A microfluidic flow chemistry platform for organic synthesis: the Hofmann rearrangement

Article abstract of DOI:10.1016/j.tetlet.2009.02.059

We report on the use of commercially available chemical microreactors to effect the Hofmann rearrangement of aromatic amides to the corresponding carbamates. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2009.02.059

Tetrahedron Letters 50 (2009) 3287–3289
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A microfluidic flow chemistry platform for organic synthesis:
the Hofmann rearrangement
b
Alessandro Palmieri a, Steven V. Ley a, , Kelvin Hammond , Anastasios Polyzos a,c, Ian R. Baxendale a
*
a Innovative Technology Centre (ACS), Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
b Advion, 19 Brown Road, Ithaca, NY 14850, USA
c CSIRO Molecular and Health Technologies, Bayview Avenue, Clayton South, Melbourne 3169, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
We report on the use of commercially available chemical microreactors to effect the Hofmann rearrange-
ment of aromatic amides to the corresponding carbamates.
Received 20 December 2008
Revised 19 January 2009
Accepted 9 February 2009
Available online 13 February 2009
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
There is considerable current interest in microfluidic systems
and in other continuous flow processes for conducting organic syn-
thesis programmes.1 The many advantages and efficiency gains,
such as reduced reaction times, that can be achieved by the use
of these systems the ability to conduct superheated and/or pres-
surized reactions, together with containment of hazardous, nox-
ious or unstable intermediates particularly attractive.2 Moreover,
the enhanced safety, reduced solvent usage and lower waste gen-
eration, combined with the potential for automation and 24 h
working schedules, adds considerable value to the concept. Our
group is interested in developing improved tools,3 techniques4
and materials for use in flow-based operations5 including multi-
step processes and complex molecule assembly.6,7 As part of this
programme, we have evaluated micro- and meso-fluidic equip-
ment for affecting challenging chemical processes, especially those
that have strategic value. Herein, we report the use of a commer-
cially available microfluidic flow chemistry platform that was pri-
marily designed for positron emission tomography (PET)
applications, but one, which we felt, could be readily expanded
to include other important chemical transformations. The Hof-
mann rearrangement is a special example in that it uniquely con-
verts amides to the corresponding carbamates via C–C to C–N bond
rearrangement, thereby affording a new product range that is not
easily accessible by other routes8 (Scheme 1). Recently, the Hof-
mann rearrangement was reported to be a key step in an alterna-
tive total synthesis of (ꢀ)-Oseltamivir (Tamiflu)9 as well as of
other biologically active natural products.10 However, the potential
toxicity of bromine (or bromine equivalent) and high reaction tem-
peratures used in these reactions can be problematic using conven-
tional laboratory methods.
platform used in this work is the Advion NanoTek LFTM device,11
which consists of a base module comprising up to three com-
puter-controlled microsyringe pumps and an array of four micro-
fluidic fused silica tubular reactors (Fig. 1).
The total internal volume of each individual reactor ranges from
7.9 to 35.4
rates ranging between 5 and 5000
for multi-step or parallel syntheses. The system employs PEEK
polymer reagent loops (200–400 L) and flow tubes. Exiting
lL. The reactors can be heated up to 200 °C, over flow
lL/min, and can be configured
l
products can be collected using a concentrator module that
enables in-line concentration or evaporation of solvents. Final
product purification may also be achieved in-line by solid-phase
extraction (SPE) or by direct injection of flow products into an
attached HPLC system.
A series of preliminary experiments were carried out on the
flow equipment to profile the reaction in terms of optimum reac-
tion temperature, concentration, residence time, solvent and stoi-
chiometry. Following rapid screening of conditions, we fixed
upon a set of reacting parameters for conducting the Hofmann
rearrangement (Scheme 2). Two separate reagent streams were
used in the reaction, which were then combined in a T-mixing
piece prior to entering a single microreactor coil.
The first flow stream contained the amide, base and appropriate
alcohol, and the second stream comprised brominating agent and
alcohol. The most suitable conditions involved N-bromosuccini-
mide (NBS) as the brominating agent, together with 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) as a base in either methanol or
We decided, therefore, that this reaction would be a good test-
bed for the new equipment. The integrated microfluidic synthesis
* Corresponding author.
E-mail address: svl1000@cam.ac.uk (S.V. Ley).
Scheme 1.
0040-4039/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.059

3288
A. Palmieri et al. / Tetrahedron Letters 50 (2009) 3287–3289
Table 1
Carbamate products 2a–n from the Hofmann rearrangement of amides 1a–n under
flow conditions using the Advion NanoTek LFTM microreactor platform (via Scheme 2)
Entry
1
R=
R0=
Me
Product (yield %)
2a (79)
2
3
Me
Me
2b (80)
2c (62)
4
5
6
7
8
Me
Et
2d (71)
2e (46)
2f (32)
2g (80)
2h (78)
Et
Me
Me
9
Me
2i (67)
Figure 1. Advion NanoTek LFTM microreactor platform. The microreactor array is
shown at the bottom.
10
11
12
Me
Me
Me
2j (74)
2k (77)
2l (41)
13
14
Me
Me
2m (57)
2n (55)
Scheme 2. General scheme for the Hofmann rearrangement of aromatic amides
using the Advion NanoTek LFTM Microreactor Platform.
ethanol (R0OH),12 to trap the intermediate rearranged isocyanate. A
total flow rate of 15 lL/min (equating to a residence time of 1 min)
and a reaction temperature of 120 °C ensured optimal conversion
Isolated yields are shown.
to the carbamate.
Reactions were carried out on a 50–100
reagents in the appropriate alcohol) in a 15.70
l
g scale (75–150 mM of
20–25 reaction runs were performed with very high reproducibility,
and samples combined to provide material for full analysis to deter-
mine the reaction integrity and efficiency. As shown in Table 1, the
microfluidic platform is broadly applicable to achieve the rearrange-
mentof aromaticamidesto the corresponding carbamatesin good to
high yields (typically 70–80% yields), and afforded very clean iso-
lated material (P97% by NMR). Notably, both electron-donating
and withdrawing substituents were tolerated under the conditions,
l
L coil per experi-
mental pass. Under these conditions, a collection of aromatic amides
1a–n was transformed into their corresponding carbamates 2a–n
(Table 1). These commercially available substrates were chosen to
examine aromatic substituent effects on the rearrangement under
flow conditions.13 The products were obtained after bulk collection
and rapid purification through a short plug of silica gel. Typically,

A. Palmieri et al. / Tetrahedron Letters 50 (2009) 3287–3289
3289
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and bromination of the benzene ring was not observed for the ben-
zamides with electron-donating substituents. Keillor and co-work-
ers14 have reported the batch synthesis of methyl carbamates 2a–
b, g and k via Hofmann rearrangement using NBS/DBU; however,
these conditions typically required reaction times of 25 min or more
in refluxing methanol. Conversely, the preparation of these com-
pounds using microfluidic conditions has resulted in a 25-fold re-
duction in reaction time with comparable yields. This
demonstrates that under the present conditions, enhanced reaction
rates result primarily from the laminar flow interaction of reagents
and the superheating of methanol. From these experiments, we
can conclude that the reaction profiling process is rapid, and that re-
liable reaction conditions can be found to deliver a useful chemical
transformation, which further extends the use of the NanoTekTM flow
platform.
Furthermore,inotherexperiments, wewereabletoshowthatthe
reaction parameters defined for this equipment can be readily trans-
ferred to other flow apparatus. In particular, the use of the Uniqsis
FlowSynTM continuous flow reactor15 readily scales the Hofmann
rearrangement reactions reported herein up to 1 g scale. The fully
integrated instrument employs a dual channel flow system, with
each channel independently driven by a variable high-pressure
pump. The starting materials and reagents are united in a T-mixing
piece and then passed into either a coil or column reactor. For our
scale-up experiments, the rearrangement conditions established
on the NanoTekTM flow platform were replicated. In a general proce-
dure, a mixtureof DBU(2 equiv) andtheappropriateamide (1 equiv)
was loaded into one channel, and NBS (2 equiv) into the second
channel. The concentration of reagents in methanol was 75–
150 mM. The combined reactant streams were directed into a
stainless steel coil reactor (20 mL volume) and a total flow rate of
2.4 mL/min. The reactor temperature was maintained at 120 °C to
ensure complete conversion. The resulting flow stream was col-
lected, then purified by passage through a short silica plug. These
conditions allowed for the scale-up synthesis of methyl carbamates
2a, g and l at 88%, 74% and 37% yields, respectively. The successful
gramscalesynthesisof these compounds demonstratesthetransfer-
ability and robustness of the optimized reactions established on the
NanoTekTM flow platform, and they are readily scalable when used in
other flow equipment, such as the Uniqsis FlowSynTM system.
It is clear that the incorporation of microfluidic flow chemistry
platforms is very effective device for effecting transformations for
organic synthesis programmes. Advances in this area of science
are developing rapidly, and the use of new, commercially available,
modular reactors has an important role to play in their future
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Acknowledgements
We gratefully acknowledge financial support from the EPRSC (to
I.R.B), the BP endowment (to S.V.L.), University of Camerino and
MIUR-Italy (to A. Palmieri), CSIRO Capability Development Fund
(CDF) (to A. Polyzos) and the Advion Flow Research Fellowship.
References and notes
1. For example, see: (a) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.;
Smith, C. D. In Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.;
Wiley-VCH: Weinheim, 2008; pp 84–122; (b) Yoshida, J.; Nagaki, A.; Yamada, T.