Continuous flow processing from microreactors to mesoscale: The Bohlmann-Rahtz cyclodehydration reaction

Article abstract of DOI:10.1039/b926387j

The cyclodehydration of a number of Bohlmann-Rahtz aminodienones exemplifies the use of continuous flow processing to transfer operations from commercial microreactors and microwave batch reactors to mesoscale production using different technology platforms, including a microwave flow reactor.

Full text of DOI:10.1039/b926387j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Continuous flow processing from microreactors to mesoscale: the
Bohlmann–Rahtz cyclodehydration reaction†‡
Mark C. Bagley,*a Vincenzo Fusillo,a Robert L. Jenkins,a M. Caterina Lubinua and Christopher Masonb
Received 16th December 2009, Accepted 25th February 2010
First published as an Advance Article on the web 11th March 2010
DOI: 10.1039/b926387j
The cyclodehydration of a number of Bohlmann–Rahtz aminodienones exemplifies the use of
continuous flow processing to transfer operations from commercial microreactors and microwave batch
reactors to mesoscale production using different technology platforms, including a microwave flow
reactor.
using microreactor technology offers additional complementary
Introduction
benefits, such as controlled temperature gradients, improved
The last decade has seen new focus on the need to harness enabling
mixing and a safe environment for the processing of toxic and/or
hazardous materials.8 These multiple emerging technologies have
been combined by Organ and co-workers, who showed that
microwave irradiation can facilitate metathesis reactions and
cross-coupling processes in a Pd-coated capillary placed within
the cavity of a single mode microwave reactor.9 Similarly, Haswell
and co-workers utilized a thin layer of gold on the outer surface as
a selective heating element under microwave irradiation for a solid-
supported catalyst in a Suzuki coupling using a continuous flow
capillary reactor.10 However, there is a clear need for microwave
reactors to have the capability to provide products routinely on
a multikilogramme scale. Towards this goal, Ley and co-workers
have demonstrated that it is possible to quickly process gramme
quantities of products from a microwave-assisted Suzuki–Miyaura
coupling using an encapsulated palladium catalyst.11 Leadbeater
and co-workers have reported the continuous flow preparation of
biodiesel using microwave heating at a staggering processing rate
of up to 7.2 L min-1.12 Other novel combinations of microwave
and flow technology have been reported, including the scale-
up of microwave-assisted cationic ring-opening polymerization
reactions,13 the use of PEEK [poly(ether ether ketone)] reac-
tors containing immobilized Pd0 catalysts accommodated within
Raschig rings,14 and the hydrodechlorination of chlorobenzene
using an active catalyst bed in a quartz U-tube reactor,15 amongst
others.4
Our own studies have described apparatus for carrying out
microwave-assisted reactions under continuous flow processing in
a single-mode reactor.16 The principal design of our flow reactor
featured the use of proprietary equipment, the need to make opti-
mum use of the standing-wave cavity and the facility to monitor the
temperature of the flow cell directly using the instrument’s in-built
IR sensor. In a number of synthetic operations, including Fischer
indole synthesis and Bohlmann–Rahtz cyclodehydration, this
equipment was found to out-perform a Teflon coil reactor heated
using the same single-mode instrument. Kappe has shown that a
similar reactor design can facilitate the Dimroth rearrangement of
1,3-thiazines to dihydropyrimidines using a 10 mL vessel under
continuous flow processing.17 A particularly attractive feature
of this apparatus is the potential for synthetic operations to be
rapidly transferred from discovery scale to process development.
It has long been established that continuous flow processing
technology in order to facilitate and simplify processes in organic
synthesis. Built upon recent advances in automation, that were
principally driven by the needs of combinatorial chemistry, the
realization that technological advances could open up new molec-
ular space, streamline process efficiency and integrate synthetic
operations with other necessary processes such as purification,
analysis and biological evaluation has driven us to re-examine the
age-old traditions of synthetic experimental design. Combining
different enabling technologies, such as solid-supported reagents,
continuous flow reactors, microwave-accelerated reactions, fluo-
rous synthesis, new reaction media and novel catalysts, has the
potential to revolutionize the way that chemists plan and carry out
their activities.1 The justification for this orchestration originates
from the enticing promise of new and formidable capability, but
of course will give rise to unfamiliar challenges and that is why it
has become hugely popular amongst academia and industry alike
in very recent times.
The combination of microwave heating2 and continuous flow
reactor design3 has long been realized as an ideal marriage of
technologies.4 Strauss first demonstrated the feasibility of this
system in 19945 and since then a number of groups have offered
their own solutions to scale up issues of microwave-assisted
reactions,6 with the limited penetration depth of microwave
irradiation into absorbing media and the physical limitations
on the dimensions of a standing wave cavity, by combining
continuous flow processing with microwave heating.7 Continuous
flow processing offers the facility for ready automation, improved
reproducibility, enhanced safety and considerable process reli-
ability, whereas microwave heating promises improved kinetics
and even selective coupling, thus providing opportunities for
the rapid processing of material. The scale out of processes
aSchool of Chemistry, Main Building, Cardiff University, Park Place, Cardiff,
UK CF10 3AT. E-mail: Bagleymc@cardiff.ac.uk; Fax: +44 29 2087 4030;
Tel: +44 29 2087 4029
bCEM (Microwave Technology) Ltd, 2 Middle Slade, Buckingham, UK
MK18 1WA; Fax: +44 29 1280 822342; Tel: +44 1280 822873
† his paper is part of an Organic & Biomolecular Chemistry web theme
issue on enabling technologies for organic synthesis
‡ Electronic supplementary information (ESI) available: NMR spectra for
compounds 3a–d and 4a–d. See DOI: 10.1039/b926387j
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Table 1 Microwave-assisted cyclodehydration of aminodienone 3a (R1 =
Et, R2 = Ph) in batch experiments to find an appropriate reaction solvent
could facilitate this transition,3,18 allowing the ready transfer from
micro- to mesoscale production without the need for extensive
re-optimization of procedures. Kappe and co-workers have shown
that for Claisen rearrangements and Mizoroki–Heck reactions,
conditions optimized under high temperature batch conditions
in a microwave reactor could be translated successfully to a flow
regime using a microtubular stainless steel conductive heating flow
reactor.19 This manuscript investigates the validity of an alternative
hypothesis: that reactions optimized using a conductive heating
microreactor platform or in microwave-assisted chemistry can
then be transferred to production, for example using microwave
dielectric heating, all under a continuous flow regime. For this
study we chose a familiar model reaction, the Bohlmann–Rahtz
cyclodehydration of aminodienones to pyridines,20 to test if the
transfer of parameters on scale up proceeds readily from apparatus
to apparatus21 for a relatively simple synthetic procedure that
we have already established can be facilitated under microwave
irradiation.22
Bohlmann and Rahtz first reported the synthesis of trisub-
stituted pyridines from ethyl b-aminocrotonate 1 and ethynyl
ketones back in 1957.20a Since that date numerous applications
have appeared in the literature,20b,22 in particular in recent years.
The reaction is completely regioselective and proceeds with
initial Michael addition to the ethynyl ketone 2 by enamine 1
C-alkylation to give an aminodiene intermediate 3 that is isolated
and purified in high yield (Scheme 1).20a The aminodienone inter-
mediate 3 is kinetically stable with respect to the heteroannelation
product, pyridine 4, due to the enone E-geometry but on heating to
temperatures of 120–170 ◦C, E/Z-isomerization precedes sponta-
neous cyclodehydration to give the 2,3,6-trisubstituted pyridine 4
in excellent overall yield and with total regiocontrol.20 This process
is reliant upon the temperature but may also be facilitated using
a Brønsted or Lewis acid catalyst in order to accelerate E/Z-
isomerization.23 Thus, it was envisaged that high temperatures
in combination with the use of a Brønsted acid catalyst would
minimize residence times and so deliver high processing rates.
Entry
Solvent
Temp/◦Ca
Time/minb
Yield (%)c
d
1
2
3
4
5
EtOH
DMSO
PhMe–AcOH (5 : 1)
PhMe–AcOH (5 : 1)
PhMe–AcOH (5 : 1)
130
170
50
70
100
40
20
20
10
2
—
98
>98
>98
>98
a A constant temperature was maintained by the moderation of the initial
microwave power (150 W). b Time that reaction is held at the given
temperature (hold time), not total irradiation time. c Isolated yield of
pyridine 4a. d A mixture of 3a and 4a was obtained.
hydration experiments were carried out on aminodienone 3a
(R1 = Et, R2 = Ph) in batch mode using microwave dielectric
heating (Table 1) in order to establish the optimum solvent and
confirm reaction homogeneity under the reaction conditions.
Preliminary experiments of this nature carried out before transfer
to continuous flow processing were found to be very useful
in identifying potential problems, such as the precipitation of
products, and are strongly recommended. Previous studies have
shown that Bohlmann–Rahtz cyclodehydration proceeds at ele-
vated temperatures in DMSO,22a alcoholic solvents25 and toluene–
acetic acid,23 and so these solvents were reviewed in the microwave
batch experiments. Of these, the Brønsted acid catalyzed procedure
(entry 3) was established as the most promising for optimization
under a flow regime, giving pyridine 4a in quantitative isolated
yield upon 20 min irradiation at a temperature of only 50 ◦C.
Increasing the temperature to 70 ◦C (entry 4) or 100 ◦C (entry 5)
did not compromise the efficiency of the process and in the latter
case reduced the reaction time to only 2 min (hold time); thus
was considered suitable for transfer to a microreactor for further
investigation.
Reaction optimization: continuous processing under conductive
heating using a microreactor
The cyclodehydration of aminodienones 3a–d was carried out
R
in a Syrris AFRICAꢀ microreactor fitted with a pressurization
module, single reagent feed and injection module, conductive
heating chip reactor and product collection module. In order to
provide a valid comparison with the microwave batch experiments,
a 0.1 M stock solution of each aminodienone 3a–d in toluene–
acetic acid in turn was processed through the chip reactor at a
temperature of 100 ◦C, varying the flow rate and thus the residence
time (Table 2). However, the cyclodehydration of aminodienone
3c at this concentration resulted in the precipitation of pyridine
4c, thus blocking the line, and so for this substrate the experiments
were performed at a concentration of 0.05 M (entry 4). In each
experiment, the outflow was sampled using GCMS and the
Scheme 1 Bohlmann–Rahtz pyridine synthesis.
1
analysis was further complemented by H NMR spectroscopic
Results and discussion
studies following aqueous extraction, once sufficient outflow was
collected. For all four substrates 3a–d, a residence time of1 or 2 min
(entry 1) gave incomplete conversion to the corresponding pyridine
4a–d, whereas residence times of 4 min resulted in complete
(>98%) conversions (entries 2–5). This discrepancy in residence
time between the conductive heating microreactor platform and
microwave batch experiment, could just be attributed to small
differences in the heating profiles of these systems, in particular
Feasibility study in a single-mode microwave batch reactor
Four aminodienones 3a–d were generated by Michael addition of
ethyl b-aminocrotonate 1 and the respective ethynyl ketone 2a–d,
prepared from the corresponding propargylic alcohol according
to our previously established methods.23,24 Prior to optimization
studies under continuous flow processing, a series of cyclode-
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Table 2 Cyclodehydration of aminodienones 3a–d in a microreactora
Table 4 Continuous processing of pyridines 4a–c in a stop-flow single-
mode microwave reactora
Entry
3
R1
R2
Residence time/min Conversion (%)b
Hold
Processing
Entry
3
R1 R2
Et Ph
mmolb time/minc time/mind Yield (%)e
c
1
2
a–d
a
2
4
4
4
4
—
Et
Et
Et
Ph
p-C6H4Cl
Me
>98
>98
>98
>98
3
b
1
2
3
a
b
c
2.0
2
2
2
21
20
15
81
94
83
4d
5
c
d
Et p-C6H4Cl 0.9
Et Me 2.0
t-Bu Me
a Reactions were carried out on a 0.1 M solution of the corresponding
aminodienone 3a–d in PhMe–AcOH (5 : 1) using a Syrris AFRICAꢀR
microreactor at 100 ◦C for the indicated residence time. b Conversion from
aminodienone 3 to the corresponding pyridine 4 was established by GCMS
and 1H NMR spectroscopy after aqueous work-up. c A mixture of 3 and 4
was obtained in each case. d A 0.05 M solution of 3c was used.
a Reactions were carried out under microwave irradiation at 100 ◦C for
2 min (hold time) in PhMe–AcOH (5 : 1) using a CEM VoyagerꢀR platform
on the DiscoverꢀR single-mode microwave synthesizer, operating at an
initial power of 150 W (which was modulated to maintain a constant
reaction temperature). b Refers to aminodienone 3. c Time the vessel was
held at a temperature of 100 ◦C under microwave irradiation. d Time
to process product through the reactor, including pump-in, temperature
ramp-up, irradiation, cooling, pump-out and the wash-out of the reactor
to the receiver. e Isolated yield of pyridine 4 after aqueous work-up.
Table 3 Microwave-assisted cyclodehydration of aminodienones 3a–c in
a multimode batch reactora
Scale-up: continuous processing under microwave heating using a
stop-flow single-mode reactor
Entry
3
R1
R2
mmolb
Yield (%)c
1d
2e
3d
4d
5d
a
a
b
c
c
Et
Et
Et
Et
Et
Ph
Ph
p-C6H4Cl
Me
1.9
7.7
1.7
0.9
3.8
96
65
78
87
93
One solution to challenges in carrying out microwave-assisted
reactions on a preparative scale is offered by the use of a single-
mode microwave reactor operating under stop-flow conditions,
R
such as with the CEM Voyagerꢀ platform. This apparatus
Me
a Reactions were carried out under microwave irradiation in a pressure
rated Teflon vessel (60 or 100 mL) at 100 ◦C for 2 min (hold time) in PhMe–
AcOH (5 : 1) using a multimodal MILESTONE BatchSynthTM instrument,
operating at an initial power of 150 W (which was modulated to maintain
a constant reaction temperature). b Refers to aminodienone 3. c Isolated
yield of pyridine 4 after aqueous work-up. d 60 mL vessel. e 100 mL vessel.
has the advantage that it enables continuous batch production
without any need to manually manipulate vessels26 and has
been shown to be an efficient and convenient system for the
R
scale-up of Buchwald–Hartwig aminations in a CEM Discoverꢀ
microwave synthesizer26 and the scaling out of pharmaceutically
relevant transformations.28 Carrying out the Bohlmann–Rahtz
cyclodehydration on this platform enabled pyridines 4a–c to be
processed in good yield (Table 4). All reactions were carried out at
0.1 M apart from aminodienone 3b (entry 2) which was processed
at 0.05 M concentration in order to prevent any problems with
product precipitation blocking the line.27c Under these conditions,
the apparatus was found to be reliable for all of the substrates,
with isolated yields varying between 81 and 94%. Stop-flow
operation facilitated the ready transfer of parameters directly
from batch-mode to continuous processing for this microwave-
assisted transformation and so offers a highly effective method for
scaling-out production,27,28 although overall the processing rates
were modest.
considering the heating and cooling ramp times but were noted as
a point of caution.
Scale-up in a multimode microwave batch reactor
Scale-up of the cyclodehydration reaction was first investigated
in a sealed vessel under microwave-assisted conditions using a
multimode batch reactor.26,27 Starting with aminodienone 1a, a
0.1 M solution in toluene–acetic acid was irradiated for 2 min
(hold time) at 100 ◦C using two different vessel sizes (60 and
100 mL) and volumes (Table 3) in order to explore any differences
in heating efficiencies on increasing scale. On a relatively small
scale (1.9 mmol of 3a in 19 mL solvent in a 60 mL vessel),
the multimode instrument was found to perform well giving
efficient conversion to the corresponding pyridine 4a (96% yield,
entry 1). However, on a larger scale (7.7 mmol of 3a in 75 mL
solvent in a 100 mL vessel) a significant reduction in the yield
of product was observed (65% yield, entry 2). When similar
conditions were investigated in the 60 mL vessel for two further
substrates 3b,c the yield of pyrdine 4b,c was found to vary
(entries 3–5). These variations were attributed to a combination
of temperature and reactivity differences. In the comparison of
reactions run in different vessels (entries 1 and 2), problems with
the penetration depth of microwave irradiation was thought to
have led to irregularities of heating, although differences in ramp
heating times could not be discounted. It was clear that a more
reliable and robust method was required for the scale-up of this
microwave-assisted reaction.
Scale-up: continuous processing under microwave heating using a
10 mL glass flow reactor
In order to investigate if improved processing rates could be
obtained by continuous flow processing, 0.1 M solutions of
aminodienones 3a–d in toluene–acetic acid were irradiated at
100 ◦C for 2 min (residence time) under continuous flow pro-
cessing, using our 10 mL flow cell apparatus,16 and the results
compared to microwave batch experiments using the same single-
mode cavity. The flow cell was fille◦d with sand, to help prevent
back-mixing, and stabilized at 100 C with eluent at a flow rate
of 1.5 mL min-1 using an initial microwave power of 200 W.
Each substrate was then passed through the flow cell in turn and
discharged with further portions of eluent into an aqueous base
quench. In all cases, the process was found to give an excellent
yield of the corresponding pyridine 4a–d (Table 5), with some
experiments showing improved performance (entries 2–4) over
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Table 5 Comparison of continuous processing of pyridines 4a–d in a
single-mode microwave glass microwave reactor and the corresponding
microwave batch reaction in a sealed tubea
isolated yield of pyridines 4a and 4b was compromised (62 and
52%, respectively) due to incomplete conversion. It was felt
the reduction in efficiency was due to differences in how the
temperature was measured between the conductive heating coil
and microwave-heated reactors. On analysis, parameters for the
stainless steel flow reactor had transferred successfully from the
corresponding microreactor, which was also less efficient at 2 min
residence time.
Entry
3
R1
R2
Batch yield (%)b Flow cell yield (%)c
1
2
3
4
a
b
c
Et
Et
Et
Ph
p-C6H4Cl
Me
>98
98
80
>98
>98
96
d
t-Bu Me
82
98
a The reaction of each aminodienone 3a–d (0.3 mmol) was carried out
under microwave irradiation at 100 ◦C for 2 min in PhMe–AcOH (5 : 1)
using a CEM DiscoverꢀR single-mode microwave synthesizer, operating
at the given initial power (150 or 200 W) which was modulated to
maintain a constant reaction temperature. b Isolated yield of pyridine 4
after irradiation at 100 ◦C (150 W initial power) in a sealed tube for 2 min
(hold time), cooling in a stream of compressed air and aqueous work up.
c Isolated yield of pyridine 4 after irradiation (200 W initial power), with a
residence time of 2 min, in the glass flow cell and aqueous work-up.
Mesoscale continuous processing under microwave heating
Finally, given the success of the microwave flow reactions in
providing efficient conversion to the corresponding pyridines,
efforts were made to improve the processing rate and transfer
the established parameters to mesoscale production under contin-
uous flow processing. For this purpose, a multimode Milestone
BatchSynthTM microwave synthesizer was operated under contin-
uous flow processing using the FlowSynthTM platform. A solution
(0.05 M) of aminodienone 3a in toluene–acetic acid (5 : 1), diluted
so as to avoid any problems of product precipitation, was passed
through the microwave cavity at a flow rate of 1 L h-1 and heated
the comparable microwave batch reaction. Considering that the
batch experiments were subjected to microwave irradiation for a
longer period of time, with ramp heating being followed by a hold
time of 2 min, the improved performance of the microwave flow
reactor could be attributed to small but significant differences in
reaction temperature between batch and flow experiments. The
flow cell might be at a higher internal reaction temperature when
registering the same measurement on the outer glass wall using
the IR sensor. Despite these small differences, it was evident that
parameters for batch microwave reactions could be transferred
readily to continuous flow processing using this flow cell and, thus,
this represents a robust and efficient means to scale up microwave
reactions, with prospects for improved performance over batch
methods.
◦
to 100 C under microwave irradiation using an initial power of
150 W (Scheme 2). At this flow rate, the residence time would be
substantially longer (~12.5 min) but it was thought this would
account for field and temperature inhomogeneities and would
still deliver improved production rates. After aqueous work up,
pyridine 4a was isolated in 93% yield. Even with the increased
dilution and longer residence time, this represented a substrate
processing rate of 0.5 mmol min-1, which was significantly higher
than with any other platform.
Scale-up: continuous processing using a stainless steel conductive
heating flow reactor
The use of conductive heating continuous flow reactor platforms
offers a viable alternative for the scale-up of microwave-assisted
transformations carried out in batch mode.19 To explore these
opportunities, 0.1 M solutions of aminodienones 3a,b were
processed using the UNI◦QSIS FlowSynTM conductive heating
platform (Table 6) at 100 C through a 5 mL stainless steel coil
for 2 min (residence time), in order to establish if this would
give efficient conversion to the corresponding pyridines 4a,b,
for comparison with the microwave-assisted methods. Although
the processing rate for this apparatus was reasonably high, the
Scheme 2 Mesoscale production of pyridine 4a using a continuous flow
microwave reactor.
Experimental
Commercially available reagents were used without further pu-
rification; solvents were dried by standard procedures. Light
petroleum refers to the fraction with bp 40–60 ◦C and ether
refers to diethyl ether. Unless otherwise stated, reactions were
performed under an atmosphere of dry nitrogen. Microwave
irradiation experiments were performed under an atmosphere
Table 6 Continuous processing of pyridines 4a,b in a stainless steel
conductive heating flow reactora
R
of air using a self-tunable CEM Discoverꢀ focused monomodal
R
microwave synthesizer, operating in batch, stop-flow Voyagerꢀ or
Residence Processing
Entry
3
R1 R2
time/minb rate/mmol min-1c Yield (%)d
continuous flow mode, MILESTONE BatchSynthTM microwave
synthesizer or on the MILESTONE FlowSynthTM platform at
the given temperature, measured using the instrument’s in-built
temperature measuring device, by varying the irradiation power
(initial power given in parentheses). Conductive heating flow
1
2
a
b
Et Ph
Et p-C6H4Cl
2
2
0.25
0.25
62
52
a Reactions were carried out using a 0.1 M solution of 3 in PhMe–AcOH
(5 : 1) in a stainless steel heating coil (5 mL) with a UNIQSIS FlowSynTM
operating at a flow rate of 2.5 mL min-1. b Time of residence in the heated
stainless steel reactor coil. c Rate of processing aminodienone 3 through
the reactor, during continuous operation. d Isolated yield of pyridine 4 after
aqueous work-up.
R
reactions were performed using a Syrris AFRICAꢀ microreactor
or the UNIQSIS FlowSynTM using the instrument’s in-built
temperature measurement. Analytical thin layer chromatography
was carried out using aluminium-backed plates coated with Merck
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Kieselgel 60 GF254 that were visualised under UV light (at 254
and/or 360 nm). In vacuo refers to evaporation at reduced pressure
using a rotary evaporator and diaphragm pump, followed by the
removal of trace volatiles using a vacuum (oil) pump.
(2Z,4E)-2-Amino-3-ethoxycarbonylheptadien-6-one (3c). Ob-
tained as a pale yellow solid, mp 135–137 ◦C (light petroleum–
◦
EtOAc) (lit.23 mp 135 C) (Found: MH+, 198.1127. C10H16NO3
[MH] requires 198.1125); Rf 0.29 (EtOAc–light petroleum, 4 : 1);
IR (nujol)/cm-1 nmax 3332, 1648, 1554, 1489, 1443, 1352, 1310,
1277, 1200, 1183, 1111, 1023; 1H NMR (400 MHz; CDCl3) d 9.62
(1H, br s, NHH), 7.52 (1H, d, J 15.4, 4–H), 6.49 (1H, d, J 15.4,
5–H), 5.53 (1H, br s, NHH), 4.20 (2H, q, J 7.1, OCH2CH3), 2.22
Fully characterized compounds were chromatographically ho-
mogeneous. Melting points were determined on a Kofler hot stage
apparatus and are uncorrected. Infra-red spectra were recorded
in the range 4000–600 cm-1 on a Perkin–Elmer 1600 series FTIR
spectrometer using KBr disks or as a nujol mull for solid samples
and thin films between NaCl plates for liquid samples and are
reported in cm-1. NMR spectra were recorded using a Bruker DPX
400 instrument or 500 Avance instrument operating at 400 MHz
(3H, s, CH3), 2.15 (3H, s, CH3), 1.27 (3H, t, J 7.1, OCH2CH3); 13
C
NMR (100 MHz; CDCl3) d 199.4 (C), 169.3 (C), 165.9 (C), 139.2
(CH), 121.1 (CH), 94.5 (C), 60.1 (CH2), 28.2 (CH3), 22.8 (CH3),
14.2 (CH3); MS (APcI) m/z (rel. intensity) 198 (MH+, 100%), 180
(57).
1
for H spectra and 100 or 125 MHz for 13C spectra; J values
were recorded in Hz and multiplicities were expressed by the
usual conventions. Low resolution mass spectra were determined
using a Fisons VG Platform II Quadrupole instrument using
atmospheric pressure chemical ionization (APcI) unless otherwise
stated. High resolution mass spectra were obtained courtesy of
the EPSRC Mass Spectrometry Service at University College of
Wales, Swansea, UK using the ionization methods specified.
(2Z,4E)-2-Amino-3-tert-butoxycarbonylheptadien-6-one (3d).
Obtained as a pale yellow solid, mp 142–144 ◦C (light petroleum–
EtOAc) (Found: MH+, 226.1441. C12H20NO3 [MH] requires
226.1438); Rf 0.26 (light petroleum–EtOAc, 1 : 1); IR (nujol)/cm-1
nmax 3344, 1654, 1543, 1488, 1442, 1360, 1321, 1289, 1221, 1161,
1103, 1031; 1H NMR (400 MHz; CDCl3) d 9.65 (1H, br s, NHH),
7.47 (1H, d, J 15.3, 4–H), 6.41 (1H, d, J 15.3, 5–H), 5.41 (1H,
br s, NHH), 2.19 (3H, s, CH3), 2.20 (3H, s, CH3), 1.46 (9H, s,
CMe3); 13C NMR (100 MHz; CDCl3) d 199.2 (C), 169.6 (C),
165.3 (C), 139.5 (CH), 121.3 (CH), 96.0 (C), 81.1 (C), 28.3 (CH3),
28.2 (CH3), 22.4 (CH3); MS (APcI) m/z (rel. intensity) 226 (MH+,
98%), 209 (56), 170 (83), 153 (100).
General procedure for the synthesis of aminodienones by Michael
addition of enamine 1 and ethynyl ketone 223,24
A solution of enamine 1 (5.8 mmol) and ethynyl ketone 2
(7.5 mmol) in EtOH (80 mL) was stirred at 50 ◦C for 1–7 h,
cooled and evaporated in vacuo to give the crude aminodienone 3.
General procedure for the microwave-assisted cyclodehydration of
aminodienone 3 in a sealed tube
(2Z,4E)-2-Amino-3-ethoxycarbonyl-6-phenylhexadien-6-one
(3a). Obtained as a yellow so◦lid, mp 159–161 ◦C (light
petroleum–EtOAc) (lit.29 mp 164 C) (Found: MH+, 260.1279.
C15H18NO3 [MH] requires 260.1281); Rf 0.38 (EtOAc–light
petroleum, 4 : 1); IR (nujol)/cm-1 nmax 3339, 1625, 1584, 1537,
1499, 1379, 1350, 1322, 1287, 1223, 1207, 1178, 1111, 1058, 1036,
1022, 982, 848, 707, 628; 1H NMR (400 MHz; CDCl3) d 9.71 (1H,
br s, NHH), 7.95 (2H, m, o-PhH), 7.88 (1H, d, J 15.1, 4–H), 7.45
(3H, m,p-PhH), 7.42 (1H, d, J 15.1, 5–H), 5.73 (1H, br s, NHH),
4.22 (2H, q, J 7.1, OCH2CH3), 2.31 (3H, s, CH3), 1.37 (3H, t, J
7.1, OCH2CH3); 13C NMR (100 MHz; CDCl3) d 191.0 (C), 169.8
(C), 166.7 (C), 141.0 (CH), 139.7 (C), 131.8 (CH), 128.3 (CH),
128.1 (CH), 115.8 (CH), 95.5 (C), 60.0 (CH2), 22.6 (CH3), 14.5
(CH3); MS (APcI) m/z (rel. intensity) 260 (MH+, 100%), 243 (26),
214 (18).
A solution of aminodienone 3 (0.31 mmol) in toluene–glacial
acetic a◦cid (5 : 1; 3 mL) was irradiated for 2 min (hold time)
R
at 100 C in a CEM Discoverꢀ microwave synthesizer at an
initial power of 150 W. The solution was allowed to cool and
partitioned between saturated aqueous NaHCO3 (25 mL) and
EtOAc (25 mL). The aqueous layer was further extracted with
EtOAc (2 ¥ 15 mL) and the combined organic extracts were washed
with brine (15 mL), dried (Na2SO4) and evaporated in vacuo to give
the corresponding pyridine 4.
General procedure for the cyclodehydration of aminodienone 3 in a
microreactor
A solution of aminodienone 3 (0.1 M) in toluene–glacial acetic acid
(5 : 1) was passed through a microfluidic reaction chip, heated at
◦
R
100 C, for 4 min using a Syrris AFRICAꢀ microreactor assembled
with a pressurization module, reagent feed module, reagent
injection module, chip reactor module and product collection
module. The reaction mixture was quenched in a solution of
saturated aqueous NaHCO3, extracted with EtOAc (3 ¥ 30 mL),
dried (Na2SO4) and evaporated in vacuo to give the corresponding
pyridine 4.
(2Z,4E)-2-Amino-3-ethoxycarbonyl-6-(4-chlorophenyl)-hexa-
dien-6-one (3b). Obtained as a yellow solid, mp 164–165 ◦C (light
petroleum–EtOAc) (Found: MH+, 294.0892. C15H1735ClNO3 [MH]
requires 294.0891); Rf 0.51 (EtOAc–light petroleum, 4 : 1); IR
(nujol)/cm-1 nmax 3348, 1655, 1628, 1596, 1570, 1542, 1488, 1353,
1321, 1289, 1224, 1175, 1122, 1089, 1058, 1040, 1011, 976, 855,
1
823, 745, 717, 646, 588, 537, 501; H NMR (400 MHz; CDCl3)
d 9.68 (1H, br s, NHH), 7.86 (1H, d, J 15.0, 4–H), 7.86 (2H,
app d, J 8.4, 2¢,6¢-PhH), 7.35 (2H, app d, J 8.4, 3¢,5¢-PhH), 7.31
(1H, d, J 15.0, 5–H), 5.81 (1H, br s, NHH), 4.23 (2H, q, J 7.1,
General procedure for the cyclodehydration of aminodienone 3 in a
multimode microwave batch reactor
OCH2CH3), 2.27 (3H, s, CH3), 1.35 (3H, t, J 7.1, OCH2CH3); 13
C
NMR (100 MHz; CDCl3) d 189.6 (C), 169.7 (C), 167.0 (C), 141.6
(CH), 138.1 (C), 138.0 (C), 129.5 (CH), 128.6 (CH), 115.1 (CH),
95.6 (C), 60.1 (CH2), 22.6 (CH3), 14.5 (CH3); MS (APcI) m/z (rel.
intensity) 296 (MH+, 32%), 294 (MH+, 100), 277 (17), 260 (18).
A solution of aminodienone 3 (0.1 M) in toluene–glacial acetic
acid (5 : 1) was irradiated at 100 ◦C for 2 min (hold time) in a
pressure rated Teflon vessel (60 or 100 mL) using a multimodal
MILESTONE BatchSynthTM microwave synthesizer at an initial
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power of 150 W. After cooling, the reaction mixture was quenched
in a solution of saturated aqueous NaHCO3 and extracted with
EtOAc (3 ¥ 30 mL). The organic extracts were dried (MgSO4) and
evaporated in vacuo to give the corresponding pyridine 4.
q, J 7.1), 2.84 (3H, s), 1.35 (3H, t, J 7.1); 13C NMR (125 MHz,
CDCl3) d 166.6 (C), 159.9 (C), 159.1 (C), 139.4 (CH), 138.4 (C),
129.7 (CH), 128.8 (CH), 127.4 (CH), 123.7 (C), 117.4 (CH), 61.2
(CH2), 25.2 (CH3), 14.3 (CH3); MS (APcI) m/z (rel. intensity) 242
(MH+, 100%), 214 (10).
General procedure for the microwave-assisted cyclodehydration of
aminodienone 3 in a stop-flow reactor
Ethyl 2-methyl-6-(4-chlorophenyl)pyrid◦ine-3-carboxylate (4b).
Obtained as a pale yellow solid, mp 46–47 C (aq. EtOH) (lit.24 mp
47–48 ◦C) (Found: MH+, 276.0787. C15H1535ClNO2 [MH] requires
276.0786); Rf 0.68 (light petroleum–EtOAc, 1 : 1); IR (nujol)/cm-1
nmax 1725, 1588, 1497, 1465, 1362, 1258, 1185, 1163, 1091, 1015,
899, 828, 784, 742, 701; 1H NMR (400 MHz; CDCl3) d 8.31 (1H,
d, J 8.0, 4–H), 7.98 (2H, app d, J 8.4, 2¢,6¢-PhH), 7.49 (1H, d, J
8.0, 5–H), 7.43 (2H, app d, J 8.4, 3¢,5¢-PhH), 4.42 (2H, q, J 7.1,
A solution of aminodienone 3 (0.05 or ◦0.1 M) in toluene–glacial
acetic acid (5 : 1) was irradiated at 100 C in a borosilicate glass
R
vessel (80 mL) using a CEM Discoverꢀ microwave synthesizer
R
operating in stop-flow Voyagerꢀ mode at an initial power of 150
W. After cooling, the reaction mixture was quenched in a solution
of saturated aqueous NaHCO3 and extracted with EtOAc (3 ¥
15 mL). The organic extracts were dried (MgSO4) and evaporated
in vacuo to give the corresponding pyridine 4.
OCH2CH3), 1.63 (3H, s, CH3), 1.37 (3H, t, J 7.1, OCH2CH3); 13
C
NMR (100 MHz; CDCl3) d 167.4 (C), 160.8 (C), 158.2 (C), 139.1
(CH), 134.2 (C), 136.0 (C), 128.9 (CH), 128.3 (CH), 124.4 (C),
117.8 (CH), 60.7 (CH2), 24.6 (CH3), 14.5 (CH3); MS (APcI) m/z
(rel. intensity) 278 (MH+, 33%), 276 (MH+, 100), 250 (18), 248
(56).
General procedure for the microwave-assisted cyclodehydration of
aminodienone 3 in a glass tube reactor
A glass tube flow cell (10 mL) filled with sand (~12 g) was
primed with toluene–glacial acetic acid (5 : 1) at a flow rate of
1.5 mL min-1, irradiated at an initial power of 200 W and stabilized
at 100 ◦C. A flask was charged with a solution of aminodienone 3
(0.31 mmol) in toluene–glacial acetic acid (5 : 1, 3 mL), which was
then passed through the cavity at the given flow rate, washing with
further batches of solvent. The reaction mixture was quenched in
a solution of saturated aqueous NaHCO3, extracted with EtOAc
(3 ¥ 30 mL), dried (Na2SO4) and evaporated in vacuo to give the
corresponding pyridine 4.
Ethyl 2,6-dimethylpyridine-3-carboxylate (4c). Obtained as a
pale yellow solid, mp 59–60 ◦C (EtOH) (lit.20a mp 60 ◦C) (Found:
MH+, 180.1020. C10H14NO2 [MH] requires 180.1019); Rf 0.44
(light petroleum–EtOAc, 1 : 1); IR (nujol)/cm-1 nmax 1730, 1593,
1
1272, 1236, 1148, 1079, 770, 722; H NMR (400 MHz; CDCl3)
d 8.05 (1H, d, J 8.1, 4–H), 7.05 (1H, d, J 8.1, 5–H), 4.33 (2H,
q, J 7.1, OCH2CH3), 2.78 (3H, s, CH3), 2.52 (3H, s, CH3), 1.34
(3H, t, J 7.1, OCH2CH3); 13C NMR (100 MHz; CDCl3) d 166.9
(C), 161.5 (C), 159.0 (C), 138.3 (CH), 122.5 (C), 120.9 (CH), 61.8
(CH2), 25.1 (CH3), 24.4 (CH3), 13.7 (CH3); MS (APcI) m/z (rel.
intensity) 180 (MH+, 95%), 152 (100), 134 (20).
General procedure for the cyclodehydration of aminodienone 3 in a
stainless steel conductive heating flow reactor
tert-Butyl 2,6-dimethylpyridine-3-carboxylate (4d). Obtained
as a pale yellow oil23 (Found: MH+, 208.1329. C12H18NO2 [MH]
requires 208.1332); Rf 0.59 (light petroleum–EtOAc, 1 : 1); IR
(film)/cm-1 nmax 2925, 2850, 1721, 1598, 1464, 1377, 1281, 1177,
A solution of aminodienone 3 (0.1 M) in toluene–glacial acetic acid
(5 : 1) was passed through a st◦ainless steel coil reactor (5 mL) of a
UNIQSIS FlowSynTM at 100 C and a flow rate of 2.5 mL min-1.
The outflow from the collection valve was quenched in a stirred
solution of saturated aqueous NaHCO3 and extracted with EtOAc
(3 ¥ 10 mL). The combined organic extracts were dried (MgSO4)
and evaporated in vacuo to give the corresponding pyridine 4.
1
1140, 1083, 775, 722; H NMR (400 MHz; CDCl3) d 7.94 (1H,
d, J 8.0, 4–H), 6.89 (1H, d, J 8.0, 5–H), 2.71 (3H, s, CH3), 2.44
(3H, s, CH3), 1.56 (9H, s, CMe3); 13C NMR (100 MHz; CDCl3) d
166.9 (C), 161.2 (C), 158.4 (C), 139.3 (CH), 124.1 (C), 120.8 (CH),
82.0 (C), 27.9 (CH3), 25.4 (CH3), 24.8 (CH3); MS (APcI) m/z (rel.
intensity) 208 (MH+, 10%), 152 (100), 134 (10).
Mesoscale production of pyridine 4a using a continuous flow
microwave reactor
Conclusions
A solution (0.05 M) of aminodienone 3a (7.90 g, 30.5 mmol) in
toluene–glacial acetic acid (5 : 1) (650 mL) was irradiated at 100 ◦C
using a MILESTONE BatchSynthTM microwave synthesizer at an
initial power of 150 W operating under continuous flow processing
on the FlowSynthTM platform at a flow rate of 1 L h-1. The
outflow was cooled using the system’s water-cooling jacket and
quenched immediately in a stirred solution of saturated aqueous
NaHCO3 and extracted with EtOAc (3 ¥ 100 mL). The combined
organic extracts were dried (MgSO4) and evaporated in vacuo to
give pyridine 4a (6.95 g, 94%) as a yellow solid, mp 41–43 ◦C
The Bohlmann–Rahtz synthesis of 2,3,6-trisubstituted pyridines
by cyclodehydration of the corresponding aminodienone was
originally reported using traditional conductive heating methods.
Following the discovery that this process can be facilitated using
microwave irradiation, heating these precursors in the presence of
a Brønsted acid gives excellent yields of the product in a very
short time without the need for chromatographic purification.
Using a Syrris microreactor platform, optimum residence times
were established for efficient reaction and these parameters trans-
ferred well to microwave-assisted batch, stop-flow and continuous
flow regimes, as well as to continuous flow conductive heating
apparatus. Differences in how the temperature of the reactor was
measured, being either the internal or external temperature of the
cell, gave small variations in the required residence time. Of the
◦
(MeOH) (lit.20a mp 44 C) (found: MH+, 242.1179; C15H16NO2
[MH] requires 242.1181); Rf 0.45 (light petroleum–ethyl acetate,
4 : 1); IR (KBr) nmax 2995, 2905, 2346, 1715, 1581, 1476, 1270,
1
1091, 1022 cm-1; H NMR (400 MHz, CDCl3) d 8.19 (1H, d, J
8.2), 7.98 (2H, m), 7.55 (1H, d, J 8.2), 7.44–7.35 (3H), 4.32 (2H,
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apparatus investigated, microwave-assisted batch processes in a
single-mode cavity were found mostly to be highly efficient and
were transferred successfully to continuous stop-flow production
in the Voyager system, continuous processing in the single-mode
Discover system and batch processing in a multimode synthesizer
on <4 mmol scale. Finally, through reaction dilution and small
adjustments in residence time, this reaction was transferred
successfully to mesoscale production using a continuous flow
multimode microwave reactor. This shows that current technology
does have the means to scale-up or scale-out microwave batch
experiments and that the reaction parameters for the Bohlmann–
Rahtz cyclodehydration reaction transfer reliably between differ-
ent technology platforms for mesoscale production.
It is premature to say whether these same design rules hold
for other systems and reactions of study. It could be anticipated
that, in a similar fashion, discoveries made in microwave batch
experiments, in particular for homogenous mixtures, will follow
similar principles. One would expect the scale up of these methods
would be relatively straightforward using a stop-flow microwave
platform, a single- or multi-mode microwave flow reactor or a
multimode batch reactor, providing with the latter that there was
not much more than a ten-fold increase in scale. Continuous flow
conductive heating platforms, on the other hand, operating on
either micro- or mesoscale production, would seem to give rise
to small but significant differences in the chemical efficiency of
reaction, that one could attribute to variations in heating profile
or temperature measurement. Whether these design rules hold for
the scale up of heterogeneous processes, such as reactions over a
catalyst bed, procedures with solid precipitation or crystallization
or for the processing of slurries, is another matter entirely and one
that will continue to provide significant challenges for continuous
flow platforms and microwave-assisted synthesis for some time to
come.
N. E. Leadbeater and V. A. Williams, Org. Process Res. Dev., 2008, 12,
41.
7 (a) K. G. Kabza, B. R. Chapados, J. E. Gestwicki and J. L. McGrath,
J. Org. Chem., 2000, 65, 1210; (b) B. M. Khadilkar and V. R. Madyar,
Org. Process Res. Dev., 2001, 5, 452; (c) E. Esveld, F. Chemat and J. van
Haveren, Chem. Eng. Technol., 2000, 23, 279; (d) E. Esveld, F. Chemat
and J. van Haveren, Chem. Eng. Technol., 2000, 23, 429; (e) W.-C. Shieh,
S. Dell and O. Repicˇ, Tetrahedron Lett., 2002, 43, 5607; (f) N. S. Wilson,
C. R. Sarko and G. P. Roth, Org. Process Res. Dev., 2004, 8, 535; (g) O.
Benali, M. Deal, E. Farrant, D. Tapolczay and R. Wheeler, Org. Process
Res. Dev., 2008, 12, 1007; (h) K. Mennecke, R. Cecilia, T. N. Glasnov,
S. Gruhl, C. Vogt, A. Feldhoff, M. A. L. Vargas, C. O. Kappe, U. Kunz
and A. Kirschning, Adv. Synth. Catal., 2008, 350, 717; (i) W. Solodenko,
K. Mennecke, C. Vogt, S. Gruhl and A. Kirschning, Synthesis, 2006,
1873; (j) R. J. J. Jachuck, D. K. Selvaraj and R. S. Varma, Green Chem.,
2006, 8, 29; (k) K. A. Savin, M. Robertson, D. Gernert, S. Green, E. J.
Hembre and J. Bishop, Mol. Diversity, 2003, 7, 171; (l) W.-C. Shieh,
S. Dell and O. Repicˇ, Org. Lett., 2001, 3, 4279.
8 (a) Microreactors in Organic Synthesis and Catalysis, ed. T. Wirth,
Wiley-VCH, Weinheim, 2008; (b) P. Watts and S. J. Haswell, Drug
Discovery Today, 2003, 8, 586; (c) C. Wiles and P. Watts, Expert
Opin. Drug Discovery, 2007, 2, 1487; (d) Microreaction Technology,
ed. W. Ehrfeld, Springer, Berlin, 1998; (e) W. Ehrfeld, V. Hessel and
H. Lc¸we, Microreactors, Wiley-VCH, Weinheim, 2000; (f) Microsystem
Technology in Chemistry and Life Sciences, ed. A. Manz and H. Becker,
Springer, Berlin, 1999.
9 (a) E. Comer and M. G. Organ, J. Am. Chem. Soc., 2005, 127, 8160;
(b) E. Comer and M. G. Organ, Chem.–Eur. J., 2005, 11, 7223; (c) G.
Shore, S. Morin and M. G. Organ, Angew. Chem., Int. Ed., 2006, 45,
2761.
10 P. He, S. J. Haswell and P. D. I. Fletcher, Appl. Catal., A, 2004, 274,
111.
11 I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer,
Chem.–Eur. J., 2006, 12, 4407.
12 T. M. Barnard, N. E. Leadbeater, M. B. Boucher, L. M. Stencel and
B. A. Wilhite, Energy Fuels, 2007, 21, 1777.
13 R. M. Paulus, T. Erdmenger, C. R. Becer, R. Hoogenboom and U. S.
Schubert, Macromol. Rapid Commun., 2007, 28, 484.
14 U. Kunz, A. Kirschning, H.-L. Wen, W. Solodenko, R. Cecilia, C. O.
Kappe and T. Turek, Catal. Today, 2005, 105, 318.
15 U. R. Pillai, E. Sahle-Demessie and R. S. Varma, Green Chem., 2004,
6, 295.
16 M. C. Bagley, R. L. Jenkins, M. C. Lubinu, C. Mason and R. Wood,
J. Org. Chem., 2005, 70, 7003.
17 T. N. Glasnov, D. J. Vugts, M. M. Koningstein, B. Desai, W. M. F.
Fabian, R. V. A. Orru and C. O. Kappe, QSAR Comb. Sci., 2006, 25,
509.
18 G. Jas and A. Kirschning, Chem.–Eur. J., 2003, 9, 5708.
19 (a) T. Razzaq, T. N. Glasnov and C. O. Kappe, Chem. Eng. Technol.,
2009, 32, 1702; (b) T. N. Glasnov, S. Findenig and C. O. Kappe, Chem.–
Eur. J., 2009, 15, 1001.
20 (a) F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265; (b) M. C.
Bagley, C. Glover and E. A. Merritt, Synlett, 2007, 2459.
21 J. D. Moseley, P. Lenden, M. Lockwood, K. Ruda, J.-P. Sherlock, A. D.
Thomson and J. P. Gilday, Org. Process Res. Dev., 2008, 12, 30.
22 (a) M. C. Bagley, R. Lunn and X. Xiong, Tetrahedron Lett., 2002, 43,
8331; (b) M. C. Bagley, Z. Lin and S. J. A. Pope, Chem. Commun., 2009,
5165.
Acknowledgements
We thank the BBSRC (BB/D524140) and EPSRC (GR/S25456)
for support of this work, Moharem El Gihani (Syrris), Mike Hawes
(Syrris), Matthew Burwood (a1-envirotech), Otman Benali (Uniq-
sis), Samantha Dunnage (Asynt), Laura Favretto (Milestone) and
Robin Wood (AstraZeneca) for valuable assistance, and CEM
(Microwave Technology) Ltd, Syrris Ltd., Milestone S.r.I. and
Uniqsis Ltd. for permitting us to test their apparatus in our
laboratories.
23 M. C. Bagley, C. Brace, J. W. Dale, M. Ohnesorge, N. G. Phillips,
X. Xiong and J. Bower, J. Chem. Soc., Perkin Trans. 1, 2002, 1663.
24 M. C. Bagley, J. W. Dale, M. Ohnesorge, X. Xiong and J. Bower,
J. Comb. Chem., 2003, 5, 41.
25 X. Xiong, M. C. Bagley and K. Chapaneri, Tetrahedron Lett., 2004, 45,
6121.
Notes and references
1 A. Kirschning, W. Solodenko and K. Mennecke, Chem.–Eur. J., 2006,
12, 5972.
2 (a) S. Caddick and R. Fitzmaurice, Tetrahedron, 2009, 65, 3325; (b) C. O.
Kappe, Chem. Soc. Rev., 2008, 37, 1127; (c) C. O. Kappe, Angew. Chem.,
Int. Ed., 2004, 43, 6250; (d) C. O. Kappe and A. Stadler, Microwaves in
Organic and Medicinal Chemistry, Wiley-VCH, Weinheim, 2005.
3 A. Kirschning and G. Jas, Top. Curr. Chem., 2004, 242, 209.
4 (a) T. N. Glasnov and C. O. Kappe, Macromol. Rapid Commun., 2007,
28, 395; (b) I. R. Baxendale, J. J. Hayward and S. V. Ley, Comb. Chem.
High Throughput Screening, 2007, 10, 802; (c) I. R. Baxendale and
M. R. Pitts, Chimica Oggi - Chemistry Today, 2006, 24, 41.
5 T. Cablewski, A. F. Faux and C. R. Strauss, J. Org. Chem., 1994, 59,
3408.
26 K. T. J. Loones, B. U. W. Maes, G. Rombouts, S. Hostyn and G. Diels,
Tetrahedron, 2005, 61, 10338.
27 (a) J. D. Ferguson, Mol. Diversity, 2003, 7, 281; (b) M. D. Bowman, J. R.
Schmink, C. M. McGowan, C. M. Kormos and N. E. Leadbeater, Org.
Process Res. Dev., 2008, 12, 1078; (c) H. Lehmann and L. LaVecchia,
˚
JALA, 2005, 10, 412; (d) R. Hoogenboom, R. M. Paulus, A. Pilotti and
U. S. Schubert, Macromol. Rapid Commun., 2006, 27, 1556.
28 J. D. Moseley and E. K. Woodman, Org. Process Res. Dev., 2008, 12,
967.
6 (a) J. M. Kremsner, A. Stadler and C. O. Kappe, Top. Curr. Chem.,
2006, 266, 233; (b) M. D. Bowman, J. L. Holcomb, C. M. Kormos,
29 J. Fetter, I. Nagy, L. T. Giang, M. Kajta´r-Peredy, A. Rockenbauer,
L. Korecz and G. Czira, J. Chem. Soc., Perkin Trans. 1, 2001, 1331.
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2245–2251 | 2251
©