.1. Synthesis of dimethyl acetals using Amberlyst-15
Amberlyst-15 (dry) 1 is a sulfonic acid based cation
exchange resin that has been widely employed for the
preparation of acetals, ketals, tetrahydropyranyl ethers and
enol ethers.25 Using the synthesis of dimethoxymethyl
benzene 2 as a model reaction, we investigated the use of
Amberlyst-15 1 in a micro fabricated device (Scheme 2).
Scheme 2. General scheme illustrating the acid catalysed synthesis of
dimethoxymethyl benzene 2 using Amberlyst-15 1.
Figure 4. Schematic illustrating the manifold set-up used for the synthesis
of dimethyl acetal 2 in an EOF-based micro reactor.
Table 1. Illustration of system stability over 15 runs for the synthesis of
dimethoxymethyl benzene 2
Run No.
Conversion (%)
1
2
3
4
5
6
7
8
100.0
99.58
99.68
99.83
99.87
99.69
99.65
99.75
99.70
99.74
99.71
99.63
99.90
100.0
99.80
Scheme 3. Deacetalisation of dimethoxymethyl benzene 2 using
Amberlyst-15 1.
Using EOF, the starting materials are passed over
Amberlyst-15 1, the reaction mixture is then collected at
the outlet and analysed by GC–MS. As Figure 3 illustrates,
Amberlyst-15 1 (dry) (2.5 mg, 1.05!10K2 mmol) was
packed into a borosilicate glass capillary (500 mm!
3.0 cm) and held in place using micro porous silica frits.26
The capillary was then primed with MeCN to remove any
9
10
11
12
13
14
15
MeanZ99.8%, % RSDZ0.13
In summary, we have synthesized 0.165 mmol of
dimethoxymethyl benzene 2 using 1.05!10K2 mmol of
Amberlyst-15 1. This result not only demonstrates the
successful incorporation of supported acids into an EOF-
based device, but also the ability to recycle the supported
reagent (O16 times) without any loss of activity. Although
the activity of Amberlyst-15 1 is also retained in batch, this
approach is advantageous as macroreticular resins are
difficult to recycle due to support degradation observed as
a result of mechanical agitation; therefore limiting the
number of times they can be recycled. In order to confirm
that the observed reaction was due to the presence of a solid-
Figure 3. Schematic of the reaction set-up used for the evaluation of the
polymer-supported acid catalysts.

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C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
supported acid catalyst and not as a result of conducting the
reaction in an electric field, the reaction was repeated in the
absence of a catalyst.
0 V cmK1, respectively, resulted in the mobilisation of the
reaction mixture at a flow rate of 1.75 ml minK1 27
After
.
10 min, the reaction products from reservoir B were diluted
with MeCN and analysed by GC–MS, whereby no acetal
formation was detected. Having confirmed that the reaction
was due to the catalytic activity of the Amberlyst-15 1, we
went on to investigate generality of the technique, preparing
dimethyl acetals 5–13 (Table 2). In all cases, no measurable
by-products were observed by GC–MS or NMR
spectroscopy.
Again, using the experimental set-up illustrated in Figure 3,
unfunctionalised polystyrene beads (2% cross-linked with
divinylbenzene) were packed into the device. A mixture of
benzaldehyde 3 and trimethylorthoformate 4 (40 ml, 1.0 and
2.5 M, respectively) in MeCN was placed in reservoir A
and MeCN in reservoir B (40 ml). Application of 100 and
Table 2. Summary of the conversions obtained for the synthesis of dimethyl acetals 2,5–13
Product
Flow rate (ml minK1
)
Conversiona (%)
RSD (%)
0.13
Yield (%)
96.6
1.75
99.77
2
5
6
1.00
1.60
2.00
1.40
99.92
99.78
99.64
99.83
0.22
0.15
0.90
0.26
96.8
98.0
97.5
95.2
7
8
0.60
99.86
0.08
95.3
9
0.35
2.00
99.70
99.88
0.15
0.93
98.13
97.5
10
11
0.50
99.84
99.65
0.24
0.29
98.4
95.4
12
13
1.30
a R15 replicates were performed for each compound.

C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
5213
Table 4. Summary of the conversions obtained for the synthesis of dimethyl
acetals using polymer supported p-toluenesulfonic acid 15
2.2. Other supported acid catalysts
Having demonstrated the successful incorporation of
Amberlyst 15 1 into an EOF-based miniaturised flow
reactor, the investigation was extended to the use of
ytterbium (III) polystyrylsulfonate 14 and polymer
supported p-toluenesulfonic acid 15.
Product
Flow rate
(ml minK1
Conversiona RSD (%)
(%)
Yield (%)
)
2
5
6
7
8
9
10
11
12
13
1.10
0.30
1.40
0.79
1.00
0.70
0.60
5.00
1.00
1.70
99.80
99.86
99.85
99.93
99.77
99.74
99.64
99.87
99.85
99.70
0.20
0.27
0.19
0.21
0.21
0.12
0.25
0.17
0.15
0.11
96.8
96.0
97.6
95.9
98.3
95.8
95.7
97.8
94.9
98.5
Using the aforementioned methodology, 2.5 mg of
ytterbium (III) polystyrylsulfonate 14 (2.0!10K3 mmol)
was packed into a micro fabricated device. Again, a solution
of benzaldehyde 3 and trimethylorthoformate 4 (40 ml, 1.0
and 2.5 M, respectively) in MeCN was placed in reservoir A
and MeCN in reservoir B (40 ml). Application of 333 and
0 V cmK1 respectively, resulted in mobilisation of the
reaction mixture at 0.40 ml minK1 (Table 3). After 10 min,
the reaction products were collected, diluted with MeCN
and analysed by GC–MS; whereby 99.7% conversion to
dimethoxymethyl benzene 2 was observed. The reaction
was repeated a further 14 times, whereby 0.010 g (94.7%) of
dimethoxymethyl benzene 2 was obtained. Due to the
slower flow rate observed with catalyst 14 cf. Amberlyst-15
1, less product is prepared over the same period of time
(0.010 g cf. 0.025 g) however the catalyst is recycled O32
times. The catalyst was subsequently evaluated for the
synthesis of dimethyl acetals 2, 5–13 whereby conversions
of greater than 99.7% and yields greater than 94.9% were
obtained (Table 3).
a R15 replicates were performed for each compound.
acetals with no detectable epimerisation compared to 20%
when aqueous HCl was employed. With this in mind, the
investigation was extended to the deacetalisation of a series
of dimethyl acetals to afford their respective aldehyde in the
presence of Amberlyst-15 1.
In order to investigate the deacetalisation, a solution of
dimethoxymethyl benzene 2 (40 ml, 1.0 M) in MeCN was
placed in reservoir A and MeCN in reservoir B (40 ml).
Application of 167 and 0 V cmK1 respectively, resulted in
mobilisation of the reaction mixture through the packed-bed
at 0.40 ml minK1 (Table 5). After 10 min the reaction
products were collected, diluted with MeCN and analysed
by GC–MS; whereby 100% conversion to benzaldehyde 3
was observed with respect to residual dimethoxymethyl
benzene 2. The reaction was repeated a further 14 times,
whereby 0.011 g (94.8%) of benzaldehyde 3 was obtained.
The procedure was subsequently repeated for the remaining
nine dimethyl acetals, affording the respective aldehydes in
greater than 99.7% conversion and 94.8% yield (Table 5).
Table 3. Summary of the conversions obtained for the synthesis of dimethyl
acetals using ytterbium (III) polystyrylsulfonate resin 14
Product
Flow rate
(ml min-1)
Conversiona RSD (%)
(%)
Yield (%)
2
5
6
7
8
9
10
11
12
13
0.40
0.40
0.28
0.52
0.40
0.40
0.70
0.55
0.95
0.90
99.72
99.96
99.97
99.92
99.87
99.72
99.88
99.83
99.83
99.64
0.13
0.06
0.08
0.05
0.15
0.06
0.03
0.08
0.12
0.14
94.7
98.8
96.3
96.8
97.7
97.2
98.7
95.5
98.6
96.1
In addition to demonstrating the deacetalisation of acetals 2,
5–13, we extended the investigation to look at the in situ
regeneration of volatile reagents (Scheme 4). Using
commercially available bromoacetaldehyde dimethyl acetal
25, the synthesis of bromoacetaldehyde 26 was investigated
using Amberlyst-15 1 in an EOF-based flow reactor.
Bromoacetaldehyde dimethyl acetal 25 (40 ml, 1.0 M) in
MeCN was placed in reservoir A and MeCN (40 ml)
in reservoir B. Application of 167 V cmK1 resulted in
mobilisation of bromoacetaldehyde dimethyl acetal 25 at a
flow rate of 0.25 ml minK1. After 10 min, the reaction
mixture was analysed by GC–MS, whereby 100% conver-
sion of dimethyl acetal 25 to bromoacetaldehyde 26 was
obtained. Compared to the standard batch approach, this
technique is advantageous as it enables us to regenerate
what is a volatile compound at the point of use, therefore
enabling more efficient reactions to be performed.
a R15 replicates were performed for each compound.
Finally, polymer-supported p-toluenesulfonic acid 15
(2.5 mg, 5.3!10K3 mmol) was evaluated, whereby again
conversions of greater than 99.7% with respect to residual
aldehyde were obtained for dimethyl acetals 2, 5 and 13
(Table 4).
2.3. Deacetalisation
One of the most important aspects of protecting a functional
group is the ability to cleanly and efficiently remove it
without affecting other moieties within the molecule. As
previously mentioned, the hydrolysis of acetals, to afford
their respective carbonyl derivative, is promoted in the
presence of aqueous acids such as hydrochloric,28 sulfuric,29
acetic30 and p-toluenesulfonic acid.31 However, more
recently, supported acids such as Amberlyst-15 1 have
been reported as efficient catalysts for the transformation
whereby excellent yields were obtained.32 In addition,
Amberlyst-15 1 has been shown to hydrolyse isomerisable
3. Conclusions
Compared to standard batch techniques, the approach
described herein, is advantageous as supported reagents
can be recycled without the need for filtration, resulting in
more consistent results between reactions. Also, the absence
of stirring or shaking greatly reduces mechanical degra-
dation of the reagent, enabling the catalyst to be employed

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C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
Table 5. Summary of the conversions obtained for the deacetalisation of dimethyl acetals 2, 5–13 and 25 using Amberlyst-15 1
Product
Flow rate (ml minK1
)
Conversiona (%)
RSD (%)
0.00
Yield (%)
94.8
0.50
100.0
3
1.00
0.65
0.80
0.80
99.85
100.0
99.93
99.71
0.10
0.00
0.03
0.08
99.5
99.3
99.0
97.2
16
17
18
19
0.50
99.81
0.01
98.6
20
0.30
0.53
99.93
100.0
0.03
0.00
99.6
99.7
21
22
0.50
99.85
0.19
97.7
23
0.55
0.25
99.99
100.0
0.02
0.00
98.5
—
24
26
a R15 replicates were performed for each compound.
for longer. In addition, the formation of localised concen-
tration gradients enable reactions to be driven to completion
without the need to employ large quantities of supported
catalyst (typically !2.5 mg is used). Consequently, reac-
tion conditions can be optimised rapidly enabling small
quantities of analytically pure compounds to be prepared in
min; alternatively, larger quantities of materials can be
Scheme 4. Synthesis of bromoacetaldehyde 26 using A-15 1.

C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
5215
synthesised by simply operating numerous reactors in
parallel.33 Applying 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 evaluated.
analysed by NMR spectroscopy. In some cases, the products
were subjected to elemental analysis.
4.1.1. Dimethoxymethyl benzene 2.34 (0.025 g, 96.6%) as
a pale yellow oil; dH (400 MHz, CDCl3) 3.33 (6H, s, 2!
OCH3), 5.40 (1H, s, CH), 7.37 (3H, m, 3!Ar) and 7.45 (2H,
m, 2!Ar); dC (100 MHz, CDCl3) 52.7 (OCH3), 103.2 (CH),
126.7 (2!CH), 128.2 (2!CH), 128.5 (CH) and 134.5 (C0);
153 (MCC1, 2%), 152 (3), 151 (5), 122 (10), 121 (100), 77
(30) and 51 (10); GC–MS retention time RTZ8.03 min.
4. Experimental
All solvents were purchased as puriss grade (R99.5%) over
molecular sieves (H2O!0.005%) from Fluka and unless
otherwise stated reagents purchased from Sigma-Aldrich
and Lancaster were used as received. Ytterbium (III)
polystyrylsulfonate resin 14 (0.8 mmol gK1) was purchased
from Novabiochem. Ytterbium (III) polystyryl sulfonate
resin 14, polymer bound p-toluenesulfonic acid 15
(2.0 mmol gK1) and Amberlyst-15 1 (4.2 mmol gK1) were
ground and sieved (Endcotts) to afford 38 and 75 mm
particles. 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 chemicals shifts given in parts
per million (ppm) with coupling constants given in Hertz
(Hz). The following abbreviations are used to report NMR
data; sZsinglet, dZ doublet, tZtriplet, br sZbroad singlet,
mZmultiplet and C0Zquaternary carbon. Elemental
analyses were performed using a Fisons Carlo Erba
EA1108 CHN analyser. Gas Chromatography–mass spec-
trometry (GC–MS) was performed using a Varian GC (CP-
3800) coupled to a Varian MS (Saturn 2000) with a CP-Sil 8
(30 m) column (Zebron ZB-5, Phenomenex) and ultra high
purity helium (99.999%, Energas) carrier gas. Samples were
analysed using the following method; injector temperature
250 8C, helium flow rate 1.0 ml minK1, oven temperature
4.1.2. 1-Bromo-4-dimethoxymethyl benzene 5.35
(0.034 g, 96.8%) as a colourless oil; dH (400 MHz,
CDCl3) 3.49 (6H, s, 2!OCH3), 5.30 (1H, s, CH), 7.69
(2H, d, JZ8.7 Hz, 2!Ar) and 7.76 (2H, d, JZ8.7 Hz, 2!
Ar); dC (100 MHz, CDCl3) 50.9 (2!OCH3), 102.3 (CH),
129.8 (C0Br), 131.0 (2!CH), 132.5 (2!CH) and 135.1
(C0); 232 (MCC1, 5%), 201 (100), 200 (90) and 77 (15);
GC–MS retention time RTZ8.78 min.
4.1.3. 1-Chloro-4-dimethoxymethyl benzene 6.35
(0.044 g, 98.0%) as a pale yellow oil; dH (400 MHz,
CDCl3) 3.31 (6H, s, 2!OCH3), 5.37 (1H, s, CH), 7.34 (2H,
d, JZ8.7 Hz, 2!Ar) and 7.40 (2H, d, JZ8.7 Hz, 2!Ar);
dC (100 MHz, CDCl3) 52.6 (2!OCH3), 102.3 (CH), 128.2
(2!CH), 129.5 (2!CH), 134.3 (C0Cl) and 136.7 (C0); 187
(MCC1, 2%), 185 (3), 157 (30), 165 (20), 155 (100) and 75
(20); GC–MS retention time RTZ9.05 min.
4.1.4. 1-Cyano-4-dimethoxymethyl benzene 7. (0.042 g,
97.5%) as a pale yellow oil (Found C, 68.00; H, 6.11; N,
7.88. C10H11O2N requires C, 67.78; H, 6.26; N, 7.90%); dH
(400 MHz, CDCl3) 3.33 (6H, s, 2!OCH3), 5.45 (1H, s,
CH), 7.58 (2H, d, JZ8.3 Hz, 2!Ar) and 7.67 (2H, d, JZ
8.3 Hz, 2!Ar); dC (100 MHz, CDCl3) 52.7 (2!OCH3),
101.8 (CH), 117.7 (CN), 118.7 (C0CN), 127.6 (2!CH),
132.1 (2!CH) and 143.2 (C0); 178 (MCC1, 2%), 177 (2),
176 (5), 146 (100) and 75 (10); GC–MS retention time RTZ
9.66 min.
50 8C for 4 min and then ramped to 270 8C at 30 8C minK1
,
with a 3.0 min filament delay.
4.1. Micro-scale methodology
The reactions described herein were carried out using a
single capillary device, as illustrated in Figure 3, with
dimensions of 500 mm (i.d.)!3.0 cm (length). To hold the
polymer-supported reagent in place, micro porous silica frits
were placed at either end of the capillary.26 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 achieved using devices of
different capillary 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 10 min, after, which the contents
of the product reservoir was analysed by GC–MS.
Comparison of the amount of product with respect to
residual aldehyde enabled the percentage conversion to be
determined. In order to obtain NMR data of the compounds
synthesised in the flow system, the reactor was operated
continuously for 2.5–3.5 h (depending on the observed flow
rate). After, which the reaction products were collected,
concentrated in vacuo, dissolved in CDCl3/TMS and
4.1.5. 2-Dimethoxymethyl naphthalene 8. (0.080 g,
95.2%) as a pale yellow oil (Found C, 77.21; H, 7.16;
C13H14O2 requires C, 77.20; H, 6.98%); dH (400 MHz,
CDCl3) 3.37 (6H, s, 2!OCH3), 5.56 (1H, s, CH), 7.50 (2H,
m, 2!Ar), 7.61 (2H, m, 2!Ar), 7.94 (2H, m, 2!Ar) and
8.34 (1H, m, Ar); dC (100 MHz, CDCl3) 52.8 (2!OCH3),
103.2 (CH), 124.4 (CH), 126.1 (2!CH), 126.2 (CH), 127.7
(CH), 128.1 (CH), 128.3 (CH), 133.4 (C0), 133.5 (C0) and
135.5 (C0); 203 (MCC1, 3%), 201 (5), 172 (20), 171 (100),
126 (5) and 75 (10); GC–MS retention time RTZ10.70 min.
4.1.6. 4-Dimethoxymethylbenzoic acid methyl ester 9.36
(0.018 g, 95.3%) as a pale yellow oil; dH (400 MHz, CDCl3)
3.33 (6H, s, 2!OCH3), 3.90 (3H, s, OCH3), 5.44 (1H, s,
CH), 7.53 (2H, d, JZ8.3 Hz, 2!ArH) and 8.05 (2H, d, JZ
8.3 Hz, 2!ArH); dC (100 MHz, CDCl3) 52.2 (COOCH3),
52.7 (2!OCH3), 102.4 (CH), 126.8 (2!Ar), 129.5 (2!
Ar), 130.2 (C0), 143.0 (C0COOCH3) and 166.9 (CO); 211
(MCC1, 2%) 210 (1), 179 (100) and 77 (5); GC–MS
retention time RTZ10.21 min.
4.1.7. 1-Benzyloxy-4-dimethoxymethyl benzene 10.
(0.200 g, 98.1%) as a pale yellow oil (Found C, 74.32; H,

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C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217
7.23; C16H18O3 requires C, 74.40; H, 7.02%); dH (400 MHz,
CDCl3) 3.31 (6H, 2!OCH3), 5.06 (2H, s, OCH2), 5.14 (1H,
s, CH), 7.07 (2H, d, JZ8.7 Hz, 2!Ar), 7.39 (5H, m, 5!Ar)
and 7.83 (2H, d, JZ8.7 Hz, 2!Ar); dC (100 MHz, CDCl3)
52.6 (2!OCH3), 70.3 (OCH2), 103.1 (CH), 114.5 (2!CH),
127.9 (2!CH), 128.6 (2!CH), 128.7 (2!CH), 136.9 (C0),
158.9 (C0O); 259 (MCC1, 1%), 258 (2), 257 (3), 228 (25),
227 (100), 91 (5) and 75 (15); GC–MS retention time RTZ
12.48 min.
4.1.15. 2-Naphthaldehyde 19. (0.018 g, 97.2%) as a white
solid; 157 (MCC1, 25%), 156 (75), 155 (100), 128 (10),
127 (15), 126 (20) and 102 (5); GC–MS retention time RTZ
10.16 min.
4.1.16. Methyl-4-formylbenzoate 20. (0.012 g, 98.6%) as a
pale orange solid; 165 (MCC1, 50%), 164 (55), 163 (50),
133 (100), 105 (25) and 77 (10); GC–MS retention time
RTZ9.46 min.
4.1.8. 2-Dimethoxymethyl-5-nitrothiophene 11.35
(0.039 g, 97.5%) as a pale yellow oil; dH (400 MHz,
CDCl3) 3.50 (6H, s, 2!OCH3), 5.61 (1H, s, CH), 7.71 (1H,
d, JZ4.2 Hz, Ar) and 7.97 (1H, d, JZ4.2 Hz, Ar); dC
(100 MHz, CDCl3) 52.7 (2!OCH3), 98.8 (CH), 124.5
(CH), 128.4 (CH), 149.8 (C0) and 151.2 (C0NO2); 203 (MC,
1%), 202 (5), 187 (10), 172 (100), 157 (10), 142 (10), 97 (5)
and 75 (%); GC–MS retention time RTZ10.23 min.
4.1.17. 4-Benzyloxybenzaldehyde 21. (0.013 g, 99.6%) as
a white solid; 213 (MCC1, 100%), 212 (74), 107 (10) and
91 (25); GC–MS retention time RTZ11.98 min.
4.1.18. 5-Nitro-2-thiophenecarboxaldehyde 22. (0.017 g,
99.7%) as a pale yellow solid; 158 (MCC1, 75%), 157 (70),
156 (80), 141 (100), 127 (25), 112 (20), 99 (45), 98 (50), 71
(40) and 55 (25); GC–MS retention time RTZ9.38 min.
4.1.9. 1-Dimethoxymethyl-3,5-dimethoxybenzene 12.
(0.030 g, 98.4%) as a colourless oil (Found C, 62.52; H,
7.41. C11H16O4 requires C, 62.25; H, 7.60%); dH (400 MHz,
CDCl3) 3.34 (6H, s, 2!OCH3), 3.80 (6H, s, 2!OCH3),
5.30 (1H, s, CH), 6.43 (1H, t, JZ2.2 Hz, 2!Ar) and 6.62
(2H, d, JZ2.2 Hz, 2!Ar); dC (100 MHz, CDCl3) 52.9 (2!
OCH3), 55.4 (2!OCH3), 100.8 (CH), 103.1 (CH), 104.5
(2!CH), 140.5 (C0) and 160.7 (2!C0OCH3); 213 (MCC
1, 5%), 212 (20), 182 (100), 134 (5) and 75 (5); GC–MS
retention time RTZ10.32 min.
4.1.19. 3,5-Dimethoxybenzaldehyde 23. (0.015 g, 97.7%)
as a white solid; 167 (MCC1, 25%), 166 (100), 135 (25), 79
(10) and 64 (15); GC–MS retention time RTZ9.75 min.
4.1.20. trans-Cinnamaldehyde 24. (0.010 g, 98.5%) as a
yellow oil; 133 (MCC1, 10%), 132 (40), 131 (100), 103
(55), 77 (45) and 50 (25); GC–MS retention time RTZ
8.98 min.
4.1.21. Bromoacetaldehyde 26. 125 (MCC1, 5%), 124
(4), 123 (7), 96 (100), 95 (25), 94 (100), 81 (25), 80 (2), 79
(25), 42 (30); GC–MS retention time RTZ2.69 min.
4.1.10. 3,3-Dimethoxypropenyl benzene 13.36 (0.022 g,
95.4%) as a yellow oil; dH (400 MHz, CDCl3) 3.38 (6H, s,
2!OCH3), 4.96 (1H, d, JZ4.9 Hz, CH), 6.16 (1H, dd, JZ
4.9, 16.0 Hz, CHCH(OCH3)2), 6.72 (1H, d, JZ16.0 Hz, Ar)
7.30 (2H, m, 2!Ar), 7.43 (2H, m, 2!Ar) and 7.57 (1H, m,
Ar); dC (100 MHz, CDCl3) 52.8 (2!OCH3), 102.9 (CH),
126.8 (2!CH), 128.5 (2!CH), 129.1 (CH) and 133.6 (C0);
179 (MCC1, 3%), 178 (20), 177 (15), 147 (100), 115 (10)
and 77 (5); GC–MS retention time RTZ9.56 min.
Acknowledgements
We gratefully acknowledge the financial support of the
EPSRC (C.W.) (Grant No. GR/S34106/01). Mike Bailey
(The University of Hull) is also acknowledged for his
assistance in the device fabrication.
The purity of aldehydes 3, 16–24 synthesized in the
miniaturized flow reactor was determined based on the
comparison of GC–MS data with that obtained for
commercially available standards.
References and notes
4.1.11. Benzaldehyde 3. (0.011 g, 94.8%) as a colourless
solid; 107 (MCC1, 20%), 106 (15), 105 (100), 77 (25) and
51 (20); GC–MS retention time RTZ6.87 min.
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time RTZ8.85 min.

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