A simple continuous flow microwave reactor

Article abstract of DOI:10.1021/jo0510235

A new simple procedure for microwave-assisted organic synthesis under continuous flow processing has been developed for use in a monomodal microwave synthesizer with direct temperature control using the instrument's in-built IR sensor. This design makes optimum use of the standing wave cavity to improve the energy efficiency of microwave-assisted flow reactions.

Full text of DOI:10.1021/jo0510235

oped.5 However, although modern monomodal instru-
ments dedicated for MAOS are very successful in small-
scale operations, efforts to process this technology in
continuous flow (CF) reactors are frustrated by the
physical limitations of microwave heating, with a pen-
etration depth of only a few centimeters and the limited
dimensions of the standing wave cavity. Current technol-
ogy has attempted to overcome these obstacles with
conventional instruments by the use of CF reactors that
pump the reagents through a small heated coil that winds
in and out of the cavity,6 with external temperature
monitoring using a fiber optic sensor, although alterna-
tive methods, such as using a multimode batch3,7 or CF
reactor,8 have also been described. We now wish to report
our new method for carrying out MAOS under CF
processing using a commercially available monomodal
microwave synthesizer.
A Simple Continuous Flow Microwave
Reactor
Mark C. Bagley,*,† Robert L. Jenkins,†
M. Caterina Lubinu,† Christopher Mason,‡ and
Robin Wood*,§
School of Chemistry, Main Building, Cardiff University,
Park Place, Cardiff, CF10 3AT, United Kingdom,
CEM Microwave Technology Ltd, 2 Middle Slade,
Buckingham, MK18 1WA, United Kingdom, and
AstraZeneca R&D, Alderley Park, Macclesfield,
Cheshire, SK10 4TF, United Kingdom
bagleymc@cf.ac.uk; robinwood@astrazeneca.com
Received May 23, 2005
The principal design of our flow cell featured the need
to make optimum use of the cavity and to be able to
monitor the temperature of the flow cell directly using
the instrument’s in-built IR sensor. To this end, a
standard pressure-rated glass tube (10 mL) fitted with
a custom built steel head was filled with sand (∼10 g)
between two drilled frits (Figure 1) to minimize disper-
sion and effectively create a lattice of microchannels,
charged with solvent (∼5 mL volume), sealed using PTFE
washers and connected to an HPLC flow system with a
back-pressure regulator (Figure 2). The flow cell was
inserted into the cavity of a self-tunable monomodal
microwave synthesizer, irradiated, and stabilized at the
required reaction temperature through moderation of
microwave power before the introduction of reagents into
the reactor. This system possessed a number of advan-
tages over commercially available coils, including simple
measurement of the flow cell temperature, no additional
and expensive equipment required short of an HPLC
pump, and the potential to carry out heterogeneous as
well as homogeneous reactions simply by immobilizing
a catalyst on the support in the glass tube.
A new simple procedure for microwave-assisted organic
synthesis under continuous flow processing has been devel-
oped for use in a monomodal microwave synthesizer with
direct temperature control using the instrument’s in-built
IR sensor. This design makes optimum use of the standing
wave cavity to improve the energy efficiency of microwave-
assisted flow reactions.
Microwave-assisted organic synthesis (MAOS) has
received increasing attention in recent years as a valu-
able alternative to the use of conductive heating for
accelerating chemical reactions.1 With no direct contact
between the chemical reactants and the energy source,
microwave-assisted chemistry is energy efficient, pro-
vides fast heating rates and enables rapid optimization
of procedures. From the early experiments in domestic
ovens2 to the use of multimodal3 or monomodal4 instru-
ments designed for organic synthesis, this technology has
been implemented worldwide and continues to be devel-
The cell was first tested in two well-precedented
microwave-assisted reactions operating under continuous
flow (CF) processing, the hydrolysis of chloromethyl-
(5) Reviews on MAOS include: (a) Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250. (b) Hayes, B. L. Aldrichim. Acta 2004, 37, 66. (c)
Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863. (d) Lidstro¨m, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (e)
Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.;
Mathe´, D. Synthesis 1998, 1213. (f) Gabriel, C.; Gabriel, S.; Grant, E.
H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213.
(g) Galema, S. A. Chem. Soc. Rev. 1997, 26, 233. (h) Caddick, S.
Tetrahedron 1995, 51, 10403. (i) Strauss, C. R.; Trainor, R. W. Aust.
J. Chem. 1995, 48, 1665.
† Cardiff University. Phone: +44-29-2087-4029. Fax: +44-29-2087-
4030.
‡ CEM Microwave Technology Ltd. Phone: +44-12-8082-2873. Fax
+44-12-8082-2342.
§ AstraZeneca R&D.
(6) http://www.cemsynthesis.com.
(1) (a) Adam, D. Nature 2003, 421, 571. (b) In Microwaves in Organic
Synthesis; Loupy, A.; Wiley-VCH: Weinheim, Germany, 2002.
(2) (a) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.;
Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279. (b) Giguere,
R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986,
27, 4945.
(7) Stadler, A.; Yousefi, B. H.; Dallinger, D.; Walla, P.; Van der
Eycken, E.; Kaval, N.; Kappe, C. O. Org. Process Res. Dev. 2003, 7,
707.
(8) (a) Cablewski, T.; Faux, A. F.; Strauss, C. R. J. Org. Chem. 1994,
59, 3408. (b) Kabza, K. G.; Chapados, B. R.; Gestwicki, J. E.; McGrath,
J. L. J. Org. Chem. 2000, 65, 1210. (c) Khadilkar, B. M.; Madyar, V.
R. Org. Process Res. Dev. 2001, 5, 452. (d) Esveld, E.; Chemat, F.; van
Haveren, J. Chem. Eng. Technol. 2000, 23, 279. (e) Esveld, E.; Chemat,
F.; van Haveren, J. Chem. Eng. Technol. 2000, 23, 429. (f) Shieh, W.-
C.; Dell, S.; Repie`, O. Tetrahedron Lett. 2002, 43, 5607.
(3) Raner, K. D.; Strauss, C. R.; Trainor, R. W.; Thorn, J. S. J. Org.
Chem. 1995, 60, 2456.
(4) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault,
P.; Mathe´, D. Synthesis 1998, 1213.
10.1021/jo0510235 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/23/2005
J. Org. Chem. 2005, 70, 7003-7006
7003

SCHEME 1. MW-Assisted CF Reactions
for the synthesis of pyridines based upon the Bohlmann-
Rahtz (B-R)11 reaction. The cyclodehydration of amino-
dienone 5 can be effected using conductive heating,12 and
with a Lewis13 or Brønsted14 acid catalyst, to give 2,3,6-
trisubstituted pyridine 6 directly and with total regio-
control, and this transformation has been applied in the
synthesis of pyridine-containing thiopeptide antibiotics,15
and their derivatives,16 as well as pyrido[2,3-d]pyrim-
idines,17 heterocyclic amino acids,18 nonsteroidal antiin-
flammatory agents,19 and combinatorial pyridine librar-
ies.20 Aminodienone 5 was prepared according to known
procedures12 and cyclodehydrated with CF processing
under homogeneous conditions in toluene-acetic acid (5:
1) over sand,21 comparing the results to batch experi-
ments carried out in a sealed tube and to the correspond-
ing homogeneous CF process with a Teflon heating coil
(Scheme 2). Under conditions that gave efficient conver-
sion (>98%) to pyridine 6, the processing rates of mate-
rial using our glass tube reactor were considerably higher
(Table 1). Additionally, CF reactions run at the same flow
rate used less magnetron energy in a glass tube than in
the heating coil (Table 1, Figures 3 and 4, and Supporting
Information), demonstrating that a glass tube CF reactor
FIGURE 1. Flow cell schematic.
FIGURE 2. Schematic diagram of the CF reactor.
thiazole 1 to give hydrochloride 29 and a Fischer indole
synthesis10 of 4 from hydrazine 3 and cyclohexanone in
acetic acid, in both cases using sand as the packing agent.
Under these conditions efficient conversions were achieved
at 150 °C, processing 1 g in 15-30 min, to give alcohol 2
and indole 4 in 85% and 91% yield, respectively (Scheme
1).
(11) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(12) Bagley, M. C.; Brace, C.; Dale, J. W.; Ohnesorge, M.; Phillips,
N. G.; Xiong, X.; Bower, J. J. Chem. Soc., Perkin Trans. 1 2002, 1663.
(13) (a) Bagley, M. C.; Dale, J. W.; Hughes, D. D.; Ohnesorge, M.;
Phillips, N. G.; Bower, J. Synlett 2001, 1523. (b) Bagley, M. C.; Glover,
C.; Merritt, E. A.; Xiong, X. Synlett 2004, 811.
(14) Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 1149.
(15) (a) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J.
J. Am. Chem. Soc. 2000, 122, 3301. (b) Moody, C. J.; Bagley, M. C.
Chem. Commun. 1998, 2049.
(16) (a) Bagley, M. C.; Dale, J. W.; Xiong, X.; Bower, J. Org. Lett.
2003, 5, 4421. (b) Bagley, M. C.; Chapaneri, K.; Xiong, X. Tetrahedron
Lett. 2004, 45, 6121. (c) Bagley, M. C.; Xiong, X. Org. Lett. 2004, 6,
3401.
(17) (a) Hughes, D. D.; Bagley, M. C. Synlett 2002, 1332. (b) Bagley,
M. C.; Hughes, D. D.; Lloyd, R.; Powers, V. E. C. Tetrahedron Lett.
2001, 42, 6585.
(18) (a) Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Pritchard,
G. J.; Rathmell, R. E. Tetrahedron 2003, 59, 2197. (b) Adlington, R.
M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J.; Tang, L. T. J. Chem.
Soc., Perkin Trans. 1 2000, 2311. (c) Baldwin, J. E.; Catterick, D.;
Pritchard, G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans. 1 2000, 303.
(d) Moody, C. J.; Bagley, M. C. Synlett 1998, 361. (e) Bagley, M. C.;
Dale, J. W.; Jenkins, R. L.; Bower, J. Chem. Commun. 2004, 102.
(19) Schroeder, E.; Lehmann, M.; Boettcher, I. Eur. J. Med. Chem.
1979, 14, 309.
(20) (a) Bagley, M. C.; Dale, J. W.; Ohnesorge, M.; Xiong, X.; Bower,
J. J. Comb. Chem. 2003, 5, 41. (b) Bashford, K. E.; Burton, M. B.;
Cameron, S.; Cooper, A. L.; Hogg, R. D.; Kane, P. D.; MacManus, D.
A.; Matrunola, C. A.; Moody, C. J.; Robertson, A. A. B.; Warne, M. R.
Tetrahedron Lett. 2003, 44, 1627.
(21) The glass tube was filled with standard quartz sand, 40-100
mesh, suitable for use in chromatography. When aminodienone 5 was
irradiated in toluene (without acetic acid) in the presence and absence
of sand in a sealed tube, no appreciable difference was observed (13%
versus 5% conversion, respectively), indicating that the sand has a
negligible (if any) effect on the cyclodehydration.
Following the success of these flow reactions, efforts
were made to develop a new microwave-assisted process
(9) For comparison, a solution of 1‚HCl (170 mg, 1.0 mmol) in H2O
(2 mL) was irradiated at 150 °C in a sealed glass tube (150 W) for 10
min and evaporated in vacuo to give 2‚HCl (151 mg, >98%). Compa-
rable conductive heating procedures carried out at 150 °C in a sealed
tube for 12 min, or at reflux for 30 min, gave thiazole 2‚HCl (90% or
85%, respectively, by HPLC). For related hydrolysis experiments using
conductive heating, see: (a) Houssin, R.; Pommery, J.; Salauen, M.-
C.; Deweer, S.; Goossens, J.-F.; Chavatte, P.; Henichart, J.-P. J. Med.
Chem. 2002, 45, 533. (b) Hagen, S. E.; Domagala, J.; Gajda, C.;
Lovdahl, M.; Tait, B. D.; Wise, E.; Holler, T.; Hupe, D.; Nouhan, C.;
Urumov, A.; Zeikus, G.; Zeikus, E.; Lunney, E. A.; Pavlovsky, A.;
Gracheck, S. J.; Saunders: J.; VanderRoest, S.; Brodfuehrer, J. Med.
Chem. 2001, 44, 2319.
(10) For comparison, a solution of cyclohexanone (196 mg, 2 mmol)
and 3 (220 mg, 2.2 mmol) in AcOH (4 mL) was irradiated at 150 °C in
a sealed glass tube (150 W) for 10 min and then evaporated in vacuo.
The residue was extracted with EtOAc, washed with H2O, aqueous
NaHCO3 solution (2 N) and brine, dried (MgSO4), and evaporated in
vacuo to give 4 (212 mg, 62%), mp 113-115 °C. The comparable
conductive heating procedure carried out at 150 °C in a sealed tube
for 10 min gave 4 (94%), mp 115-117 °C, after purification by column
chromatography on SiO2 eluting with light petroleum-EtOAc (9:1).
For related Fischer indole syntheses, see: (a) An, J.; Bagnell, L.;
Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62,
2505. (b) Robinson, B. Chem. Rev. 1969, 69, 227. (c) Hughes, D. L.
Org. Prep. Proced. Int. 1993, 25, 607. (d) Franco, L. H.; Palermo, J. A.
Chem. Pharm. Bull. 2003, 51, 975. (e) Lipin’ska, T. Chem. Heterocycl.
Compd. 2001, 37, 231. (f) Lipin’ska, T.; Guibe-Jampel, E.; Petit, A.;
Loupy, A. Synth. Commun. 1999, 29, 1349.
7004 J. Org. Chem., Vol. 70, No. 17, 2005

SCHEME 2. Bohlmann-Rahtz Synthesis of 6a
heating efficiency for reactions in the glass tube, as
heating coils by design wind in and out of the optimum
space.
In conclusion, a CF microwave reactor has been
developed for use with a monomodal instrument for
homogeneous reactions that enables the direct measure-
ment of flow cell temperature using an IR sensor and
possesses many advantages over existing CF technology.
The use of this instrumentation in a heterogeneous
process through use of an immobilized catalyst and the
transfer of this processing technology to large-scale
operations on a kilogram scale in an 80 mL cell are now
underway and will be reported in due course.
a Reagents and conditions: (a) 150 W (initial power), sealed
tube, 2 min; (b) 300 W (initial power), CF in Teflon heating coil,
1 mL/min; (c) 300 W (initial power) with simultaneous cooling,22
CF in a glass tube charged with sand, 1 or 1.5 mL/min.
TABLE 1. Comparing MAOS of Pyridine 6 Using Sealed
Tube or CF Processing
sealed CF
CF CF glass CF glass
tubea coilb coilb
tubec
tubec
Experimental Section
isolated yield, %
residency time,e min
flow rate, mL min-1
processing rate,
mmol min-1
>98
>98 85d
>98
3
>98
2
1.5
0.15
Microwave Reactions under CF Processing. The flow cell
(see the Supporting Information for flow cell assembly) was
primed with solvent at a given flow rate and stabilized at the
reaction temperature. A flask was charged with the reaction
mixture, which was then passed through the cavity at the given
flow rate, washing with further batches of solvent.
4-Hydroxymethylthiazole (2) Hydrochloride. A solution
of 4-chloromethylthiazole hydrochloride (2.0 g, 12 mmol) in H2O
(20 mL) was irradiated at 150 °C (150 W) in a pressure-rated
glass tube (10 mL) filled with sand (∼12 g) in a MW CF reactor
at a flow rate of 1.0 mL min-1. The cell was washed with H2O
(20 mL) at 150 °C and the combined solutions were evaporated
in vacuo. Purification by recrystallization (Et2O-EtOH) gave the
title compound (1.5 g, 85%) as pale brown crystals, mp 112-
114 °C (lit.23 mp 115 °C) (found: M•+, 115.0093; C4H5NOS
requires M 115.0092); 1H NMR (400 MHz, d6-DMSO) δ 9.35 (1H,
s), 8.20-7.70 (2H, br s), 7. 60 (1H, s), 4.65 (2H, s).
2
5f
3.3f
1.5
1
0.1
1
0.15
0.1
total energy,g kJ
1411 762
850
735
a Batch experiment in a sealed glass tube. b CF processing in a
Teflon heating coil. c CF processing in glass tube reactor charged
with sand. d Based upon 1H NMR analysis of crude reaction
mixture. e Residency in the microwave cavity. f Residency in the
heating coil. g Energy delivered by the magnetron in a flow
reaction, obtained by integrating the power versus time profile.
2,3,4,9-Tetrahydro-1H-carbazole (4). A solution of cyclo-
hexanone (1.96 g, 20 mmol) and phenylhydrazine (2.20 g, 22
mmol) in glacial AcOH (40 mL) was irradiated at 150 °C (150
W) in a pressure-rated glass tube (10 mL) filled with sand (∼12
g) in a MW CF reactor at a flow rate of 0.5 mL min-1. The cell
was washed with AcOH (15 mL) at 150 °C and the combined
solutions were evaporated in vacuo. The residue was extracted
with EtOAc, washed with H2O and brine, dried (MgSO4), and
evaporated in vacuo. Purification by recrystallization (EtOAc-
hexane) gave the title compound (3.1 g, 91%) as pale beige
crystals, mp 114-116 °C (lit.24 mp 115-116 °C) (found: M•+
,
FIGURE 3. Reaction profile of the CF heating coil reactor at
1.5 mL min-1 flow rate.
171.1057; C12H13N requires M 171.1048); 1H NMR (400 MHz,
d6-DMSO) δ 10.56 (1H, s), 7.30 (1H, d, J ) 7 Hz), 7.20 (1H, d, J
) 8 Hz), 6.96 (app t, 1H, J ) 7 Hz), 6.89 (1H, app t, J ) 8 Hz),
2.68 (2H, t, J ) 5.7 Hz), 2.60 (2H, t, J ) 6.0 Hz), 1.86-1.74
(4H).
Ethyl 2-Methyl-6-phenylpyridine-3-carboxylate (6):
Batch Synthesis in a Sealed Tube. A solution of amino-
dienone 511,12 (80 mg, 0.3 mmol) in PhMe-AcOH (5:1) (3 mL)
was irradiated for 2 min at 100 °C (150 W) in a sealed pressure-
rated glass tube. The reaction mixture was cooled by a flow of
compressed air then partitioned between saturated aqueous
NaHCO3 and EtOAc, and the aqueous layer was further
extracted with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated in vacuo to
give the title compound (75 mg, >98%) as a yellow oil. CF
Synthesis in a Heating Coil Reactor. A solution of amino-
dienone 5 (1.3 g, 5.1 mmol) in PhMe-AcOH (5:1) (50 mL) was
irradiated at 100 °C (300 W) in a Teflon heating coil in a MW
CF reactor at a flow rate of 1 mL min-1 and quenched in a
FIGURE 4. Reaction profile of the CF glass tube reactor at
1.5 mL min-1 flow rate.
offers (i) improved heating efficiency, (ii) the potential
for operation on a large scale, (iii) successful transfer from
batch to CF processing, and (iv) improved performance
over commercial Teflon heating coils. A higher processing
rate is possible with a glass tube reactor as a faster flow
rate can be maintained without compromising the reac-
tion temperature and yield. We have attributed this
observation to be a direct consequence of the improved
(22) With simultaneous cooling, IR temperature measurement may
not record the accurate bulk temperature of the reaction mixture;
see: Leadbeater, N, E.; Pillsbury, S. J.; Shanahan, E.; Williams, V. A.
Tetrahedron 2005, 61, 3565.
(23) Houssin, R.; Pommery, J.; Salau¨n, M.-C.; Deweer, S.; Goossens,
J.-F.; Chavatte, P.; He´nichart, J.-P. J. Med. Chem. 2002, 45, 533.
(24) Rogers, C. V.; Corson, B. B. Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, p 884.
J. Org. Chem, Vol. 70, No. 17, 2005 7005

solution of saturated aqueous NaHCO3. The mixture was
extracted three times with EtOAc and the organic extracts were
combined, dried (MgSO4), and evaporated in vacuo to give the
title compound (1.2 g, >98%) as a yellow solid. CF Synthesis
in a Glass Tube Reactor. A solution of aminodienone 5 (80
mg, 0.3 mmol) in PhMe-AcOH (5:1) (3 mL) was irradiated at
100 °C (300 W) in a pressure-rated glass tube (10 mL) filled with
(3H, s), 1.35 (3H, t, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ
165.7 (C), 159.1 (C), 158.1 (C), 138.5 (CH), 137.6 (C), 128.7 (CH),
128.0 (CH), 126.5 (CH), 122.8 (C), 116.5 (CH), 60.3 (CH2), 24.6
(Me), 13.5 (Me); MS (APcI) m/z (rel intensity) 241 (M+, 91%),
240 (69), 212 (32), 196 (100), 195 (98), 168 (43), 167 (40).
Acknowledgment. We thank the EPSRC (award to
M. C. Lubinu) and the Royal Society for their generous
support.
sand (∼12 g) in a MW CF reactor at a flow rate of 1.5 mL min-1
,
while simultaneously cooling the tube in a flow of compressed
air.22 The mixture was quenched immediately in a solution of
saturated aqueous NaHCO3 and extracted with EtOAc. The
organic extract was dried (MgSO4) and evaporated in vacuo to
give the title compound (75 mg, >98%) as a yellow solid, mp
44-45 °C (MeOH) (lit.11 mp 44 °C) (found: C, 74.4; H, 6.5; N,
5.6l calcd for C15H15NO2: C, 74.7; H, 6.3; N, 5.8) (found: MH+,
242.1182; C15H15NO2 requires MH 242.1182); IR (KBr) νmax 2980,
Supporting Information Available: General experimen-
tal procedures, diagrams and photographs of apparatus,
instructions for assembly, and all power/temperature versus
time flow reaction profiles for the synthesis of pyridine 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
2925, 2890, 1717, 1581, 1476, 1277, 1090, 1022 cm-1; H NMR
(400 MHz, CDCl3) δ 8.19 (1H, d, J ) 8.2 Hz), 8.00 (2H, m), 7.55
(1H, d, J ) 8.2 Hz), 7.41 (3H), 4.33 (2H, q, J ) 7.1 Hz), 2.85
JO0510235
7006 J. Org. Chem., Vol. 70, No. 17, 2005