E. Riva et al. / Tetrahedron 66 (2010) 3242–3247
3247
3. (a) Handbook of Grignard Reagents; Silverman, G. S., Rakita, P. E., Eds.; Marcel
Dekker: New York, NY, 1996; (b) Wakefield, B. J. Organomagnesium Methods in
Organic Synthesis; Academic: London, 1995; (c) Grignard Reagents: New De-
velopment; Richey, H. G., Jr., Ed.; Wiley: New York, NY, 1999; Recent literature
on Grignard reagents; (d) Seyferth, D. Organometallics 2009, 28, 1598–1605;
(e) Luderer, M. R.; Bailey, W. F.; Luderer, M. R.; Fair, J. D.; Dancer, R. J.; Sommer,
M. B. Tetrahedron: Asymmetry 2009, 20, 981–998; (f) Harutyunyan, S. R.; den
Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824–
2852; (g) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn,
T.; Sapountzis, I.; Anh Vu, V. Angew. Chem., Int. Ed. 2003, 42, 4302–4320;
(h) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 497–500;
(i) Ackermann, L.; Althammer, A. Chem. Unserer Zeit 2009, 43, 74–83.
4. (a) Panke, G.; Schwalbe, T.; Stirner, W.; Taghavi-Moghadam, S.; Wille, G. Syn-
thesis 2003, 18, 2827–2830; (b) Zhang, X.; Stefanick, S.; Villani, F. J. Org. Process
Res. Dev. 2004, 8, 455–460 The article reports on the addition of (3-methox-
yphenyl)lithium, generated under flow condition, to cylohexanone, as a set up
for Tramadol synthesis.
5. (a) Taghavi-Moghadam, S.; Kleemann, A.; Golbig, G. Org. Proc. Res. Dev. 2001, 5,
652–658; (b) Golbig, K.; Hohmann, M.; Kursawe, A.; Shwalbe, T. Chem. Ing. Tech.
2004, 76, 598–603.
6. Koop, U.; Krummradt, H.; Schwarz, M.; Stoldt, J.; Eckstein, J.; Zehner, S.;
Melichar, W. U.S. Patent 0,004,357, 2003.
7. Yoneda, N.; Oda, Y.; Nakanishi, Y. Int. Pat. Appl. WO 2008/035633, 2008.
8. (a) Roberge, D. M.; Bieler, N.; Mathier, M.; Eyholzer, M.; Zimmermann, B.;
Barthe, P.; Guermeur, C.; Lobet, O.; Moreno, M.; Woehl, P. Chem. Eng. Technol.
2008, 31, 1155–1161; (b) Roberge, D.; Bieler, N.; Ducry, L. Int. Pat. Appl. WO
2008/009378, 2008.
9. (a) Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem., Int. Ed. 2008, 47, 7833–7836;
(b) Nagaki, A.; Tomida, Y.; Usutani, H.; Kim, H.; Takabayashi, N.; Nokami, T.;
Okamoto, H.; Yoshida, J. Chem. Asian J. 2007, 2, 1513–1523.
10. (a) Haswell, S. J.; O’Sullivan, B.; Styring, P. Lab Chip 2001, 1, 164–166; (b) Phan,
N. T. S.; Brown, D. H.; Styring, P. Green Chem. 2004, 6, 526–532; (c) Wakami, H.;
Yoshida, J. Org. Process Res. Dev. 2005, 9, 787–791.
11. R-2 Pump Module and R-4 Reactor Module from Vapourtec Ltd. (www.vapourtec.
12. (a) Anderson, N. G. Org. Process. Res. Dev. 2001, 5, 613–621; (b) Wheeler, R. C.;
Benali, O.; Deal, M.; Farrant, E.; MacDonald, S. J. F.; Warrington, B. H. Org.
Process Res. Dev. 2007, 11, 704–710; (c) Styring, P.; Parracho, A. I. R. Beilstein J.
Org. Chem. 2009, 5. doi:10.3762/bjoc.5.29 No. 29.
13. (1R*,2R*)-2-((Dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol.
14. (a) Von Flick, K.; Frankus, E.; Friderichs, E. Arzneim.-Forsh. 1978, 28, 107–113; (b)
Flick, K.; Frankus, E. U.S. Patent 3,652,589, 1972; (c) Jarvi, E.T.; Grayson, N.A.;
Halvachs, R.E. U.S. Patent 6,399,829, 2002.
ether/AcOEt 9.5/0.5) to obtain 382.1 mg of desired compound as
off-white powder. 91% Yield.
4.5. General procedure for the flow addition of benzyl
magnesium bromide to aldehydes and ketone in the presence
of nitrile
Two solutions of starting materials were prepared and stored at
room temperature under N2 atmosphere. Reagent stock bottle A:
suitable aldehyde or ketone (1 equiv); 200 mg dissolved in dry THF in
order to obtain a 0.25 M solution. Reagent stock bottle B: phenyl-
magnesium bromide (THF solution; 1 equiv); dissolved in dry THF in
order to obtain a 0.25 M solution. The system was primed flowing dry
THF for 30 min. Using the automated injection system, both solutions
were transferred at a constant flow rate (0.8 ml/min) into a PTFE tubing
reactor (reactor volume 10 ml) maintained at room temperature
(residence time 12.5 min). The reactor was connected to a OmnifitÒ
glass column (6.6 mm id) packed with PS-Benzaldehyde (loading
1.09 mmol/g; 1 equiv) to trap unreacted Grignard reagent. After this
purification step, the product was collected in an apposite product
stock bottle. The solvent was evaporated under vacuum and the crude
was partitioned between saturated solution of NH4Cl and DCM. The
organic phase was dried and evaporated and the product was purified
by the product was purified by the suitable reported method.
4.5.1. 4-(Hydroxy(phenyl)methyl)benzonitrile17f (28). Starting mate-
rial: 4-formylbenzonitrile (27); 94% Yield; Off-white solid; Purifica-
tion: flash chromatography (Eluent: Petroleum ether/AcOEt 9.8/0.2).
4.5.2. 3-Hydroxy-3-phenylpropanenitrile18b (30). Starting material:
3-oxopropanenitrile (29); 85% Yield; Colourless oil; Purification:
flash chromatography (Eluent: Petroleum ether/AcOEt 9.9/0.1).
15. A higher ratio was achieved when aryllithium was used instead of the Grignard
reagent at low temperature as reported in Kupper, R.; Stumpf, A. U.S. Patent
200,230,065,221, 2003.
4.5.3. 4-(1-Hydroxy-1-phenylethyl)benzonitrile29 (32). Starting mate-
rial: 4-acetylbenzonitrile (31); 89% Yield; Off-white solid; Purifica-
tion: flash chromatography (Eluent: Petroleum ether/AcOEt 9.5/0.5).
´
16. Alvarado, C.; Guzma´n A; Dı´az, E.; Patin˜o, R. J. Mex. Chem. Soc. 2005, 49, 324–327.
17. (a) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed.
1998, 37, 1701–1703; (b) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 3333–3336; (c) Lee, J.; Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R.; Rieke, R. D.
J. Org. Chem. 2000, 65, 5428–5430; (d) Chen, J.; Zhang, X.; Feng, Q.; Luo, M. J.
Organomet. Chem. 2006, 691, 470–474; (e) Furstner, A.; Brunner, H. Tetrahedron
Lett. 1996, 37, 7009–7012; (f) Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett.
2001, 3, 803–805; (g) Bisogno, F. R.; Lavandera, I.; Kroutil, W.; Gotor, V. J. Org.
Chem. 2009, 74, 1730–1732; (h) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem.,
Int. Ed. 1998, 37, 3279–3281; (i) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J.
Org. Chem. 2005, 70, 2200–2205.
Acknowledgements
The authors gratefully acknowledge Dr. Sergio Menegon for
NMR characterization of products.
References and notes
18. (a) Ciaccio, J. A.; Smrtka, M.; Maio, W. A.; Rucando, D. Tetrahedron Lett. 2004, 45,
7201–7204 and references cited therein; (b) Kamal, A.; Ramesh Khanna, G. B.;
Ramu, R. Tetrahedron: Asymmetry 2002, 13, 2038–2051; (c) Caron, M.; Sharpless,
K. B. J. Org. Chem. 1985, 50, 1557–1560.
19. Kaiser, E. W.; Hauser, C. R. J. Org. Chem. 1967, 89, 4566–4568.
20. Matsukawa, S.; Kitazaki, E. Tetrahedron Lett. 2008, 49, 2982–2984.
21. Bates, R. B.; Beavers, W. A.; Gordon, B., III; Mills, N. S. J. Org. Chem. 1979, 44,
3800–3803.
1. Recent literature on flow chemistry: (a) Baxendale, I. R.; Hayward, J. J.; Ley, S. V.;
Tranmer, G. K. ChemMedChem 2007, 2, 768–788; (b) Baxendale, I. R.; Hayward, J. J.;
Lanners, S.; Ley, S. V.; Smith, C. D., Chapter 4.2 In Microreactors in Organic Synthesis
and Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008; pp 84–122; (c) Hodge,
P. Curr. Opin. Chem. Biol. 2003, 7, 362–373; (d) Jahnisch, K.; Hessel, V.; Lowe, H.;
Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406–446; (e) Kirschning, A.; Solodenko,
W.; Mennecke, K. Chem.dEur. J. 2006, 12, 5972–5990; (f) Ahmed-Omer, B.;
Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 355–359; (g) Glasnov, V. T. N.;
Kappe, C. O. Macromol. Rapid Commun. 2007, 28, 395–410; (h) Benito-Lopez, F.;
Egberink, R. J. M.; Reinhoudt, D. N.; Verboom, W. Tetrahedron 2008, 64, 10023–
10040; (i) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T.
Chem. Rev. 2007, 107, 2300–2318; (j) Jas, G.; Kirshning, A. Chem.dEur. J. 2003, 9,
5708–5723; (k) Geyer, K.; Code´e, J. D. C.; Seeberger, P. H. Chem.dEur. J. 2006, 12,
Geyer, K.; Gustafsson, T.; Seeberger, P. H. Synlett 2009, 2382–2391; (n) Hartman,
R. L.; Jensen, K. F. Lab Chip 2009, 9, 2495–2507.
22. Hatano, M.; Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9, 4535–4538.
`
23. Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651–5666.
24. Comm. available compound: Atlas Sigma Aldrich.
25. Huang, W. S.; Pu, L. J. Org. Chem. 1999, 64, 4222–4223.
26. Froimowitz, M.; Gu, Y.; Dakin, L. A.; Kelley, C. J.; Parrish, D.; Deschamps, J. R.
Bioorg. Med. Chem. Lett. 2005, 15, 3044–3047.
27. Froimowitz, M.; Gu, Y.; Dakin, L. A.; Nagafuji, P. M.; Kelley, C. J.; Parrish, D.;
Deschamps, J. R.; Janowsky, A. J. Med. Chem. 2007, 50, 219–232.
28. Wu, K.-H.; Chuang, D.-W.; Chen, C.-A.; Gau, H.-M. Chem. Commun. 2008,
2343–2345.
2. (a) Ducry, L.; Roberge, D. M. Angew. Chem., Int. Ed. 2005, 44, 7972–7975; (b)
Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J. Angew. Chem., Int. Ed.
2005, 44, 2413–2416.
29. (a) Tada, M.; Inoue, K.; Okabe, M. Bull. Chem. Soc. Jpn. 1983, 56, 1420–1423;
(b) Arnold, D. R.; Du, X.; Chen, J. Can. J. Chem. 1995, 73, 307–318.