An efficient and fast procedure for the Hantzsch dihydropyridine synthesis under microwave conditions

Article abstract of DOI:10.1055/s-2001-16043

Abstract: A single-mode microwave cavity synthesizer with temperature and pressure control was used to accelerate the Hantzsch synthesis of 4-aryl and 4-alkyl-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylates. In comparison with both conventional method

Full text of DOI:10.1055/s-2001-16043

1296
LETTER
An Efficient and Fast Procedure for the Hantzsch Dihydropyridine Synthesis
under Microwave Conditions
Liselotte Öhberg,a Jacob Westmanb
aSIK AB, Uppsala Science Park, SE-751 83 Uppsala, Sweden. bPersonal Chemistry AB, Hamnesplanaden 5, SE- 753 23 Uppsala, Sweden
Fax (46) 18 489 9200; E-mail: jacob.westman@personalchemistry.com
Received 10 May 2001
the amount of substrate or reagents the rate of temperature
Abstract: A single-mode microwave cavity synthesizer with tem-
increase will also change. When optimizing a chemical re-
perature and pressure control was used to accelerate the Hantzsch
action, one of the parameters that is important to have
control of is the temperature. The two reports described
synthesis of 4-aryl and 4-alkyl-2,6-dimethyl-1,4-dihydro-3,5-py-
ridinedicarboxylates. In comparison with both conventional meth-
ods and microwave-assisted reactions performed in a domestic above encouraged us to investigate if the yield could be
microwave oven, shorter reaction times and higher yields were ob-
increased and the reaction time decreased, by the use of a
tained. The improved yields under microwave conditions made it
microwave cavity with temperature control. We used a
possible to synthesize a small library, with acceptable purity.
SmithsynthesizerTM,9 a single-mode closed vessel micro-
Key words: microwave, multicomponent reaction, temperature
control, combinatorial synthesis
wave synthesizer with both temperature and pressure con-
trol.
In the search for optimal reaction conditions different
equivalents of benzaldehyde, ethyl aceto-cetate and aque-
The preparation of 1,4-dihydropyridines by classical
ous ammonium hydroxide were used. Temperature and
Hantzsch synthesis,1 a one-pot condensation of an alde-
reaction times were also varied (Table 1). When using the
hyde with alkyl acetoacetate and ammonia was developed
same temperature (110 °C) as described in the paper by
more than one hundred years ago. In the forties the inter-
Watanabe et al, we obtained 55% yield in only 10 min. It
est for this substance class increased due to their pharma-
should also be noted that the best results were obtained
cological activity.2 4-Aryl-1,4-dihydropyrdines form an
when the reaction temperature was more than 40° C above
important class of calcium channel antagonists.3 When
the normal boiling point, something that could only be
sterically hindered aldehydes are employed in classical
achieved in a closed vessel system.10
Hantzsch synthesis, extended reaction times under reflux
are needed and still the yields are generally low.4,5 Im-
Table 1 Optimization of Reaction Condition for the Synthesis
of Diethyl 4-phenyl-2,6-dimethyl-1,4-dihydro-3,5-pyridine
dicarboxylate
proved methods for the Hantzsch synthesis have previous-
ly been described by Alajarin et al 6 and Watanabe et al.7
The former authors were able to shorten the reaction times
from 12 hours to 4 minutes by using a domestic micro-
wave oven and sealed Teflon bombs. The yields obtained
however, were equal or slightly higher compared to those
obtained by conventional heating. Watanabe et al im-
proved the yields with the use of an autoclave. The draw-
back was extended reaction times compared to
conventional heating. Considerable attention has been re-
ceived for microwave assisted organic synthesis since
1986, but it is still a bit unclear why many reactions works
extremely well with microwave dielectric heating in com-
parison with conventional methods. It seems however to
be accepted that the different temperature range caused by
microwave dielectric heating is the main contributing fac-
tor to any acceleration observed.8 It is however important
to emphasize that in domestic microwave ovens, the tem-
perature will increase with time when the power is con-
stant, due to lack of temperature control which was well
observed by Alajarin et al since the Teflon bombs they
used were deformed when running at 500 W. Heating at a
fixed power of 400 W for 4 min, appeared for them to be
the best compromise between efficiency and safety. The
temperature increase is also dependent on the volume and
the content of the sample, which mean that when changing
b
aIsolated yield > 95% purity, volume 2.6 mL, solvent:
25% NH4OH (aq), cvolume 5.0 mL, solvent: 25% NH4OH (aq),
d volume 5.0 mL, solvent: ethanol.
Synlett 2001, No. 8, 1296–1298 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Efficient and Fast Procedure for the Hantzsch Dihydropyridine Synthesis
1297
Table 2 Synthesis of Diethyl 4-aryl-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylates (1a-1g) and Diethyl 4-alkyl-
2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylates (2a-2c)
avolume 2.6 mL, solvent: 25% NH4OH (aq), b volume 5.0 mL, solvent: 25% NH4OH (aq), ctemp: 110º, solvent: ethanol,
eisolated yield > 95% purity.
The so called superheating effect11 could only increase the recrystallized from ethanol and water. All 24 compounds
boiling point between 10-20 °C compared to the boiling were formed in moderate to good yield (39%-89%) and
point at atmospheric pressure. When excluding ethanol, a with low to excellent purity (53%-99%, determined by
common solvent in Hantzsch synthesis, from the reaction LC/MS) (Table 3). Reactions assisted with microwave di-
and using aqueous ammonium hydroxide both as a re- electric heating are described in the literature to give
agent and a solvent, a slightly higher yield was obtained shorter reaction times and often higher yields compared to
(see entry VII and VIII, Table 1). Various substituted ben- conventional methods.13 In conclusion, our results show
zaldehydes with electron withdrawing or electron donat- that microwave assisted synthesis of 1,4-dihydropyridines
ing groups and some aliphatic aldehydes were treated with with temperature control made it possible to increase the
ethyl acetoacetate and aqueous ammonium hydroxide yields compared to other methods and still with short re-
(Table 2) under the conditions found for entry V, Table 1. action times. With the use of the syntheziser, it was also
In our study we found that a reaction time of 10-15 min- possible to synthesize 24 compounds within a few hours.
utes was enough to get 20-40% higher yield compared
We also believe that the reason why microwave heating
both to conventional heating and the use of a domestic ov-
has not been more accepted in the scientific community
en.7 Compared to the yields obtained by the use of an au-
during the last 15 years is the lack of controllability and
toclave our yields are slightly lower. The reaction times
reproducability, and therefore we believe the introduction
are however much shorter, which is in many cases benefi-
of instrument with temperature control will change the
cial (Table 2). Due to short reaction times, high yield and
common attitude towards the technology.
easy work-up procedure by recrystallization were possi-
ble when following the protocol developed above (entry
Acknowledgement
V, Table 1), a serial synthesis of 24 compounds was per-
formed.
In order to increase the diversity,12 6 different aldehydes
and 4 different -keto esters or 1,3- dicarbonyl substrates
were used (Table 3). After the reaction the samples were
evaporated in a Savant Speed-vac and the residues were
We are grateful for financial support to the Foundation for Know-
ledge and Competence Development (Sweden), Prof. Åke Pilotti
for his assistance in the preparation of the manuscript and Mr An-
dreas Hoel for assistance in the library production.
Synlett 2001, No. 8, 1296–1298 ISSN 0936-5214 © Thieme Stuttgart · New York

1298
L. Öhberg, J. Westman
LETTER
Table 3 Showing the Building Blocks Used in the Library Syntheses.
aIsolated yield, bpurity determined by LC/MS analysis, cthe product precipitated as an oil together with the starting
materials.
microwave cavity. The reaction mixture was stirred at 140° C
for 10 min. (see Tables 1-3). After completion, crude reaction
mixture was evaporated to dryness and purified on a silica gel
column (heptane/ethyl acetate 3:1-2:1), which gave pure 2,6-
dimethyl-1,4-dihydro-4-phenyl-3,5-pyridinecarboxylate in
84% yield as a white solid. The product was recrystallized
from EtOH and water giving a white powder (mp 156-157 C
(lit. Ref4. mp 157-159 C)), 13C NMR(CDCl3): 14.6 (CH3),
19.8 (CH3), 40.0 (CH), 60.1 (CH2O-), 104.4 (C=C), 126.5-
128.4 (aromatic C), 144.4 (C=C), 148.2 (aromatic C), 168.1
(carbonyl C); 1H NMR (CDCl3): 1.27 (t, 6H, CH3), 2.35 (s,
6H, CH3), 4.15 (m, 4H, CH2O-), 5.04 (s, 1H, CH), 5.88 (s, 1H,
NH), 7.10-7.35 (5H, aromatic H).
References and Notes
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1983, 761.
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K. D.; Strauss, C. R.; Vyskoc, F.; Mokbel, L. J. Org. Chem.,
1993, 58, 950. Galema, S. A. Chem. Soc. Rev., 1997, 26, 233.
(9) SmithSyntheziser is availible from Personalchemistry.
(10) General procedure: The preparation of Diethyl 4-phenyl-2,6-
dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is
representative for all syntheses.
(11) Baghurst, D. R.; Mingos, D.M. P. J. Chem. Soc. Commun.
1992, 674.
(12) Cotterill, I. C.; Usyatinsky, A. Y.; Arnold, J. M.; Clark, D. S.;
Dordick, J. S.; Michels, P. C.; Khmelnitsky, Y. L.
Tetrahedron Lett. 1998, 39, 1117.
(13) Majetich, G.; Hicks, R. Res. Chem. Intermed. 1994, 20, 61.
Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665.,
Caddick, S. Tetrahedron 1995, 36, 10403.
Benzaldehyde (2.5 mmol), ethyl acetoacetate (12.5 mmol) and
25% aqueous ammonium hydroxide (10.0 mmol) were placed
in a glass vial, sealed with a teflon septa and then placed in the
Article Identifier:
1437-2096,E;2001,0,08,1296,1298,ftx,en;D10401ST.pdf
Synlett 2001, No. 8, 1296–1298 ISSN 0936-5214 © Thieme Stuttgart · New York