in THF; and (ii) 11.6 M aqueous solution of MeNH
2
(69 mL; 800
Springer-Verlag: Berlin, Heidelburg, 2007; (c) A. Kirschning, W.
Solodenko and K. Mennecke, Chem.–Eur. J., 2006, 12, 5972–5990;
mmol). Each solution was loaded individually into the Vapourtec
R Series flow system using the two pumps R2+ system. The
solutions were first pumped in, then merged into a T-connector
and finally directed into the R4 flow reactor (10 mL, 1 mm i.d.)
(
d) I. R. Baxendale and M. R. Pitts, Chimica Oggi, 2006, 24, 41–45;
e) C. Oliver Kappe, A. Stadler, Microwaves in organic and medicinal
(
chemistryWiley-VCH, 2005.
2 (a) Organic chemistry in Microreactors, ed. T. Wirth, Wiley-VCH, 2008;
(b) T. Fukuyama, T. Rahman, M. Sato and I. Ryu, Synlett, 2008, 151–
◦
◦
heated at 80 C(when iodo-alcohol 3 used) or 140 C (when chloro-
alcohol 2 used), flowing at a residence time of 10 min (solution
1
63; (c) P. S. Dittrich and A. Manz, Nature, 2006, 5, 210–218.
3
J. P. McMullen, M. T. Stone and K. F. Jensen, Angew. Chem., Int. Ed.,
2010, 49, 7076–7080.
-
1
(
i) flow rate at 1 equiv. = 279 mL min ; and solution (ii) flow rate
1
-
4 B. Ahmed-Omer, D. A. Barrow and T. Wirth, Arkivoc, 2011 in press.
at 50 equiv. = 721 mL min ). The collected crude mixture was
5
(a) T. Razzaq, T. N. Glasnov and C. O. Kappe, Eur. J. Org. Chem., 2009,
321–1325; (b) C. B. McPake, C. B. Murray and G. Sandford, Tetrahe-
then concentrated under vacuum, to remove the excess MeNH
then purified using the catch-and-release purification technique.
2
,
1
22
dron Lett., 2009, 50, 1674–1676; (c) M. Baumann, I. R. Baxendale and
S. V. Ley, Synlett, 2008, 14, 2111–2114; (d) T. Gustafsson, F. Pont e´ n and
P. H. Seeberger, Chem. Commun., 2008, 1100–1102; (e) M. Baumann,
I. R. Baxendale, S. V. Ley, N. Nikbin and C. D. Smith, Org. Biomol.
Chem., 2008, 6, 1587–1593; (f) C. Wiles and P. Watts, Eur. J. Org. Chem.,
2008, 1655–1671; (g) B. Ahmed-Omer, J. C. Brandt and T. Wirth, Org.
Biomol. Chem., 2007, 5, 733–740.
C. C. Lee, G. D. Sui, A. Elizarov, C. Y. J. Shu, Y. S. Shin, A. N. Dooley,
J. Huang, A. Daridon, P. Wyatt, D. Stout, H. C. Kolb, O. N. Witte, N.
Satyamurthy, J. R. Heath, M. E. Phelps, S. R. Quake and H.-R. Tseng,
Science, 2005, 310, 1793–1796.
The crude was poured over a flash SCX-2 column and washed
with MeOH (150 mL) followed by 7 M solution of ammonia in
MeOH (150 mL) to release the desired secondary amine product.
The obtained material was concentrated under vacuum to afford
the amino-alcohol 4 (2.53 g; 95% yield (from 2)) and (2.4 g; 89%
6
7
yield (from 3)) as colourless oil. Retention time = 1.42 min, M + H
1
m/z = 166.20 (High pH). H NMR (400 MHz, CDCl
3
): d (ppm)
7
.4–7.2 (5H, m), 4.9 (1H, dd, J = 3.0, 8.3 Hz), 4.3 (2H, s), 2.9–2.7
I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer,
Synlett, 2005, 427–430.
8 I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby
(
2H, m), 2.4 (3H, s), 1.9 –1.7 (2H, m).
10
Preparation of (±)-fluoxetine (5) in flow. The following solu-
tions were prepared: (i) 1.1 M solution of the amino-alcohol 4 (1 g;
and G. K. Tranmer, Chem. Commun., 2006, 2566–2568.
9
D. T. Wong, K. W. Perry and F. P. Bymaster, Nature Mater., 2005, 4,
5
.9 mmol) in DCM; (ii) 1 M solution of p-hydroxybenzotrifluoride
764–774.
1
1
1
1
0 E. J. Corey and G. A. Reichard, Tetrahedron Lett., 1989, 30, 5207–5210.
1 Presearch Ltd, Kingsland Business Park, Basingstoke, RG24 8PZ.
2 Vapourtec Ltd, Place Farm, Ingham, Suffolk, IP31 1NQ, UK.
7
(1.1 g; 6.68 mmol) in a mixture of DCM : dimethylacetamide
(
4 : 1) ; (iii) 1.6 M solution of PBu
3
(4.5 mL; 18 mmol) in DCM;
(
iv) 3 M solution of DIAD (3.6 mL; 18 mmol) in DCM. Each
3 Flask conditions: NaBH
yield).
4
(1.2 eq.), THF-water (14 : 1), r.t., 12 h, (85%
solution was loaded individually into the Vapourtec R Series
flow system in the required addition order (Fig. 7) using the
four-pump modification of the Vapourtec R Series system. The
solutions were mixed using a T-connector then directed into the
1
4 R. Silvestri, M. Artico, G. L. Regina, A. D. Pasquali, G. D. Martino,
F. D. D’Auria, L. Nencioni and A. T. Palamara, J. Med. Chem., 2004,
4
7, 3924–3926.
15 (a) U. T. Bornschauer, R. J. Kazlauskas, Hydrolases in Organic
Synthesis: Regio- and Stereoselective BiotransformationsWiley-VCH,
Weinheim-New York, 2006; (b) A. Ghanem and H. Y. Aboul-Enein,
Chirality, 2005, 17, 1–15; (c) K. Faber, Biotransformations in Organic
Chemistry, 4th ed., Springer, Berlin, 2004; (d) L. Poppe, L. Nov a´ k,
Selective Biocatalysis: A Synthetic Approach, Wiley-VCH, Weinheim-
New York, 1992.
◦
R4 flow reactor (2 mL, 1 mm i.d) heated at 70 C, flowing at
a residence time of 5 min (solution (i) flow rate at 1 equiv. =
-
1
-1
7
6 mL min , solution (ii) flow rate at 1.1 equiv. = 84 mL min ; and
-
1
solution (iii) flow rate at 3 equiv. = 157 mL min , (iv) flow rate
-
1
at 3 equiv. = 84 mL min ). The collected crude mixture was then
concentrated under vacuum followed by dilution with diethyl ether
and slow addition of hexane (30 mL) while stirring until the cloud
point was reached. The precipitated tributylphosphine oxide was
then removed by filtration then the filtrate was concentrated and
purified by chromatography using 10% DCM in MeOH to afford
the (±)-fluoxetine 5 (1.6 g; 86%) as a pale yellow oil. Retention
1
6 (a) K. Koch, R. J. F van den Berg, P. J. Nieuwland, R. Wijtmans,
H. E. Schoemaker, J. C. M. Van Hest and F. P. J. T. Rutjes, Biotechnol.
Bioeng., 2008, 99, 1028–1033; (b) A. Liese, K. Seelbach, C. Wandrey,
Industrial Biotransformations, 2nd ed., Wiley-VCH, Weinheim, 2006;
(
c) A. Sanchez, F. Valero, J. Laufente and C. Sola, Enzyme Microb.
Technol., 2000, 27, 157–166; (d) R. N. Patel, A. Banerjee and L. J.
Szarka, J. Am. Oil Chem. Soc., 1996, 73, 1363–1375.
17 C. Csaj a´ gi, G. Szatzker, E. R. T o˝ ke, L. U¨ rge, F. Darvas and L. Poppe,
1
Tetrahedron: Asymmetry, 2008, 19, 237–246.
time = 0.98 min, M + H m/z = 310.20. H NMR (400 MHz,
ˆ
1
8 (a) A. A. M. Lapis, A. de F a´ tima, J. E. D. Martins, V. E. U. Costa and
CDCl
3
): d (ppm) 7.4 (2H, d, J = 8.3 Hz), 7.3 –7.2 (5H, m), 6.9
R. A. Pilli, Tetrahedron Lett., 2005, 46, 495–498; (b) C. E. Garrett, K.
Prasad, O. Repi cˇ and T. J. Blacklock, Tetrahedron: Asymmetry, 2002,
13, 1347–1349.
(
2H, d, J = 8.3 Hz), 5.3 (1H, dd, J = 4.8, 7.8 Hz), 2.7 (2H, t, J =
6
.8 Hz), 2.4 (3H, s), 2.2–2.1 (1H, m), 2.0–1.9 (1H, m).
1
9 D. W. Robertson, J. H. Krushinski, R. W. Fuller and J. D. Leander,
J. Med. Chem., 1988, 31, 1412–1417.
20 Flask conditions: NaI (2.0 eq.), acetone, reflux, 16 h, (91% yield).
Acknowledgements
2
1 A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844–
4845.
2 (a) T. Wirth, D. Barrow and B. Ahmed, Adv. Synth. Catal., 2006, 348,
1
The authors would like to dedicate their special thanks to Andrew
C. Williams, Andrew Faller, Andrew J. Ledgard of Eli Lilly and
Company including Gary Sherman for the analytical support and
Faye Price for the IT support.
2
1
1
043–1048; (b) A. Gunther and K. F. Jensen, Lab Chip, 2006, 6, 1487–
503; (c) J. D. Tice, H. Song, A. D. Lyon and R. F. Ismagilov, Langmuir,
2003, 19, 9127–9133.
2
3 Silica propylsulfonic acid (SCX-2), capacity of 0.7 mmol/g, commer-
cially available from Biotage, cat. No. 9536–0010.
References
24 Catch-and-release procedure: The crude mixture containing the amino-
alcohol product was passed through a pre-packed column of SCX-2
(capacity of 0.6 mmol(g) to catch the product. The SCX-2 column
was then washed with excess of methanol to remove any unbound
substrates, followed by releasing the amino- product by eluting the
column with a 7 M solution of ammonia in methanol.
1
(a) M. Colombo and I. Peretto, Drug Discovery Today, 2008, 13,
6
77–684; (b) I. R. Baxendale, S. V. Ley, New Avenues to Efficient
Chemical Synthesis: Emerging Technologies Ernst Schering Foundation
Symposium Proceedings, 2006-3, ed. P. H. Seeberger and T. Blume,
This journal is © The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3854–3862 | 3861