Microwave-enhanced hydrogenations at medium pressure using a newly constructed reactor

Article abstract of DOI:10.1016/j.tetlet.2005.01.002

The newly constructed reactor for hydrogenations in microwave fields allows to work out the syntheses up to 25 bar. This is shown for the synthesis of intermediates of active agents. In order to demonstrate the superiority of the microwave-assisted hydrogenation, the reactions are compared with classical hydrogenations. The following reactions were carried out: dearomatization, debenzylation, azide hydrogenation and the hydrogenation of strychnine.

Full text of DOI:10.1016/j.tetlet.2005.01.002

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1247–1249
Microwave-enhanced hydrogenations at medium pressure using
a newly constructed reactor
Eberhard Heller, Werner Lautenschla¨ger and Ulrike Holzgrabe*
Institut fu¨r Pharmazie und Lebensmittelchemie, Universita¨t Wu¨rzburg, Am Hubland D-97074, Germany
Received 17 November 2004; revised 23 December 2004; accepted 4 January 2005
Available online 18 January 2005
Abstract—The newly constructed reactor for hydrogenations in microwave fields allows to work out the syntheses up to 25 bar. This
is shown for the synthesis of intermediates of active agents. In order to demonstrate the superiority of the microwave-assisted
hydrogenation, the reactions are compared with classical hydrogenations. The following reactions were carried out: dearomatiza-
tion, debenzylation, azide hydrogenation and the hydrogenation of strychnine.
Ó 2005 Elsevier Ltd. All rights reserved.
The concept of microwave-assisted organic synthesis is
well established for a huge variety of reactions which
were recently summarized in Microwaves in Organic
Synthesis.1 However, only a few microwave-enhanced
hydrogenations were reported, for example,2–6 whereas
Yanagida and co-workers4a and Pillai et al.4b used
hydrogen gas at normal air pressure for the reaction,
other authors applied solid hydrogen donors. In this
paper we want to report on hydrogenation reactions
performed in a newly constructed reactor with hydrogen
gas at medium pressure (up to 25 bar). In order to dem-
onstrate the superiority of the microwave-assisted
hydrogenation reaction temperature, time and yield will
be compared to the results obtained under classical con-
ditions. The following hydrogenations were carried out:
dearomatization, debenzylation, azide hydrogenation
and hydrogenation of strychnine. All synthesized com-
pounds are intermediates on the synthesis pathway to
pharmacologically active agents, which were synthesized
in our laboratory both by the classical way and by
microwave irradiation.
and optimized in collaboration with MLS/Milestone
for a Milestone Ethos 1600 during the course of the
described reactions. The reactor consists of a polytetra-
fluoroethylene (PTFE) tube (4.0 cm inner diameter,
25.5 cm length) which is covered by a polyetheretherke-
tone (PEEK) tube to protect the system from explo-
sions. The gas inlet including a back pressure valve,
preventing the back flow of the reaction mixture into
the hydrogen tube is on the bottom side of the micro-
wave oven outside of the reaction room. On the top of
the tube again outside of the reaction room, a pressure
sensor, a temperature sensor, an excess pressure valve
(30 bar) and an outlet valve are located. The Ethos
1600 system is equipped with a solvent sensor (QP-sen-
sor). If there is a leakage in the vessel and solvent vapour
penetrates into the cavity the microwave heating will
stop immediately.7 The minimum volume of the solution
is 20 mL and the maximum 200 mL.
Dearomatization: pyridine-2-carboxylic acid 1 was
hydrogenated to give pipecolic acid 2, which is used as
starting material in the synthesis of AFDX 384 deriva-
tives8 which are allosteric modulators of the muscarinic
M2-receptor. The conditions of the microwave-assisted
reaction (25 bar, 125 °C and 1 h) were different from
the conditions classically described in Ref. 9 (2.5–
60 bar, 25–160 °C, 2–24 h). However, a 99% yield was
achieved (85–100%9) and the reaction time was substan-
tially shortened.
The reactors that are commercially available for pres-
sure reactions in the microwave field cannot be used
for this purpose. Thus, a new hydrogenation reactor,
taking this reactor as a starting point, was constructed
Keywords: Microwave-enhanced hydrogenations; Medium pressure;
Hydrogen gas.
*
Corresponding author. Tel.: +49 931 8885461; fax: +49 931
8885494; e-mail: u.holzgrabe@pzlc.uni-wuerzburg.de
MLS GmbH, Mikrowellen-Laborsysteme, Auenweg 37, D-88299
Leutkirch im Allga¨u, Germany.
The piperidinium compound 4 is a key intermediate for
the synthesis of a series of acetylcholinesterase inhibitors
of the oxime type.10 Compound 4 can be obtained by
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.002

1248
E. Heller et al. / Tetrahedron Letters 46 (2005) 1247–1249
hydrogenation of the corresponding pyridinium bro-
mide 3. Whereas 72h are needed at 50 bar hydrogen
and 25 °C for quantitative reaction (85% yield), the reac-
tion is completed after 1.5 h at 20 bar and 60 °C. In
addition an almost 100% of 4 was obtained and logically
no working-up procedure was necessary.
O
O
N
N
N
N
iii
N
N
O
O
N
N
N
N
Debenzylation: within the same reaction pathway lead-
ing to the AFDX 384 derivatives,8a a deprotecting step
is necessary. N-Debenzylation is usually performed at
50 bar H2 and 60 °C. After 18 h a quantitative debenzyl-
ation could be observed.8a Carrying out the reaction in
the microwave reactor the deprotection is already
complete after 2h. 16
NH
N
H3C
H3C
5
6
Scheme 3. Reagents and conditions: (iii) EtOH, Pd–C, H2, 25 bar,
125 °C, 2h.
Azide hydrogenation: (S)-5-hydroxy-2-piperidone 8 is a
key intermediate in the synthesis of pipecolic acids of
interest as GABA antagonists.11 As reported by Her-
deis,12 8 can be obtained by a catalytic hydrogenation
of azide 7. After 3 h at 30 °C and a pressure of 3 bar,
8 could be isolated in 77% yield. Applying microwave-
assisted hydrogenation resulted in 90% of the piperidone
8 already after 25 min.
HO
iv
N3
O
O
N
H
O
7
8
Scheme 4. Reagents and conditions: (iv) MeOH, Pd–C, H2, 15 bar,
90 °C, 25 min.
Hydrogenation of strychnine: the natural product
strychnine 9, a starting material for the synthesis of
caracurine compounds, which attract interest as highly
potent allosteric modulators for the M2-receptor,
was hydrogenated to dihydrostrychnine 10 by Zlotos
et al.13 The hydrogenation was accomplished classically
at 5 bar, 25 °C and 48 h to obtain 94% of 10. By micro-
wave heating the yield was even better (98%) and the
reaction time was decreased to 2h.
H
N
N
H
v
H
H
H
H
N H
H
O
N H
O
H
O
H
O
All the examples described herein clearly demonstrate
that hydrogenations under microwaves led to substan-
tially shorter reaction times (Schemes 1–5) and often
better yields (Schemes 1–4). This cannot be explained
by the higher temperatures applied in the microwave
enhanced hydrogenations only, because hydrogenations
10
9
Scheme 5. Reagents and conditions: (v) 10% acetic acid, Pd–C, H2,
20 bar, 90 °C, 2h.
using microwaves are not directly comparable to the
classical way. Microwaves interact with the surface of
the catalyst and create Ôhot spotsÕ. The catalyst surface
is much hotter than the surrounding medium.14 One
may argue that microwaves interact only with reagents
having a dipole moment. Even though the hydrogen in
gaseous phase does not have a dipole moment, however,
binding to the catalyst surface in a monomolecular layer
a dipole moment can be induced.15 Thus, the micro-
waves are able to interact with the hydrogen and
catalyze the reaction.
O
O
H
N
N
i
OH
OH
1
2
Scheme 1. Reagents and conditions: (i) EtOH, PtO2, H2, 25 bar,
125 °C, 1 h.
We showed with these examples that catalytic hydroge-
nations at medium pressure with microwaves are new
useful tools in the multi-step synthesis of active agents.
Br
Br
O
O
H
N+
ii
O
O
N+
References and notes
1. Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Weinheim, 2002.
2. Al-Qahtani, M. H.; Cleator, N.; Danks, T. N.; Garman,
R. N.; Jones, J. R.; Stefaniak, S.; Morgan, A. D.;
Simmonds, A. J. J. Chem. Res. 1998, 400–401.
3
4
Scheme 2. Reagents and conditions: (ii) EtOH, PtO2, H2, 20 bar,
60 °C, 1.5 h.

E. Heller et al. / Tetrahedron Letters 46 (2005) 1247–1249
1249
3. Banik, B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M.
S.; Bose, A. K. J. Org. Chem. 1999, 64, 5746–5763.
4. (a) Wada, Y.; Yin, H.; Kitamura, T.; Yanagida, S. Chem.
Lett. 2000, 632–633; (b) Pillai, U. R.; Sahle-Demessie, E.;
Varma, R. S. Green Chem. 2004, 6, 295–298.
5. Desai, B.; Danks, T. N. Tetrahedron Lett. 2001, 5965–5965.
6. Chappelle, M. R.; Kent, B. B.; Jones, S. R.; Lu, S.-Y.;
Morgan, A. D. Tetrahedron Lett. 2002, 5117–5118.
7. http://www.milestonesci.com/synth-tech.php.
8. (a) Holzgrabe, U.; Heller, E. Tetrahedron 2003, 59, 781–
787; (b) Mohr, M.; Heller, E.; Ataie, A.; Mohr, K.;
Holzgrabe, U. J. Med. Chem. 2004, 47, 3324–3327.
9. (a) Freifelder, M.; Robinson, R. M.; Stone, G. R. J. Org.
Chem. 1962, 27, 284–286; (b) Shuman, R. T.; Ornstein, P.
L.; Pascal, J. W.; Gesellchen, P. D. J. Org. Chem. 1990, 55,
738–741(c) Ito, K.; Mashiba, Y. Jpn. Kokai Tokkyo Koho,
1991, JP 03002162 A2 19910108.
10. Alptuezuen, V.; Kapkova, P.; Baumann, K.; Erciyas, E.;
Holzgrabe, U. J. Pharm. Pharmacol. 2003, 55, 1397–
1404.
11. (a) Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1993,
4, 2085–2094; (b) Herdeis, C.; Heller, E. Tetrahedron:
Asymmetry 1997, 8, 1115–1121.
12. Herdeis, C. Synthesis 1986, 232–233.
13. Zlotos, P. D.; Buller, S.; Holzgrabe, U.; Mohr, K. Bioorg.
Med. Chem. 2003, 11, 2627–2634.
14. Microwaves in Organic Synthesis; (a) Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2002; pp 366–368; (b) Zhang, X.;
Hayward, D. O.; Mingos, D. M. P. Chem. Commun. 1999,
975–976.
15. (a) Schlosser, E.-G.. Heterogene Katalyse; Verlag Chemie:
Weinheim, 1972; pp 21–27; 114–124; (b) Catalysis in
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34–37.
16. Typical hydrogenation procedure in the microwave reactor:
10 mmol (3.50 g) of the pyridinium compound 2 and 0.1 g
of platinum on activated carbon (5% Pt) were diluted in
150 mL methanol. The solution was flushed with argon for
5 min to remove the oxygen. Hydrogen was filled until the
reaction pressure of 20 bar was reached. The mixture was
heated to 60 °C within 3 min. The temperature was kept
constant for 1.5 h. The solution was cooled to 25 °C, the
catalyst was filtered off and the solvent was evaporated to
yield 3.55 g (100%) of 4-(1,3-dioxolan-2-yl)-N-(3-phenyl-
propyl)piperidine hydrobromide 4 as a colorless solid. The
compound can be recrystallized from acetone/diisoprop-
ylether. However, this was not necessary for the next
step. 1H NMR (CDCl3, 400 MHz): d 11.29 (br, 1H, NH+),
7.30–7.16 (m, 5H, aromat.), 4.79 and 4.64 (d, J = 5.6 Hz,
1H, O–CH–O), 3.70–3.60 (m, 2H, 7-H), 3.07–2.71 (m, 4H,
2-H, 6-H), 4.08–3.99 (m, 4H, O–(CH2)2–O), 2.68–2.16 (m,
7H, 3-H, 4-H, 5-H, 9-H), 1.76–1.69 (m, 2H, 8-H). 13C
NMR (CDCl3, 400 MHz): d 139.5 and 139.4 (C-10), 128.8
and 128.4 (C-11, C-12, C-14, C-14), 126.8 and 126.7 (C-
13), 105.3 and 103.5 (O–CH–O), 65.2and 65.1 (O–
(CH2)2–O), 57.3 (C-7), 53.3 and 52.6 (C-2, C-6), 38.7 (C-
4), 32.9 (C-9), 24.9 (C-8), 23.9 (C-3, C-5).