Rapid preparation of pyranoquinolines using microwave dielectric heating in combination with fractional product distillation

Article abstract of DOI:10.1016/j.tetlet.2007.02.052

4-Hydroxy-6-methyl-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione was prepared by microwave-assisted cyclocondensation of N-methylaniline with 2 equiv of diethyl malonate. Key to the success of the synthesis was the use of open vessel controlled microwave heating technology, allowing the simultaneous removal of the formed ethanol from the reaction mixture by fractional distillation.

Full text of DOI:10.1016/j.tetlet.2007.02.052

Tetrahedron Letters 48 (2007) 2513–2517
Rapid preparation of pyranoquinolines using microwave
dielectric heating in combination with fractional product distillation
Tahseen Razzaq and C. Oliver Kappe*
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry,
Karl-Franzens University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 29 December 2006; revised 5 February 2007; accepted 7 February 2007
Available online 15 February 2007
Abstract—4-Hydroxy-6-methyl-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione was prepared by microwave-assisted cyclocondensation
of N-methylaniline with 2 equiv of diethyl malonate. Key to the success of the synthesis was the use of open vessel controlled micro-
wave heating technology, allowing the simultaneous removal of the formed ethanol from the reaction mixture by fractional
distillation.
ꢀ
2007 Elsevier Ltd. All rights reserved.
In the past few years, heating and driving chemical reac-
tions by microwave energy has been an increasingly
popular theme in the scientific community. This non-
classical heating technique is slowly moving from a lab-
oratory curiosity to an established technique heavily
used in both academia and industry. The efficiency of
be eliminated from the reaction mixture, for example,
in the case of an equilibrium process.
3
,4
Despite the large body of published work on microwave
5
,6
chemistry using solvents under open vessel conditions,
we are not aware of any report that describes the com-
bination of microwave heating with the simultaneous
‘
microwave flash heating’ in dramatically reducing reac-
7
tion times and increasing product yields/purities is one
preparative distillation of one of the reaction products.
1
,2
of the key advantages of this enabling technology.
In the present Letter we disclose the one-pot preparation
of a synthetically valuable pyranoquinolone heterocycle
Most of the published applications of controlled micro-
wave-assisted organic synthesis (MAOS) today involve
the use of sealed vessel technology. Here the advantages
of rapid and direct volumetric microwave heating are
combined with the capability to superheat solvents far
above their boiling points in a sealed vessel (autoclave).
This method allows higher reaction temperatures to be
reached than under conventional reflux conditions,
and therefore often results in significant rate enhance-
ments when compared to the experiment carried out at
employing a microwave-assisted cyclocondensation
reaction. This process requires the use of open vessel
microwave technology with continuous removal of the
ethanol product from the reaction mixture by fractional
distillation from the reagents.
The specific example discussed herein involves the con-
densation of N-methylaniline with 2 equiv of diethyl
malonate, producing pyrano[3,2-c]quinolone 2 in a
one-pot double cyclocondensation process (Scheme
1
,2
8,9
the boiling point of the solvent. There are some cases,
however, where the use of open vessel microwave tech-
nology is essential for a particular transformation to
1). Pyranoquinolone heterocycles of type 2 are valu-
able intermediates for the preparation of a variety of
functionalized 2-quinolone derivatives via chemical deg-
3
,4
10
proceed efficiently. Typically, this is the case when
one of the (volatile) products or by-products needs to
radation of the pyrone ring. Traditionally, the prepa-
ration of 2 (and its analogs) is performed in a round
bottom flask equipped with a reflux condenser and dis-
8
–10
tillation head.
The setup is immersed into an oil bath
(or heating mantle) and during 3–5 h of conductive heat-
Keywords: Heterocycles; Cyclocondensation; Microwave irradiation;
ing, the formed ethanol product (4 equiv) is continu-
ously removed by distillation from the reaction
mixture. Employing diphenyl ether (bp 259 ꢁC) as a
Distillation.
*
Corresponding author. Tel.: +43 316 3805352; fax: +43 316
809840; e-mail: oliver.kappe@uni-graz.at
8
,9
3
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.052

2514
T. Razzaq, C. O. Kappe / Tetrahedron Letters 48 (2007) 2513–2517
Scheme 1.
solvent, the temperature of the reaction mixture gradu-
ally rises to the boiling point of diphenyl ether as the
two substrates, N-methylaniline (bp 196 ꢁC), and diethyl
malonate (bp 199 ꢁC) are being consumed. At this stage
the formation/distillation of ethanol stops and the
double cyclocondensation is completed.
Figure 1. Multimode microwave reactor setup (MicroSYNTH, Mile-
stone s.r.l.) for combined synthesis and simultaneous fractionated
product distillation. A: round bottom reaction flask with magnetic stir
bar (Pyrex, 500 mL); B: 8 · 6.5 cm cylinder made of Weflon (black,
top) and PTFE (white, bottom); C: remote infrared temperature
sensor; D: Vigreux column (60 cm length); E: fiber-optic temperature
sensor; F: distillation head with condenser (water cooled); G:
graduated receiver. Inset H: fiber-optic temperature probe in protective
thermowell mounted on distillation head. Inset I: mercury thermo-
meter on distillation head.
We were interested to explore how direct microwave
1
,2
dielectric heating of the reaction mixture would influ-
ence the outcome of this cyclocondensation reaction.
Based on our experience with a related cyclocondensa-
3
tion process, we were not surprised to find that experi-
ments using sealed vessel microwave heating in a single-
mode reactor failed. Microwave irradiation of a mixture
of 0.005 mol of N-methylaniline, 0.01 mol of diethyl
malonate and 4 mL of diphenyl ether in a 10 mL sealed
reaction vessel at 250 ꢁC for 90 min led to only a small
amount (<5%) of the desired pyranoquinolone 2 being
1
formed. As confirmed by HPLC and H NMR analysis,
For accurately monitoring the reaction temperature in
the microwave heated runs, we investigated both the
possibility of internal temperature measurement via a
fiber-optic probe and the determination of the outside
surface temperature of the reaction vessel with the
built-in IR sensor mounted in the sidewall of the cav-
the majority of the crude reaction mixture under these
conditions still consisted of unreacted starting materials
and a minor amount (ca. 10%) of the monocondensation
product N-methyl-4-hydroxy-2(1H)-quinolinone (1).
The progress of the reaction could be monitored online
by following the pressure build up in the microwave ves-
sel. While the reaction temperature quickly reached the
desired set temperature of 250 ꢁC within 2–3 min, the
initially observed autogenic pressure at 250 ꢁC of 4 bar
gradually increased to 6.5 bar after 90 min as a conse-
quence of the produced volatile ethanol (see Supplemen-
tary data for more details).
1
1
ity. Since simultaneous monitoring of both tempera-
ture values revealed only minor discrepancies between
the two methods, we decided to employ the IR sensor
for establishing the reaction temperature and to use
the fiber-optic probe for online monitoring of the tem-
perature at the distillation head (Fig. 1). Our initial trial
runs were conducted with 0.2 moles of N-methylaniline
(ca. 23 mL), 0.4 moles of diethyl malonate (ca. 62 mL)
We therefore moved to open vessel microwave technol-
ogy and since we were also interested in the scale-up
possibilities of this process, we decided to use a larger
and 100 mL of diphenyl ether as solvent in a set-up sim-
ilar to the one shown in Figure 1, but using a shorter
Vigreux column (30–45 cm). Attempts to heat the reac-
tion mixture as quickly as possible to the boiling point
of diphenyl ether (259 ꢁC) in the 1000 W microwave
reactor showed that ethanol started to be produced at
around 150 ꢁC and that it was possible to raise the tem-
perature within 5 min to ca. 200 ꢁC. In the case of too
rapid heating (i.e., by applying high levels of microwave
power), the observed refluxing of the reaction mixture
was very intense and the temperature at the distillation
head (at both positions, see Fig. 1) increased above
80 ꢁC, indicating an undesired co-distillation of the N-
methylaniline (bp 196 ꢁC) and/or diethyl malonate (bp
6
multimode microwave reactor and to perform the
reaction on a 0.2 mol scale. Our experimental setup
was designed to closely mimic the traditional oil bath
experiment (Fig. 1). Thus, a 500 mL 2-necked round
bottom flask was placed inside the multimode reactor
and was fitted with a 60 cm Vigreux column through
the protective mount in the ceiling of the microwave
cavity. A standard atmospheric pressure distillation kit
was attached to the top of the column and was con-
nected to a graduated receiver for measuring the amount
of the collected ethanol.

T. Razzaq, C. O. Kappe / Tetrahedron Letters 48 (2007) 2513–2517
2515
1
99 ꢁC) starting materials. A careful balance between
(3.3 L of oil, max temperature 240 ꢁC) and one employ-
ing a high-powered heating mantle (300 W, max temper-
ature >350 ꢁC). Confirming previous literature
the length of the Vigreux column, the amount of micro-
wave power used and the programmed temperature pro-
file ultimately allowed us to complete the synthesis of
pyranoquinolone 2 in 82 min following the tempera-
ture-power-time profile shown in Figure 2. After several
programmed heating ramps from room temperature to
8
–10
reports,
the formation of pyranoquinolone 2 in the
comparatively inert oil bath with a temperature limit
of 240 ꢁC required 26 h to reach completion, but other-
wise provided the desired product in similar yield and
purity as in the microwave experiment. In contrast, the
heating mantle experiment allowed us to more closely
mimic the time–temperature profile followed in the
microwave run (Fig. 2), and therefore also required a
similar time period (120 min).
2
33 ꢁC (21 min), the temperature of the reaction mixture
was continuously raised to 259 ꢁC within a 55 min time
period and then kept at this temperature for an addi-
tional 6 min. At this point the double cyclocondensation
shown in Scheme 1 was completed, all starting material
consumed and the formation/distillation of ethanol
(
44.5 mL, theoretical amount: 46.5 mL) had ceased,
As far as the energy balance for the three processes is
concerned, we have employed a commercially available
domestic electricity meter (‘Watt-hour meter’) to mea-
clearly indicated by a drop of the distillation head tem-
perature (Fig. 2). Addition of dioxane to the ca. 120 ꢁC
warm reaction mixture led to crystallization of the crude
reaction product, which was subsequently collected by
filtration to furnish pyranoquinolone 2 in 81% yield
and excellent purity (>98% by HPLC and H NMR).
The published oil bath protocol requires 3–5 h and pro-
vided a 66% product yield.
1
2
sure the consumed energy in all three processes. As
expected, the oil bath experiment not only required the
longest time (26 h) but also consumed the most energy
(17.59 kW h, Table 1). We were surprised to find that
the heating mantle experiment required only 0.62 kW h
and therefore proved to be the most energy efficient
way to produce pyranoquinolone 2. The microwave
run involving the 1000 W multimode cavity consumed
three times as much energy as the heating mantle exper-
iment. This is even true if the energy used for magnetic
stirring and the cooling fan in the reactor was taken into
account (Table 1). It seems that the comparatively low
efficiency of the magnetrons in converting electrical
1
8
Having optimized the synthesis of pyranoquinolone 2
via open vessel microwave technology on a 0.2 mol
scale, we were interested to compare these results with
8
the previously published traditional oil bath protocol,
not only in terms of reaction time and product yield,
but also in terms of the required energy consumption.
For this purpose we have conducted two additional con-
trol experiments on the same scale employing a similar
experimental set-up: one in a conventional oil bath
1
3
energy into electromagnetic radiation (70%) and the
amount of power inadvertently lost in a comparatively
large multimode system are perhaps responsible for this
outcome.
In addition to the microwave-assisted synthesis of pyr-
ano[3,2-c]quinolone 2, we also wanted to adapt the
two-step degradation of 2 into N-methyl-4-hydroxy-
3
2
2
1
1
00
50
00
50
00
8
00
T1
700
2(1H)-quinolinone (1) to a microwave protocol. Tradi-
tionally, the ring-opening/decarboxylation of pyrano-
quinolone 2 to 3-acetylquinolone 3 is performed by
heating of a solution of pyranoquinolone 2 with aque-
ous sodium hydroxide (5.0 equiv) in 1,2-ethanediol
as solvent, furnishing the desired product in very
high product yield within 1 h (after precipitation by
6
5
4
3
2
1
0
00
00
00
00
00
00
P
8
acidification) (Scheme 2). After some experimentation
T2
5
0
0
Table 1. Comparison of energy efficiency between three different
heating modes in the synthesis of pyranoquinolone 2 (Scheme 1)
0
10
20
30
40
50
60
70
80
a
Heating method
Reaction time
min)
Energy
consumption (kW h)
Time [min]
b
(
Figure 2. Temperature and power profile for the open vessel cyclo-
condensation of N-methylaniline and diethyl malonate in diphenyl
ether (Scheme 1). Multimode microwave irradiation with simultaneous
distillation of ethanol product (Fig. 1). The following heating profiles
were programmed: step 1: 18–193 ꢁC (5 min, max power 850 W), step
Oil bath
1560
120
82
17.59
0.62
1.67
1.29
Heating mantle
Microwave heating
Microwave heating
c
82
a
2
(
6
: 193–230 ꢁC (8.5 min, max power 800 W), step 3: 230–233 ꢁC
7.5 min, max power 700 W), step 4: 233–259 ꢁC (55 min, max power
00 W), step 5: hold at 259 ꢁC (6 min, max power 600 W), step 6: cool
For a graphical representation of the employed heating apparatus,
see the Supplementary data.
An electricity meter (Energy Check 3000, Voltcraft) was set in serial
between the power supply and the heating device. The power con-
sumption of the computer terminal of the microwave instrument was
not considered.
b
to 125 ꢁC (15 min, not shown). The total microwave irradiation time
was 82 min. Shown is the reaction temperature T1 measured with the
IR sensor, the temperature at the distillation head T2 monitored by
fiber-optic probe, and the microwave power P (pulsed microwave
power).
c
After adjustment for the energy consumption for magnetic stirring
and the cooling fan (0.38 kW h).

2516
T. Razzaq, C. O. Kappe / Tetrahedron Letters 48 (2007) 2513–2517
We are indebted to Professor W. Stadlbauer for helpful
suggestions and comments and to Hana Prokopcov a´ for
experimental assistance.
Supplementary data
Supplementary data associated with this article (experi-
mental procedures, images of equipment) can be found
in the online version at doi:10.1016/j.tetlet.2007.02.052.
References and notes
1
. (a) Books: Microwaves in Organic Synthesis, 2nd ed.;
Loupy, A., Ed.; Wiley-VCH: Weinheim, 2006; (b) Kappe,
C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005; (c) Microwave-
Assisted Organic Synthesis; Lidstr o¨ m, P., Tierney, J. P.,
Eds.; Blackwell: Oxford, 2005; (d) Hayes, B. L. Microwave
Synthesis: Chemistry at the Speed of Light; CEM:
Matthews, NC, 2002.
Scheme 2.
involving variation of the solvent, amount of base, reac-
tion time, and temperature, we arrived at microwave-
assisted conditions that allowed the ring-opening step
to proceed within only 4 min (including a 3 min heating
ramp) providing a similar high product yield. One of the
best set of conditions was found to involve ethanol as
solvent, 4.0 equiv of base and 190 ꢁC reaction tempera-
ture. After successful optimization on a small scale in a
sealed microwave vessel, the preparation of 3-acetylqui-
nolone 3 was scaled to 100 mL reaction volume (0.04
mol) in a high-pressure microwave autoclave system
2
3
. Recent reviews: (a) Kappe, C. O. Angew. Chem., Int. Ed.
2
004, 43, 6250; (b) Hayes, B. L. Aldrichim. Acta 2004, 37,
6
6; (c) De La Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem.
Soc. Rev. 2005, 34, 164.
. (a) Stadler, A.; Pichler, S.; Horeis, G.; Kappe, C. O.
Tetrahedron 2002, 58, 3177; (b) Lange, J. H. M.; Verveer,
P. C.; Osnabrug, S. J. M.; Visser, G. M. Tetrahedron Lett.
2001, 42, 1367; (c) Rivkin, A.; Adams, B. Tetrahedron
Lett. 2006, 47, 2395.
(
Milestone HPR 100 mL rotor), which tolerated the
4
5
6
. (a) Strohmeier, G. A.; Kappe, C. O. J. Comb. Chem. 2002,
ca. 24 bar reaction pressure resulting from the super-
heated ethanol. Using these conditions, the desired
4, 151; (b) Vo-Tanh, G.; Lahrache, H.; Loupy, A.; Kim,
I.-J.; Chang, D.-H.; Jun, C.-H. Tetrahedron 2004, 60,
3
-acetylquinolone 3 was produced in 93% isolated yield.
5
4
539; (c) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004,
5, 7205; (d) Nosse, B.; Schall, A.; Jeong, W. B.; Reiser, O.
Finally, the deacetylation 3!1 was performed using
Adv. Synth. Catal. 2005, 347, 1869.
7
0% sulfuric acid at 200 ꢁC in 4 min (including a 2 min
. For reviews on microwave-assisted synthesis using open
vessel technology in conjunction with organic solvents,
see: (a) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.;
Jayaraman, M.; Manhas, M. S. Chemtech 1997, 27, 18; (b)
Bose, A. K.; Manhas, M. S.; Ganguly, S. N.; Sharma, A.
H.; Banik, B. K. Synthesis 2002, 1578.
. For recent examples of large scale open vessel microwave
synthesis in dedicated multimode instruments, see: (a)
Leadbeater, N. E.; Williams, V. A.; Barnard, T. M.;
Collins, M. J., Jr. Org. Proc. Res. Dev. 2006, 10, 833; (b)
Leadbeater, N. E.; Williams, V. A.; Barnard, T. M.;
Collins, M. J., Jr. Synlett 2006, 2953; (c) Barnard, T. M.;
Vanier, G. S.; Collins, M. J., Jr. Org. Proc. Res. Dev. 2006,
10, 1233; For a review on microwave synthesis on large
scale, see: (d) Kremsner, J. M.; Stadler, A.; Kappe, C. O.
Top. Curr. Chem. 2006, 266, 233.
heating ramp) on a 0.035 mol scale (20 mL). The iso-
lated product yield of 95% compared well with the tra-
ditional thermal protocol employing 90% sulfuric acid
at 140 ꢁC for 15 min.
8
In conclusion we have demonstrated that the combina-
tion of microwave heating under atmospheric pressure
conditions with simultaneous product distillation is
a very valuable—but underutilized—technology for
organic synthesis. In the specific example provided
herein, the cyclocondensation of N-methylaniline with
diethyl malonate leading to pyrano[3,2-c]quinolone 2
must be carried out under these unusual reaction condi-
tions. The conversion in this transformation can be
conveniently monitored by the amount of the formed
ethanol collected in the receiver and the rate of the
reaction can be controlled by the level of the applied
microwave power. Using more common sealed vessel
microwave technology virtually no reaction takes place.
7
. The only exception we are aware of involves the micro-
wave-assisted distillation of essential oils. For more
details, see: Chemat, F.; Lucchesi, M.-E. In Microwaves
in Organic Synthesis; 2nd ed.; Loupy, A., Ed., Wiley-VCH:
Weinheim, 2006, Chapter 2, pp 959–985.
8
. (a) Roschger, P.; Stadlbauer, W. Liebigs Ann. Chem. 1990,
8
21; For the original synthesis of 2, see: (b) Bowman, R.
E.; Campbell, A.; Tanner, E. M. J. Chem. Soc 1959, 444.
. For related examples, see: (a) Roschger, P.; Fiala, W.;
Stadlbauer, W. J. Heterocycl. Chem. 1992, 29, 225; (b)
Kappe, T.; Aigner, R.; Hohengassner, P.; Stadlbauer, W.
J. Prakt. Chem. 1994, 336, 596; (c) Stadlbauer, W.;
Badawey, E.-S.; Hojas, G.; Roschger, P.; Kappe, T.
Molecules 2001, 6, 345.
9
Acknowledgments
This work was supported by a grant from the Christian
Doppler Society (CDG). T.R. thanks the Higher Educa-
tion Commission of Pakistan for a Ph.D. scholarship.

T. Razzaq, C. O. Kappe / Tetrahedron Letters 48 (2007) 2513–2517
2517
1
1
0. For a review, see: Kappe, T. Il Farmaco 1999, 54, 309.
1. For a discussion of different temperature monitoring
methods in microwave synthesis, see: (a) N u¨ chter, M.;
Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004,
12. For a previous comparison of energy consumption using
this technique, see: Gronnow, M. J.; White, R. J.; Clark, J.
H.; Macquarrie, D. J. Org. Process Res. Dev. 2005, 9,
516.
6
, 128; (b) N u¨ chter, M.; Ondruschka, B.; Weiß, D.; Beckert,
R.; Bonrath, W.; Gum, A. Chem. Eng. Technol. 2005, 28,
71; (c) Leadbeater, N. E.; Pillsbury, S. J.; Shanahan, E.;
13. Roberts, B. A.; Strauss, C. R. In Microwave-Assisted
Organic Synthesis; Lidstr o¨ m, P., Tierney, J. P., Eds.;
Blackwell: Oxford, 2005; Chapter 9, pp 237–271, in
particular p 266.
8
Williams, V. A. Tetrahedron 2005, 61, 3565; (d) Kremsner,
J. M.; Kappe, C. O. J. Org. Chem 2006, 71, 4651.