KMnO4-mediated oxidation as a continuous flow process

Article abstract of DOI:10.1021/ol101345z

An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and downstream processing of MnO₂ slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow system.

Full text of DOI:10.1021/ol101345z

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3618-3621
KMnO4-Mediated Oxidation as a
Continuous Flow Process
Jo¨rg Sedelmeier,* Steven V. Ley,* Ian R. Baxendale, and Marcus Baumann*
InnoVatiVe Technology Centre, Department of Chemistry, UniVersity of Cambridge,
Lensfield Road, Cambridge CB2 1EW, U.K.
theitc@ch.cam.ac.uk
Received June 11, 2010
ABSTRACT
An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding
carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and
downstream processing of MnO2 slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow
system.
Over the past few years, flow chemistry has been extensively
used by the chemical community as a valuable replacement
or supplement to traditional batch-processing methods. The
associated benefits such as improved mass and heat transfer,
safer and more reproducible performance,1 and the ability
to conduct multistep sequences2 have been demonstrated by
numerous laboratories.3 However, an often mis-stated limita-
tion of continuous flow chemistry is the inability of microre-
actors to cope with reactions that lead to precipitates due to
the potential for reactor clogging. Although this is a concern,
specifically engineered reactors have been constructed to deal
with the problems associated with slurry transport.4 Unfor-
tunately, these solutions are less easily accommodated when
using standard commercial flow equipment. We encountered
such a problem of solid generation when attempting to
conduct permanganate mediated Nef oxidation as a continu-
ous flow process in a Uniqsis FlowSyn reactor.5 We found
that the oxidation of alcohols and aldehydes to carboxylic
acids and the Nef oxidation6 of nitroalkanes to their carbonyl
derivatives proceeded smoothly by treatment with alkaline
(3) (a) Ja¨hnisch, K.; Hessel, V.; Lo¨we, H.; Baerns, M. Angew. Chem.,
Int. Ed. 2004, 43, 406–446. (b) Kirschning, A.; Solodenko, W.; Mennecke,
K. Chem.sEur. J. 2006, 12, 5972–5990. (c) Benito-Lopez, F.; Egberink,
R. J. M.; Reinhoudt, D. N.; Verboom, W. Tetrahedron 2008, 64, 10023–
10040. (d) Ahmed-Omer, B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem.
2007, 5, 733–740. (e) Seeberger, P. H. Nat. Chem. 2009, 1, 258–260. (f)
Bogdan, A.; McQuade, D. T. Beilstein J. Org. Chem. 2009, 5(17). (g)
Brasholz, M.; Johnson, B. A.; Macdonald, J. M.; Polyzos, A.; Tsanaktsidis,
J.; Saubern, S.; Holmes, A. B.; Ryan, J. H. Tetrahedron 2010, DOI: 10.1016/
j.tet.2010.04.092; (h) O’Brien, M.; Baxendale, I. R.; Ley, S V. Org. Lett.
2010, 12, 1596–1598.
(1) (a) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008,
151–163. (b) Jas, G.; Kirschning, A. Chem.sEur. J. 2003, 9, 5708–5723.
(c) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K.
Synlett 2006, (3), 427–430. (d) Baxendale, I. R.; Deeley, J.; Griffiths-Jones,
C. M.; Ley, S. V.; Tranmer, G. K.; Saaby, S. Chem. Commun. 2006, 24,
2566–2568. (e) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V.
Tetrahedron 2009, 65, 6611–6625. (f) Sedelmeier, J.; Baxendale, I. R.; Ley,
S. V. Green Chem. 2009, 11, 683–685. (g) Carter, C. F.; Baxendale, I. R.;
O’Brien, M.; Pavey, J. B. J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, 4594–
4597. (h) Brandt, J. C.; Wirth, T. Beilstein J. Org. Chem. 2009, 5 (30).
(2) (a) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D.
Angew. Chem., Int. Ed. 2009, 48, 4017–4021. (b) Baxendale, I. R.; Schou,
S. C.; Sedelmeier, J.; Ley, S. V. Chem.sEur. J. 2010, 16, 89–94. (c) Hopkin,
M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 46, 2450–2452.
(d) Qian, Z.; Baxendale, I. R.; Ley, S. V. Synlett 2010, (4), 505–508. (e)
Venturoni, F.; Nikbin, N.; Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem.
2010, (8), 1798–1806.
(4) (a) Takagi, M.; Maki, T.; Miyahara, M.; Mae, K. Chem. Eng. J.
2004, 101, 269–276. (b) Horie, T.; Sumino, M.; Tanaka, T.; Matsushita,
Y.; Ichimura, T.; Yoshida, J. Org. Process Res. DeV. 2010, 14, 405–410.
(c) Amador, C.; Gavriilidis, A.; Angeli, P. Chem. Eng. J. 2004, 101, 379–
390. (d) Buisson, B.; Donegan, S.; Wray, D.; Parracho, A.; Gamble, J.;
Caze, P.; Jorda, J.; Guermeur, C. Chim. Oggi 2009, 27, 12–16. (e)
Kockmann, N.; Kastner, J.; Woias, P. Chem. Eng. J. 2008, 135S, 110–116.
(f) Poe, S. L.; Cummings, M. A.; Haaf, M. P.; McQuade, D. T. Angew.
Chem., Int. Ed. 2006, 45, 1544–1548.
(5) http://www.uniqsis.com/.
(6) Nef, J. U. Justus Liebigs Ann. Chem. 1894, 280, 264.
10.1021/ol101345z  2010 American Chemical Society
Published on Web 07/22/2010

potassium permanganate under flow conditions. However,
stoichiometric quantities of manganese dioxide were formed
that deposited in the reactor causing fouling of the system.
This prevented a truly continuous process from being realized
as the system needed to be periodically stopped in order to
clean the T-piece connector. A simple modification to the
reactor setup involving submerging the T-piece mixer and a
short length of the subsequent reactor tubing within an
ultrasound bath7 proved ideal for dispersing the aggregate
manganese dioxide that immediately formed (Figure 1). Once
Nef oxidation was optimized using 1,2-dimethoxy-4-(ni-
tromethyl)benzene (1a) as the substrate, with the solvent,
base, residence time (flow rate), reaction temperature, reagent
concentrations, and stoichiometries being systematically
varied (Scheme 1). The reactions were rapidly screened as
Scheme 1
.
Nef Oxidation of Nitroalkanes to the Corresponding
Carbonyl Compounds
Figure 1. General reactor setup.
passed the mixing point, the reaction mixture was easily
pumped through the remaining coil reactor exiting as a fine
suspension that showed no signs of coating the internal
tubing, therefore allowing a continuous flow process.
While the Nef oxidation of aliphatic nitro compounds can
be achieved via a large number of different reaction
conditions8 our choice of oxidant was made due to the fact
that potassium permanganate is a cheap reagent and the
manganese dioxide byproduct can be easily isolated and used
in other oxidation processes.9 This significantly reduces the
environmental and financial impact of employing the per-
manganate as an oxidant.10 Furthermore, high chemoselec-
tivity can be achieved; the use of a single equivalent of the
oxidant smoothly converts nitroalkanes into aldehydes (or
ketones), whereas an excess results in the clean generation
of the carboxylic acids.11
The flow reactor consists of two HPLC pumps which
deliver stock solutions from reservoirs being mixed at a
T-piece. The resulting reaction stream was then progressed
through a PFA (per-fluoro-alkoxy) tubular coil (14 mL
internal volume) where the reaction takes place. The final
flow stream was collected, the phases were separated, and
the organic layer evaporated to afford the product. The initial
small flow plugs of reagents and analyzed by LC-MS and
proton NMR for both conversion and associated purity. It
was quickly discovered that protic, water-miscible solvents
such as methanol and ethanol were crucial for achieving high,
rapid, and clean reactions.12 Other solvents such as hexane
and dichloromethane which formed biphasic systems gave
noticeably slower reactions, even in the presence of various
phase-transfer catalysts. Ultimately, methanol proved to be
the best solvent giving full solubility of the in situ generated
nitronate species prepared during the Nef process. The effect
of the base was also investigated. Amine bases such as
Hu¨nig’s base, triethylamine, and 1,1,3,3-tetramethyl guani-
dine (TMG) were all as equally efficient for the formation
of the required nitronate anion as were inorganic bases such
as KOH and K2CO3. In each case, the reactions were found
to proceed very rapidly as they were extremely exothermic.
Consequently, careful control of stoichiometries and flow
rates and ensuring effective dissipation of the heat generated
were required in order to realize good conversions.
(7) An U300H Ultrasound bath from Ultrawave was used (http://
www.ultrawave.co.uk/). Although constant sonication was effective, we
found that only short pulses of irradiation were actually required; for
example, 5 s every minute.
(8) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047.
(9) Baumann, M.; Baxendale, I. R.; Wegner, J.; Kirschning, A.; Ley,
S. V. Heterocycles 2010, accepted.
(10) Singh, N.; Lee, D. G. Org. Process Res. DeV. 2001, 5, 599–603.
(11) (a) Kornblum, N.; Erickson, A. S.; Kelly, W. J.; Henggeler, B. J.
Org. Chem. 1982, 47, 4534–4538. (b) Steliou, K.; Poupart, M.-A. J. Org.
Chem. 1985, 50, 4971–4973. (c) Shechter, H.; Williams, F. T. J. Org. Chem.
1962, 27, 3699–3701. (d) Saville-Stones, E. A.; Lindell, S. D. Synlett 1991,
591–591. (e) Fatiadi, A. F. Synthesis 1987, 85–127.
Finally, optimal conditions were determined that involved
introduction of a 0.25 M solution of the nitroalkane (1.0
equiv) and KOH (1.2 equiv) in methanol via an injection
(12) No analysis for oxidation products derived from the alcohol solvents
was conducted during the reactions; following workup, these products were
also not detected. It is known that the relative rates of oxidation of MeOH
and EtOH are substantially slower than for higher order species.
Org. Lett., Vol. 12, No. 16, 2010
3619

loop (1, 2, or 5 mL) as stream 1 which was then mixed within
a T-piece mixer with a 0.2 M aqueous solution of KMnO4
(0.8 equiv) similarly dispensed from an injection loop (1, 2,
or 5 mL) as stream 2 (Scheme 1). Interestingly, it was
determined that even substoichiometric quantities of the
permanganate oxidant gave excellent conversions within
short residence times of between 5-8 min (14 mL tube
reactor). On exiting the reactor, the reaction output was
collected into a vigorously stirred biphasic system comprising
saturated aqueous sodium chloride (50 mL; for 5 mL sample
loop) and ethyl acetate (20 mL; for 5 mL sample loop). The
ethyl acetate layer was decanted and the aqueous portion
repeatedly re-extracted with further aliquots of ethyl acetate
(dried over MgSO4). The solvent was removed in vacuo
using a Vapourtec V10 system providing the desired product
1
in high yield and purity >95% (as determined by H NMR
Figure 2. Reactor setup for the synthesis of 1,2-dimethoxy-4-
(nitromethyl)benzene (1d).
and LC-MS) with no overoxidation being detected.
As can be seen from the examples depicted in Scheme 1 the
oxidation of both benzylic and aliphatic nitroalkanes proceeded
smoothly with additional functionalities such as esters, alcohols,
and nitriles being tolerated. However, some limitations were
encountered; nitroalkanes possessing an amino group ꢀ to the nitro
functionality gave exclusively elimination to the nitro olefin.
Furthermore, with the exception of a single example, 2g attempted
oxidation of nitro-aldol products led to C-C bond cleavage.
Nevertheless, this procedure provides a valuable alternative to the
classical methods of preparing aromatic building blocks using
Friedel-Crafts acylation or formylation.13 High yields of essentially
analytically pure compounds can be prepared from easily synthe-
sized starting materials. For example, compound 2g is derived from
a base-catalyzed nitro-aldol reaction, whereas substrates 2a,c,e,i
arise from nitroalkane conjugate addition into the corresponding
unsaturated systems. Finally, direct substitution of a halide furnishes
compounds 2b,h,j. Each of these sequences can be performed as
a flow-based protocol generating diversely functionalized noncom-
mercial nitro-containing materials. Indeed, the number of com-
mercially available nitromethylene-substituted aliphatic and aro-
matics are very limited.14 As a consequence, we wished to
demonstrate a flow synthesis of one such substrate at scale for use
in the Nef chemistry and as a key intermediate within an additional
natural product program.
The nitro derivative 1,2-dimethoxy-4-(nitromethyl)benzene (1d)
was generated on a multigram scale (177 g) using the flow
sequence depicted in Figure 2. A concerted procedure involving
initial deprotonation with a 2-fold excess of base, followed by
reaction of the resulting enolate with isopropyl nitrate and
subsequent hydrolysis of the ethyl ester with aqueous NaOH gave
a reaction stream containing reactive intermediate 3. This was
flowed into a collection tank containing a stirred solution of 2.5
M HCl which spontaneously induced decarboxylation of 3, and
the resulting product precipitated from solution as a yellow solid.
The desired product could be isolated in moderate yield by direct
filtration of the mixture (114.3 g; 58%). Additional material could
be further recovered by extraction of the acid solution with
dichloromethane giving an overall yield of 177.3 g, 90%. This
large-scale synthesis clearly demonstrates the value of flow based
processing for the generation of novel building blocks.
With methods available to prepare significant quantities of
nitro adducts, we turned our attention to the corresponding scale
up of the Nef oxidation. We considered this to be an important
proof of principle due to the potential for exothermic run-away
as evidenced by the rapid heat liberation of the small scale
reactions. Our aim was therefore to demonstrate that the flow
reactor could be operated under a steady state as a continuous
flow process for a number of hours, thereby generating
multigram quantities of product. The integrated control features
that constantly monitor the system temperature and pressure
enabling automatic shutdown (based upon user selected pa-
rameters) gave us confidence in directly scaling the sequence
by a factor of 200.
A 0.25 M solution of methyl 4-nitrobutanoate (1f) (7.36
g, 50.0 mmol) was processed at a flow rate of 1.40 mL/min
(using only a 14 mL coil reactor) to yield 5.05 g (43.5 mmol,
87%) of the corresponding aldehyde 2f over a period of 3.3 h.
As well as yielding the product in essentially the same yield,
chemoselectivity, and high purity as for the small-scale
reaction demonstrating good consistency, we also encoun-
tered no issues due to manganese dioxide fouling of the
reactor. The general principle of using short pulses of
ultrasonic irradiation proved highly efficient at preventing
build-up of solid within the reactor.
In order to further expand the synthetic potential of the
continuous flow process, conditions for the direct conversion
of nitroalkanes 1 into the corresponding acids 4 were devised
(Scheme 2). Optimal conversions were achieved by com-
bining a 0.25 M solution of a primary nitroalkane (1.0 equiv)
and KOH (1.2 equiv) in methanol as stream 1 with a 0.50
M buffered solution of KMnO4 (2.0 equiv) and Na2HPO4
(2.0 equiv) in water as stream 2 using the same reactor setup
as described above. The output stream was dispensed into a
vigorously stirred biphasic mixture of ethyl acetate and
aqueous 1 M HCl saturated with sodium chloride and
containing a substoichiometric amount of sodium thiosulfate
(as a reducing agent for excess permanganate). Under these
conditions, the in situ generated manganese dioxide was
(13) PTC/US98/11194 .
(14) A SciFinder search (24/05/10) for nitromethylene substrates supplied
at synthetically useful quantities (g10 g) returned a list of only 25
compounds.
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Org. Lett., Vol. 12, No. 16, 2010

Scheme 2
.
Transformation of Nitroalkanes to the Corresponding
Carboxylic Acids
Scheme 4
.
Transformation of Alcohols to the Corresponding
Carboxylic Acids and Aminal Formation
solubilized permitting a simple extractive workup. This
provided the desired product in high yield and excellent
purity. While only four examples were examined using this
process (Scheme 2), we found the reaction to be very reliable.
As an obvious extension to this protocol, we also examined
the KMnO4-mediated oxidation of alcohols and aldehydes
to carboxylic acids.15 The most effective conditions found
were to coelute a 0.25 M solution of the alcohol (for 4k and
4l) or aldehyde (1.0 equiv) in methanol as stream 1 with a
0.25 M solution of KMnO4 (1.0-2.0 equiv) and Na2HPO4
(1.0-2.0 equiv) in water as stream 2. An identical reactor
setup and workup protocol as described previously was
employed, furnishing again the products in high yields and
purities (Schemes 3 and 4).
the oxidation of the tertiary amine to an iminium species
proceeded faster than the oxidation of the benzylic alcohol
(Scheme 4). The resultant aminal 4m was obtained in high
yield with a dr of 19:1 via intramolecular trapping of this
reactive electrophile by the adjacent hydroxyl group. This
series of reactions highlights the complementary nature of
this facile oxidation process that can be tailored to deliver
aldehydes (ketones) or acids as required.
In summary, we have developed an efficient, rapid, and
easy to conduct process for the KMnO4-mediated oxidation
of alcohols, aldehydes, and nitroalkanes under flow condi-
tions. The value of the transformation is in using cheap
reagents that deliver oxidation products in high yields and
excellent purities following simple workup and evaporation
of the solvent. As part of this study, we have successfully
shown that MnO2 slurries can be handled within a flow
reactor by application of ultrasonication. Furthermore, we
have demonstrated the ease of scale-up by running the flow
setup at steady state processing 50 mmol of starting material.
The simple experimental setup in combination with the
benefits given by continuous flow technology renders this
procedure synthetically very interesting.
Scheme 3
.
Transformation of Aldehydes to the Corresponding
Carboxylic Acids
Acknowledgment. We thank the following organizations
for financial contributions to this project. The Cambridge
European Trust and the Ralph Raphael Studentship award
(M.B.), Novartis (J.S.), the BP 1702 Chemistry Professorship
(S.V.L.), and the Royal Society (I.R.B.).
Supporting Information Available: Experimental pro-
cedures and full characterization (1H and 13C NMR data and
spectra, IR, and HRMS) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101345Z
These conditions were additionally applied to the oxidation
of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (6a) where
(15) Wiles, C.; Watts, P.; Haswell, S. J. Tetrahedron Lett. 2006, 47,
5261–5264.
Org. Lett., Vol. 12, No. 16, 2010
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