This study therefore aids in realising the potential of electroosmotic
flow as a pumping mechanism for the production of fine chemicals
and pharmaceuticals. Further development of such parallel
reaction systems is however required in order to synthesise the
quantities of material required for large-scale production.
Employing the aforementioned technology, 15 THP ethers were
synthesised in near quantitative yield and excellent purity, without
competing DHP 1 polymerisation (which is frequently observed in
batch reactions), along with quantitative depyranylation when
MeOH was used as the reaction solvent.
Table 2 Summary of the results obtained for the deprotection of
THP ethers under continuous flow (single channel, residence time =
20 s)
Flow rate/
ml min21
Alcohol
Conv. (%)
Yielda/g
Benzyl alcohol
Butan-1-ol
Hexan-1-ol
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
0.0241 (99.2)
N/Ab
0.0229 (99.6)
0.0292 (99.7)
0.0355 (99.7)
0.0223 (99.1)
0.0256 (99.6)
0.0274 (99.6)
0.0420 (99.8)
0.0319 (99.4)
0.0276 (99.6)
0.0301 (99.7)
0.0322 (99.4)
0.0414 (99.9)
0.0210 (99.2)
Octan-1-ol
Decyl alcohol
Cyclohexanol
Methylcyclohexanol
1-Phenylethanol
4-Bromobenzyl alcohol
4-Chlorobenzyl alcohol
4-Aminobenzyl alcohol
3-Phenylprop-2-en-1-ol
2-Naphthol
In addition, through the incorporation of supported catalysts
into such miniaturised packed-beds, efficient catalyst recycle is
achieved without the need to filter, wash and recover catalytic
material between reactions. Based on the investigation presented
herein, the silica-supported sulfonic acid derivative 2 afforded a
turn over in excess of 2760 times, showing no sign of degradation
to date. Furthermore, the system flexibility described enables the
reactor to be employed, as a means of increasing the production
capacity of a micro reaction, whilst also enabling the same reactor
set-up to be used for catalyst or reagent screening; with minimal
reagent or catalyst investment. Further work is currently underway
into ways of increasing throughput of such reactors, along with
their application to more complex reactions systems.
Benzhydrol
Phenol
a
The number in parentheses represents the % isolated yield, after
removal of the reaction solvent in vacuo. Due to volatility of the
resulting alcohol, an isolated yield was not recorded.
b
Table 3 Summary of the results obtained for the synthesis of
2-benzyloxytetrahydropyran 4, using an array of solid-supported acid
catalystsa
Notes and references
Loading/ Flow rate/
mmol g21 ml min21
Supported Lewis acid
Conv. (%)
1 For leading references, see: (a) C. Wiles and P. Watts, Chem. Commun.,
2007, 443; (b) B. Ahmed-Omer, J. C. Brandt and T. Wirth, Org. Biomol.
Chem., 2007, 5, 733; (c) P. W. Miller, N. J. Long, R. Vilar, H. Audrain,
D. Bender, J. Passchier and A. Gee, Angew. Chem., Int. Ed., 2007, 46,
2875; (d) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan and
D. T. McQuade, Chem. Rev., 2007, DOI: 10.1021/cr050944c.
2 (a) R. D. Chambers, M. A. Fox, D. Holling, T. Nakano, T. Okazoe and
G. Sandford, Lab Chip, 2005, 2, 191; (b) Y. Kikutani, A. Hibara,
K. Uchiyama, H. Hisamoto, M. Tokeshi and T. Kitamori, Lab Chip,
2002, 2, 193.
3 C. L. Rice and R. Whitehead, J. Phys. Chem., 1965, 69, 4017.
4 (a) C. Wiles, P. Watts and S. J. Haswell, Tetrahedron, 2005, 61, 5209; (b)
C. Wiles, P. Watts and S. J. Haswell, Tetrahedron Lett., 2006, 47, 5261;
(c) C. Wiles, P. Watts and S. J. Haswell, Chem. Commun., 2007, 9, 966;
(d) C. Wiles, P. Watts and S. J. Haswell, Lab Chip, 2007, 7, 322.
5 J. Hooper and P. Watts, J. Labelled Compd. Radiopharm., 2007,
50, 189.
6 A. Aota, M. Nonaka, A. Hibara and T. Kitamori, Angew. Chem., Int.
Ed., 2007, 46, 878.
7 T. W. Greene and P. G. M. Wutz, Protective Groups in Organic
Synthesis, John Wiley and Sons, Inc., New York, 1991.
8 M. Narender, M. S. Reddy and K. R. Rao, Synthesis, 2004, 1741.
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and R. S. Mohan, Eur. J. Org. Chem., 2003, 3827; (b) G. A. Olah,
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T. Parvin and L. H. Choudhury, Synthesis, 2006, 2497.
10 J.-E. Choi and K.-Y. Ko, Bull. Korean Chem. Soc., 2001, 1177.
11 P. D. Christensen, S. W. P. Johnson, T. McCreedy, V. Skelton and
N. G. Wilson, Anal. Commun., 1998, 35, 341.
Pyridinium
toluene-4-sulfonate
Scandium trifluoromethane 0.60
sulfonate
Amberlyst-15 2
Ytterbium polystyryl
sulfonate
3.50
1.10
1.60
100.0 (0.0)b
99.9
(3.5 6 1024
100.0 (0.0)
99.9
)
)
4.20
2.00
1.80
1.50
(2.6 6 1024
b
a
Alcohol (1.0 M), DHP 1 (1.0 M) and MeCN as solvent. The
number in parentheses represents the % RSD, where n = 15.
Having demonstrated the synthesis of an array of THP ethers in
excellent yield and purity, and their subsequent deprotection, the
next step was to investigate the scale-out of the technique via
parallel synthesis. Again, employing the synthesis of 2-benzyloxy-
tetrahydropyran 4 as the model reaction, all four reaction channels
were operated in parallel, under the previously optimised reaction
conditions (Table 3).
Using this approach, a throughput of 50 mg h21 was obtained,
compared with the 12.5 mg h21 from a single channel reactor. To
ensure reactor stability was maintained over multiple channels, the
reaction products were again monitored regularly by GC-MS,
confirming reproducibility over the entire device (n = 60, % RSD =
5.48 6 1024). In addition to the obvious increase in productivity
achieved using the reaction set-up described, this approach also
provides system flexibility, enabling the optimisation of multiple
reactions in parallel or catalyst screening.
12 W. D. Bossaert, D. E. De Vos, V. M. Van Rhijin, J. Bullen, P. J. Grobert
and P. A. Jacobs, J. Catal., 1999, 182, 156.
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L. Turet and M. Wiaux, Tetrahedron Lett., 1999, 40, 5613; (b)
K. J. Davis, U. T. Bhalrao and B. V. Rao, Synth. Commun., 2000, 30,
2301.
In summary, using the protection of alcohols as a model
reaction we have described a simple, efficient and robust technique
for the scale-out of micro reactions conducted under EOF
conditions, employing solid-supported reagents and catalysts.
15 J. H. Van Boom and J. D. M. Herschied, Synthesis, 1973, 169.
4930 | Chem. Commun., 2007, 4928–4930
This journal is ß The Royal Society of Chemistry 2007