ACS Catalysis
Letter
Table 4. Integrated Multistep Thioesterification/Fukuyama Reduction
(3) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050−7051. (b) Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.;
Fukuyama, T. Synthesis 2002, 1121−1123.
columns 1, 2, and 5 was undertaken after each run using
standard washing techniques.21
Reduction of acid oxidation state substrates to the aldehyde
is a routine, but often challenging, transformation in organic
synthesis. As a consequence, overreduction to the alcohol, then
oxidation to the aldehyde, is often applied. Through our
studies, we have developed continuous flow strategies to
achieve the synthesis of aldehydes from either thioester starting
materials (i.e., 1) or acyl chlorides (i.e., 3) using the Fukuyama
reduction. Both approaches exploit immobilized catalysts that
are highly reusable, with a single system used for all scope
investigations. Pivotal to the success of these approaches has
been the development of continuous flow thioesterification,
thiol capture, and catch-and-release purification strategies.
(4) For a review, see: Fukuyma, T.; Tokuyama, H. Aldrichim. Acta
2004, 37, 87−96.
(5) This has been described recently in: Burns, N. Z.; Baran, P. S.;
Hoffmann, R. W. Angew. Chem., Int. Ed. 2009, 48, 2854−2867.
(6) For a discussion on the challenges of such reductions and a
́
continuous flow variant, see: (a) Munoz, J. de M.; Alcazar, J.; de la
̃
Hoz, A.; Díaz-Ortiz, A. Eur. J. Org. Chem. 2012, 260−263. (b) Webb,
D.; Jamison, T. F. Org. Lett. 2012, 14, 568−571 and references therein.
For further applications of this chemistry, see: (c) Webb, D.; Jamison,
T. F. Org. Lett. 2012, 14, 2465−2467.
(7) Odorless protocols using long chain thiols have been developed:
Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 3,
477−480.
(8) Purification of aldehyde from thiosilyl ether by-products can be
challenging, particularly with the odorless variant of the reaction; see:
Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219−3223.
(9) For examples of our work in oxidation catalysis, see:
(a) Gartshore, C. J.; Lupton, D. W. Adv. Synth. Catal. 2010, 352,
3321−3328. (b) Ngatimin, M.; Frey, R.; Levens, A.; Nakano, Y.;
Kowalczyk, M.; Konstas, K.; Hutt, O. E.; Lupton, D. W. Org. Lett.
2013, 15, 5858−5861. (c) Ngatimin, M.; Frey, R.; Andrews, C.;
Lupton, D. W.; Hutt, O. E. Chem. Commun. 2011, 47, 11778−11780.
(d) Ngatimin, M.; Gartshore, C. J.; Kindler, J. P.; Naidu, S.; Lupton, D.
W. Tetrahedron Lett. 2009, 50, 6008−6011.
(10) For examples of continuous flow reaction development, see:
(a) Polyzos, A.; O’Brien, M.; Petersen, T. P.; Baxendale, I. R.; Ley, S.
V. Angew. Chem., Int. Ed. 2011, 50, 1190−1193. (b) O’Brien, M.;
Taylor, N.; Polyzos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2,
1250−1257. (c) Nakano, Y.; Savage, G. P.; Saubern, S.; Scammells, P.
J.; Polyzos, A. Aust. J. Chem. 2013, 66, 178−182.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization of all new com-
pounds and copies of 1H and 13C NMR spectra. This material is
AUTHOR INFORMATION
■
Corresponding Authors
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) For selected application of continuous flow reductions and
oxidations, see: (a) Takahashi, Y.; Mitsudome, T.; Mizugaki, T.;
Jitsukawa, K.; Kaneda, K. Green Chem. 2013, 15, 2695−2698.
(b) Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Lett. 2013, 15,
D.W.L. thanks the ARC for financial support through the
Future Fellowship and Discovery programs. D.W.L. and A.P.
thank the CSIRO Flagship Collaboration Research Fund for
seed funding. The authors acknowledge the use of facilities
within the Monash Centre for Electron Microscopy.
́
2278−2281. (c) Munoz, J. de M.; Alcazar, J.; de la Hoz, A.; Díaz-Ortiz,
̃
A. Tetrahedron Lett. 2011, 52, 6058−6060. (d) Gutmann, B.; Elsner,
P.; Roberge, D.; Kappe, C. O. ACS Catal. 2013, 3, 2669−2676.
(e) Ambreen, N.; Kumar, R.; Wirth, T. Beilstein J. Org. Chem. 2013, 9,
1437−1442.
REFERENCES
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dx.doi.org/10.1021/cs5004917 | ACS Catal. 2014, 4, 2070−2074