ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Mild and Efficient Flow Procedure for the
Transfer Hydrogenation of Ketones and
Aldehydes using Hydrous Zirconia
Claudio Battilocchio,† Joel M. Hawkins,‡ and Steven V. Ley*,†
Innovative Technology Centre, Department of Chemistry, University of Cambridge,
Lensfield Road, CB2 1EW, Cambridge, U.K., and Pfizer Worldwide Research and
Development, Eastern Point Road, Groton, Connecticut 06340, United States
Received March 28, 2013
ABSTRACT
A flow chemistry MeerweinÀPonndorfÀVerley (MPV) reduction procedure using partially hydrated zirconium oxide via a machine-assisted
approach is reported. The heterogeneous reductive system could be applied to a wide range of functionalized substrates, allowing clean and fast
delivery of the alcohol products within a few minutes (6À75 min). In three examples the system was scaled to deliver 50 mmol of product.
The increasing demand for clean and environmentally
benign processes is driving the way we develop and deliver
our chemistry.1 Reductions and oxidations represent
a significant part of the synthesis repertoire and conse-
quently are under intense scrutiny.2 The MeerweinÀ
PonndorfÀVerley (MPV) reduction is recognized as an
attractive process due to many favorable features such
as high selectivity, mild conditions, and use of relatively
cheap reagents.3 In recent years modifications to the MPV
reaction have been introduced to address some of the
remaining problems with its application, including long
reaction times, solvent selection, side reactions, workup
issues, and catalyst effectiveness.3dÀv However to date a
completely reliable, fast, safe, and sustainable procedure
has not been fully developed.
Nevertheless, there are still a number of limitations to our
protocol, such as the high temperature required, the use of
a lithiated reagent, and its inability to process aldehydes.
(3) (a) Meerwein, N. H.; Schmidt, R. Liebigs Ann. Chem. 1925, 444,
221–238. (b) Ponndorf, W. Z. Angew. Chem. 1926, 39, 138–143. (c)
Verley, M. Bull. Soc. Chim. Fr. 1925, 37, 871. (d) Ooi, T.; Ichikawa, H.;
Maruoka, K. Angew. Chem., Int. Ed. 2001, 40, 3610–3612. (e) Node, M.;
Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J. Am. Chem. Soc. 2000,
122, 1927–1936. (f) Corma, A.; Domine, M. E.; Nemeth, L.; Valencia, S.
J. Am. Chem. Soc. 2002, 124, 3194–3195. (g) Mojtahedi, M. M.;
Akbarzadeh, E.; Sharifi, R.; Abaee, M. S. Org. Lett. 2007, 9, 2791–
2793. (h) Yin, J.; Huffman, M. A.; Conrad, K. M.; Armstrong, J. D.
J. Org. Chem. 2006, 71, 840–843. (i) Seifert, A.; Scheffler, U.; Markert,
M.; Mahrwald, R. Org. Lett. 2010, 12, 1660–1663. (j) Akamanchi, K. G.;
Varalakshmy, N. R.; Chaudari, B. A. Synlett 1997, 371. (k) Akamanchi,
K. G.; Varalakshmy, N. R. Tetrahedron Lett. 1995, 36, 3571–3572. (l)
Akamanchi, K. G.; Noorani, V. R. Tetrahedron Lett. 1995, 36, 5085–
5088. (m) Barbry, D.; Torchy, S. Tetrahedron Lett. 1997, 38, 2959–2960.
(n) Akamanchi, K. G.; Chaudhari, B. A. Tetrahedron Lett. 1997, 38,
6925–6928. (o) Anwander, R.; Palm, C.; Gerstberger, G.; Groeger, O.;
Engelhardt, G. Chem. Commun. 1998, 1811–1812. (p) Mebane, R. C.;
Mansfield, A. M. Synth. Commun. 2005, 35, 3083–3086. (q) Baratta, W.;
Siega, K.; Rigo, P. Adv. Synth. Catal. 2007, 349, 1633–1636. (r) Su, F.-Z.;
He, L.; Ni, J.; Cao, Y.; He, H.-Y.; Fan, K.-N. Chem. Commun. 2008,
3531–3533. (s) Polshettiwar, V.; Varma, R. S. Green Chem. 2009, 11,
1313–1316. (t) Lee, J.; Ryu, T.; Park, S.; Lee, P. H. J. Org. Chem. 2012,
77, 4821–4825. (u) Mollica, S.; Genovese, S.; Pinnen, S.; Stefanucci, A.;
Curini, M.; Epifano, F. Tetrahedron Lett. 2012, 53, 890–892. (v)
Sedelmeier, J.; Ley, S. V.; Baxendale, I. R. Green Chem. 2009, 11, 683–
685.
We have previously reported a flow chemistry protocol
for the transfer hydrogenation of carbonyl compounds
using a catalytic amount of lithium tert-butoxide.3v
† University of Cambridge.
‡ Pfizer Worldwide Research and Development.
(1) Ley, S. V. Chem. Rec. 2012, 12, 378–390.
(2) Sheldon, R. A.; Arens, I.; Hanefeld, U. Green Chemistry and
Catalysis; Wiley-VCH Verlag GmbH & Co. kGaA: 2007.
r
10.1021/ol400856g
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