Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines

Article abstract of DOI:10.1039/b709043a

A new approach to the synthesis of 5-amino-4-cyanopyrazoles has been developed, utilising a novel flow microwave device. These products are then converted by a batch mode microwave process to structurally more complex dimeric and 'mixed' pyrazolopyrimidine structures. The Royal Society of Chemistry.

Full text of DOI:10.1039/b709043a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Flow and batch mode focused microwave synthesis of
5-amino-4-cyanopyrazoles and their further conversion to
4-aminopyrazolopyrimidines†
Catherine J. Smith, Francisco Javier Iglesias-Sigu¨enza, Ian R. Baxendale and Steven V. Ley*
Received 14th June 2007, Accepted 4th July 2007
First published as an Advance Article on the web 19th July 2007
DOI: 10.1039/b709043a
A new approach to the synthesis of 5-amino-4-cyanopyra-
zoles has been developed, utilising a novel flow microwave
device. These products are then converted by a batch mode
microwave process to structurally more complex dimeric and
‘mixed’ pyrazolopyrimidine structures.
The use of focused microwave techniques1 has become a routine
component of modern organic synthesis programmes. The en-
hanced reaction rate for serial processing to generate chemical
libraries or the ability to achieve reactions not previously possible,
or at least difficult, by conventional heating are key factors in
the success of this technology. Furthermore, the opportunities
presented by continuous flow processing methods2,3 for the
efficient scale-up of chemical transformations are impacting the
way we design, plan and execute molecule assembly, especially
within the pharmaceutical context.4 Nevertheless, these techniques
Fig. 1 A) Teflon core. B) Flow microwave coil.
need to constantly evolve in order to accommodate the developing
trends and requirements that relate to cost, scale, sustainability and
reproducibility of the methods.
can be easily re-wrapped in the laboratory to replace blocked or
damaged devices or to allow access to new configurations; for
example, wrapping different lengths of tubing to provide reactors
with varying internal volumes or wrapping multiple tubing to
accommodate different reactions or flow rates within the same
microwave device.
The microwave flow device described above fits into the standard
cavity of commercially available microwave equipment (Emrys
Optimiser or Initiator8) with the input and exit tubes on the
underside of the microwave unit. One or more HPLC pumps9
were used to drive the overall system, which is kept under pressure
by the use of a 100 psi back-pressure regulator at the exit.
Finally, purification is achieved by passage of the exiting flow
stream through columns packed with solid-supported reagents
and scavengers.3,10 These clean-up units can be varied depending
upon the chemistry being conducted in the system and the scale
of the process.
The choice of pyrazoles and pyrazolopyrimidines as products
for the application of this new technology was based on the preva-
lence of these structures in pharmaceuticals and agrochemicals.
In particular, the pyrazolopyrimidine core has been used as a
scaffold for the design of anti-tumour agents11 and inhibitors of
kinases,12a–c adenosine receptors12d and adenosine deaminase.12e
Our route to these important compounds involved two stages: the
advanced pyrazolopyrimidine structures were prepared via batch
mode elaborations of the corresponding 5-amino-4-cyanopyrazole
intermediates, which were themselves easily generated on multi-
gram scale under continuous flow conditions.
Here we report a new protocol for the synthesis of 5-amino-
4-cyanopyrazoles and their subsequent reaction to form 4-
aminopyrazolopyrimidines. Our approach is based upon the use
of simple chemical inputs such as hydrazines, ethoxymethylene
malononitrile and nitriles to create more complex product ar-
chitectures via the application of both continuous flow and
batch mode focused microwave methods.1,5,6 To facilitate this
synthesis, we have developed a novel flow microwave device which
permits reactions to be performed on scale, and in combination
with supported reagent techniques, allows the isolation of clean
products in high yield without recourse to chromatography.
We believe that this flow microwave device represents a useful
addition to existing flow-based microwave technologies,5,6 as it is
readily adaptable to a variety of transformations at a low cost.
The microwave flow device itself consists of fluorinated polymer
tubing wound around a central Teflon core fitted with a dummy
pressure cap typical of microwave reaction vessels (see Fig. 1a).
The unit used for the work described below is wrapped with
11.5 m of 0.4 mm i.d. tubing, providing an internal volume in the
microwave cavity of 1.45 mL (Fig. 1b). A major benefit of this new
device over glass or metal microwave inserts previously described
in the literature6,7 is the versatility and low production cost of
the polymer tubing. The Teflon spigots (also relatively low-cost)
Innovative Technology Centre (ACS), Department of Chemistry, University
of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. E-mail:
svl1000@cam.ac.uk; Fax: +44 1223 336442; Tel: +44 1223 336398
† The HTML version of this article has been enhanced with colour images.
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Scheme 1 Flow microwave synthesis of 5-amino-4-cyanopyrazoles.
The flow synthesis of 5-amino-4-cyanopyrazoles 3a–n
(Scheme 1) was achieved through the reaction of a series of
aryl hydrazines 1a–n with ethoxymethylene malononitrile 2 in
methanol by passage through the flow device described above
(Fig. 1b).11 This process involved exposure of the reaction mixture
rotary evaporator for larger samples to give high purity products
(≥95%) in good to excellent isolated yields (62–96%, Table 1,
3a–n).
The 5-amino-4-cyanopyrazole products 3a–n can be considered
as useful materials for other synthesis programmes; in this work we
have chosen to investigate their further reaction with aryl nitriles,
or dimerisation leading to 4-aminopyrazolopyrimidines under
focused microwave heating at higher temperatures (Scheme 2).
These reactions were first pioneered by Taylor et al. in the early
1960s using conventional heating and required long reaction times
under harsh conditions.16 Recent work by our laboratory17 and
others12e,18 on the formation of substituted pyrimidine rings using
similar synthetic strategies has shown that these reactions can
be greatly accelerated by the application of focused microwave
irradiation.
to focused microwave irradiation (temperatures of 100–120 ◦C 13
)
for a short period of time, usually 0.8–4.0 min (corresponding to
flowrates of 0.36–1.75mL min−1). The exiting flow stream was then
processed in-line by passage through a column of benzyl amine
resin (QuadrapureTM BZA)14 acting as a scavenging agent for any
unreacted starting material 2 or uncyclised intermediates, followed
by a column packed with activated carbon to remove coloured
or polymeric impurities. After exiting through a 100 psi back-
pressure regulator, the product was obtained by direct evaporation
R
using a Vapourtec V-10ꢀ apparatus15 for smaller samples, or a
Table 1 Yields for flow microwave synthesis of 5-amino-4-cyanopyrazoles and their subsequent dimerisations
Isolated yield of
Isolated yield
Isolated yield of
Isolated yield
Entry
R =
pyrazole 3 a
of dimer 4 a
Entry
R =
pyrazole 3 a
of dimer 4 a
a
62%
89%
—
h
75%
90%
68%
76%
b
64%
i
c
d
e
84%
82%
91%
42%
NRb
28%
j
85%
84%
96%c
82%
60%
NRb
k
l
f
81%
82%
48%
53%
m
n
62%
90%
NRb
80%
g
a Yields reported for products of ≥95% purity as determined by 1H NMR. b NR = no reaction. c BZA excluded; product isolated in 90% purity.
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Table 2 Yields for the synthesis of ‘mixed’ pyrazolopyrimidines
Entry
R =
Rꢀ =
Isolated yielda
5a
94%
5b
5c
88%
91%
a Yields reported for products of ≥95% purity as determined by 1H NMR.
Scheme 2 Synthesis of dimeric and ‘mixed’ pyrazolopyrimidines.
under batch-mode microwave conditions to access potentially
useful 4-aminopyrazolopyrimidines.
By heating under microwave irradiation we have accessed a
small collection of these structurally more complex dimeric pyra-
zolopyrimidines 4a–n as shown in Scheme 2. These dimerisation
reactions are performed in batch mode in toluene in the presence of
sub-stoichiometric amounts of potassium tert-butoxide, allowing
access to the dimeric pyrazolopyrimidines in drastically reduced
reaction times (30 min to 3.5 h) compared to conventional
Acknowledgements
We gratefully acknowledge financial support from the Paul Mellon
Fellowship (CJS), the Programa Nacional de Formacio´n de
Profesorado Universitario (FJI-S), the RS Wolfson Fellowship
(IRB and SVL), and the BP 1702 Professorship (SVL).
◦
heating (20 h at 200 C in methanol–ammonia).16 Not all of
the substrates prepared showed equal propensity for dimerisation
under the specified reaction conditions. Certain pyrazoles gave
no observable transformation while others furnished the desired
dimer albeit sometimes accompanied by additional side products.
Establishing a general workup for these often extremely insoluble
mixtures has proven challenging. However, an effective method
has been developed employing a ‘catch-and-release’ protocol with
solid-supported sulfonic acid (AmberlystTM 15) in DMF. The
crude reaction mixtures are taken up in DMF and the desired
products trapped onto AmberlystTM 15 as their salts, enabling side
products to be eluted by washing with DMF. Subsequent release
by treatment with triethylamine–DMF allows isolation of clean
(≥95% purity) products in reasonable yields (see Table 1, 4a–n)
after evaporation of solvents.
References and notes
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Microwave Methods in Organic Synthesis, Springer, Berlin, 2006; (b) A.
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We have also begun to investigate the reactivity of these 5-
amino-4-cyanopyrazole products with various aryl nitriles to
access ‘mixed’ 4-aminopyrazolopyrimidine structures (Scheme 2,
5a–c) under microwave conditions. Pyrazolopyrimidines 5a–c
(Table 2) were prepared by cycled microwave heating of neat
reagents to access the desired products in excellent yields (88–
94%) and purities (≥95%), and again, in drastically reduced
reaction times (3 × 15 min) compared to previous syntheses using
conventional heating (20 h at 200 ◦C in methanol–ammonia).16
In summary, this work describes a low-cost, practical approach
to flow microwave chemistry. Our novel flow microwave device
renders pyrazole synthesis easily scalable by simply including
larger purification columns or by column-switching; we have found
the existing setup capable of delivering over 250 g of material
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range of substituted pyrazoles in excellent purity (≥95%) without
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process can in turn be dimerised or reacted with various nitriles
3 For recent examples of flow chemistry from our group, see: (a) C. H.
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G. K. Tranmer, M. Baumann, S. C. Smith, R. A. Lewthwaite and S. V.
Ley, Org. Biomol. Chem., 2007, 5, 1562–1568; (e) C. M. Griffiths-Jones,
M. D. Hopkin, D. Jo¨nsson, S. V. Ley, D. J. Tapolczay, E. Vickerstaffe
and M. Ladlow, J. Comb. Chem., 2007, 9, 422–430; (f) I. R. Baxendale,
S. V. Ley, C. D. Smith and G. K. Tranmer, Chem. Commun., 2006,
4835–4837; (g) M. Baumann, I. R. Baxendale, S. V. Ley, C. D. Smith
and G. K. Tranmer, Org. Lett., 2006, 8, 5231–5234; (h) I. R. Baxendale,
J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby and G. K. Tranmer,
Chem. Commun., 2006, 2566–2568; (i) I. R. Baxendale, C. M. Griffiths-
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28, 395–410; (c) I. R. Baxendale and M. R. Pitts, Chem. Today, 2006,
24, 41–45.
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6 For recent examples of flow microwave chemistry from our group, see:
(a) I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer,
Chem.–Eur. J., 2006, 12, 4407–4416; (b) S. Saaby, I. R. Baxendale and
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