COMMUNICATION
An efficient and transition metal free protocol for the transfer
hydrogenation of ketones as a continuous flow process†
Jo¨rg Sedelmeier, Steven V. Ley* and Ian R. Baxendale
Received 4th December 2008, Accepted 4th March 2009
First published as an Advance Article on the web 12th March 2009
DOI: 10.1039/b821752a
We report the efficient reduction of a selection of ketones to
the corresponding secondary alcohols using only catalytic
amounts of LiOtBu in iPrOH facilitated by using a contin-
uous flow reactor.
This study revealed that the nature of the alkali metal ion had
a significant influence on the rate of the resulting reduction.
LiOtBu was superior to the corresponding Na or K salts,
producing the secondary alcohol in excellent yield. In these
initial transformations a reproducible 94% isolated yield of the
desired alcohol was achieved using only 10 mol% of LiOtBu.
Of significant developmental interest was that stock solutions of
the appropriate ketone and base could be prepared in advance
under aerobic conditions using standard laboratory grade
iPrOH.
This procedure was then directly transferred to a small
footprint, continuous flow through reactor. We selected an
experimental prototype unit from ThalesNano (X-CubeTM Flow
Reactor)5 for our investigation (Fig. 1).6 The X-Cube system
consists of a stand-alone Knauer K120 HPLC pump providing
a continuous flow stream of reactants or solvent to the reactor.
The main reactor itself comprises an integrated back-pressure
regulator (200 bar max.) and detector, a heating module (350 ◦C
max.) that encompasses an exchangeable stainless steel coil
(various reactor cells can be inserted to give different reactor
volumes of 4, 8 and 16 mL). A heat exchanger is also positioned
at the exit of the reactor to rapidly cool the exiting flow stream.
Use of an in-line cartridge7 containing an excess of tosyl-
hydrazine resin allows the scavenging of any residual ketone. For
the examples described in this article no attempt was made to
recover the ketone, although in practice more valuable starting
materials could be subsequently released from the resin via a
mild hydrolysis procedure.8
The development of new and improved chemical processing
techniques that are both economically viable with greater
environmentally compatibility are of paramount importance to
the chemical industry. The ability to conduct both complex and
routine chemical transformations in a safe, reproducible and
scalable fashion without recourse to costly route modification
or redevelopment is highly desirable. The introduction of
continuous flow reactor technologies1,2 offers the ability to
rapidly test, optimise and create scalable syntheses using a
single bench top device. Furthermore, the intrinsic design of
these microreactors and their high temperature and pressure
tolerances enables utilisation of enhanced reaction conditions
that were previously difficult to evaluate.
The formation of secondary alcohols through the direct
reduction of the precursor ketone typically requires either
stoichiometric amounts of a hydride donor or a combination
of a transition metal catalyst and a molecular hydrogen source.
Recently, Adolfsson reported upon an alternative protocol that
excluded the use of expensive and toxic metal complexes, and
avoided the need for molecular hydrogen.3 Instead, a combi-
nation of inexpensive LiOiPr and iPrOH was used. Expanding
upon this idea we have developed a simple and highly efficient
continuous flow process for the alkali metal catalysed reduction
of ketones which makes potential scale up, with regard to
industrial application, very straightforward.
We have previously shown that there is a significant benefit
attained from the rapid co-evaluation of new high temperature
reactions using microwave heating techniques and their subse-
quent translation into flow chemistry processes.4 Consequently,
our initial screening involved heating an iPrOH solution of
4-methoxy acetophenone in a sealed vial under microwave
irradiation to 180 ◦C for 20 minutes (Scheme 1).
Fig. 1 Pictorial description of the flow reactor configuration.
The control of the reaction parameters (flow rate, temperature
and pressure) can be programmed, monitored and modified
through a basic keypad user interface.
An initial screening of conditions was performed, which
included reaction temperature, internal pressure, reagent con-
centration and residence time (flow rate). Optimal conversions
were achieved using a 0.3–0.4 M concentration of ketone in
iPrOH at 180 ◦C and a back-pressure of 160 bar. Increasing the
temperature to 200 ◦C gave no additional benefits in conversion
or reaction rates. The relatively high back-pressure employed
Scheme 1 Alkali metal tert-butoxide catalysed reduction of ketones.
Innovative Technology Centre, Department of Chemistry, University of
Cambridge, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: svl1000@cam.ac.uk
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra for the alcohols. See DOI: 10.1039/b821752a
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 683–685 | 683
©