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

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 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 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 solidsupported 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 counterparts, one main limitation is the support degradation that occurs as a result of stirring or shaking. Therefore by Keywords: Acetals; Micro reactor; Deprotection. * Corresponding author. Tel.: C44 1482 465471; fax: C44 1482 466416; e-mail: [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.03.082

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 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. 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-toluenesulfonic acid are generally used, other catalysts include ferric chloride,8 ammonium nitrate9 rhodium(III) complexes10 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-supported 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

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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. 1.2. 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, consisting 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 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.

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.

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

Equation 1. Determination of electroosmotic flow (EOF) velocity.24

C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217

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 fabricated devices, we are able to conduct reactions that otherwise could not be performed efficiently within EOFbased devices.

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.

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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.

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

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

Figure 3. Schematic of the reaction set-up used for the evaluation of the polymer-supported acid catalysts.

Run No.

Conversion (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 MeanZ99.8%, % RSDZ0.13

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

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 EOFbased 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-

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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. 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

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.

Table 2. Summary of the conversions obtained for the synthesis of dimethyl acetals 2,5–13 Product

Flow rate (ml minK1)

Conversiona (%)

RSD (%)

Yield (%)

1.75

99.77

0.13

96.6

1.00

99.92

0.22

96.8

1.60

99.78

0.15

98.0

2.00

99.64

0.90

97.5

1.40

99.83

0.26

95.2

0.60

99.86

0.08

95.3

0.35

99.70

0.15

98.13

2.00

99.88

0.93

97.5

0.50

99.84

0.24

98.4

1.30

99.65

0.29

95.4

2

5

6

7

8

9

10

11

12

13 a

R15 replicates were performed for each compound.

C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217

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2.2. Other supported acid catalysts

Table 4. Summary of the conversions obtained for the synthesis of dimethyl acetals using polymer supported p-toluenesulfonic acid 15

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). 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

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

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). 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% conversion 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.

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 degradation of the reagent, enabling the catalyst to be employed

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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 (%)

Yield (%)

0.50

100.0

0.00

94.8

1.00

99.85

0.10

99.5

0.65

100.0

0.00

99.3

0.80

99.93

0.03

99.0

0.80

99.71

0.08

97.2

0.50

99.81

0.01

98.6

0.30

99.93

0.03

99.6

0.53

100.0

0.00

99.7

0.50

99.85

0.19

97.7

0.55

99.99

0.02

98.5

0.25

100.0

0.00

—

3

16

17

18

19

20

21

22

23

24

26 a

R15 replicates were performed for each compound.

Scheme 4. Synthesis of bromoacetaldehyde 26 using A-15 1.

for longer. In addition, the formation of localised concentration 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, reaction conditions can be optimised rapidly enabling small quantities of analytically pure compounds to be prepared in min; alternatively, larger quantities of materials can be

C. Wiles et al. / Tetrahedron 61 (2005) 5209–5217

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. 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 spectrometry (GC–MS) was performed using a Varian GC (CP3800) 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 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

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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. 4.1.2. 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. 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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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. 4.1.8. 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. 4.1.9. 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. 36

4.1.10. 3,3-Dimethoxypropenyl benzene 13. (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. 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.

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. 4.1.17. 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. 4.1.19. 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.

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.

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. 4.1.12. 4-Bromobenzaldehyde 16. (0.027 g, 99.5%) as a white solid; 186 (MCC1, 20%), 185 (100), 184 (75), 157 (15), 155 (15), 77 (20) and 50 (25); GC–MS retention time RTZ9.51 min. 4.1.13. 4-Chlorobenzaldehyde 17. (0.014 g, 99.3%) as a white solid; 142 (MCC1, 20%), 141 (98), 140 (50), 139 (100), 110 (10) and 77 (10); GC–MS retention time RTZ 8.18 min. 4.1.14. 4-Cyanobenzaldehyde 18. (0.015 g, 99.0%) as a colourless solid; 132 (MCC1, 15%), 131 (20), 130 (100), 103 (7), 102 (45), 76 (20) and 50 (20); GC–MS retention time RTZ8.85 min.

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