Thin layer chromatography as a tool for reaction optimisation in microwave assisted synthesis

Article abstract of DOI:10.1039/a909305b

Reaction parameters for the microwave assisted synthesis of N'- substituted arylpiperazines were optimised via their rapid synthesis on thin layer chromatography (TLC) plates.

Full text of DOI:10.1039/a909305b

Thin layer chromatography as a tool for reaction optimisation in microwave
assisted synthesis
Lorenzo Williams
SINTEF Applied Chemistry, P.O. Box 124 Blindern, N-0314 Oslo, Norway.
E-mail: Lorenzo.Williams@chem.sintef.no
Received (in Liverpool, UK) 23rd November 1999, Accepted 18th January 2000,
Published on the Web, 1st March 2000
Reaction parameters for the microwave assisted synthesis of
NA-substituted arylpiperazines were optimised via their
rapid synthesis on thin layer chromatography (TLC)
plates.
appeared to occur rather more slowly than the desired
transformation, and the reactions remained unaffected since the
arylpiperazine component was completely consumed to yield
the desired product.
Upon identification of the optimum reaction parameters, the
reactions were scaled up to several hundred milligrams in size.
Reagents were dissolved in a minimum amount of CH2Cl2 and
adsorbed onto silica gel (230–400 mesh). After removal of
solvent the mixture was irradiated for 5 min. The silica gel was
allowed to cool and was then washed with CH2Cl2 and the
washings filtered through a Celite pad. Evaporation of the
solvent in vacuo yielded the desired product in high yield and
purity. Although unnecessary, it was often advantageous to use
a slight excess of the amine component to drive the reaction to
completion and facilitate isolation of the final product in pure
form, without the need to resort to chromatography. Reactions
involving equimolar amounts of reagents worked equally as
Piperazines form the backbone of many biologically interesting
molecules.1 Their incorporation into biologically active mole-
cules has even been associated with an increase in potency.2
Recent examples of piperazine-containing molecules include
many fluoroquinolone antibiotics, the HIV protease inhibitor
Crixivan™ and the PDE-5 inhibitor Viagra™, used for male
erectile dysfunction. As part of a program dedicated to the
development of new techniques for combinatorial chemistry,3
we describe herein a simple procedure for reaction optimisation
in microwave assisted synthesis.4 This procedure is exemplified
by the rapid derivatisation of a number of monoarylpiper-
azines.
Previously we synthesised several 2-iodobenzylamines as
radical precursors for an investigation of the a-alkylation of
amines via a 1,5-hydrogen shift.5 During the synthesis of these
precursors it was observed that, in some cases, amines would
react partially with benzyl halides when co-spotted on a TLC
plate.6 After elution a new spot was sometimes seen that
corresponded to that of the expected benzylated amine product.
Product conversion was often poor since considerable amounts
of unreacted starting materials were usually present. We were
able to utilise this information in the design of methodology
toward the rapid and efficient synthesis of the arylpiperazine
derivatives shown in Table 1.†‡
Table
synthesis
1 Arylpiperazine derivatives formed via microwave assisted
Initial observations for the co-spotting of an arylpiperazine
and an electrophile, either neat or as dilute solutions in CH2Cl2,
onto a TLC plate confirmed the above in that reactions occurred
sporadically if at all, and without complete consumption of the
starting material. It was anticipated that the reactions could be
accelerated by microwave irradiation of the reagents on a glass-
backed TLC plate prior to elution, since the TLC plate would act
as a support without the silica gel absorbing or restricting the
transmission of microwaves. TLC plates (Merck silica gel 60
F254) with preadsorped reagents were irradiated in a domestic
microwave oven with varying power outputs and at various time
intervals. Method of application, loading and stoichiometry of
the reagents were varied as an array on plates in order to
discover the optimum conditions for the reaction. After cooling,
the plates were eluted and viewed under UV light (254 nm) and
by development with either I2 or ninhydrin. The most
convenient method involved the application of reagents in
solution (at a concentration of ca. 1 mg in 1 ml CH2Cl2) in 5 ml
aliquots onto a plate with a 0.2 mm layer of SiO2. Complete
consumption of one or other of the reagents occurred after
irradiation for 5 min at an output of 585 watts. Reactions were
complete under these conditions, regardless of the stoichio-
metry of the reagents. Only one product spot was seen, the Rf
value of which was consistent with that of the expected product.
Confirmation was later afforded through direct synthesis (vide
infra). A rather serendipitous discovery was made in that
excesses of sulfonyl chlorides appeared to degrade under these
conditions to a product with a polar baseline spot, presumably
the corresponding sulfonic acid. Fortunately the degradation
DOI: 10.1039/a909305b
Chem. Commun., 2000, 435–436
This journal is © The Royal Society of Chemistry 2000
435

mmol) in CH2Cl2 (1 ml) were mixed thoroughly with silica gel (Merck
230–400 mesh, 1 g) in a glass vial and the solvent removed under reduced
pressure. The mixture was then irradiated in a domestic microwave oven
(Electrolux NF4884) at an output of 585 watts for 5 min. Water (50 ml) was
placed in another vessel and irradiated simultaneously. After cooling to
room temperature the product was dissolved in CH2Cl2 (ca. 5 ml) and
filtered through a Celite pad. The solvent was removed under reduced
pressure to afford the corresponding sulfonamide as a yellow solid (0.41 g,
91%, > 98% pure by HPLC); Rf 0.55 (MeOH–CH2Cl2, 5%); dH(CHCl3, 300
MHz) 8.01 (1H, d, J 9.3), 7.72 (2H, m), 7.63 (1H, m), 7.37 (1H, t, J 7.7),
7.14 (3H, m), 3.51 (4H, m), 3.31 (4H, m).
well, though occasionally the purity of the final product was
compromised due to the presence of small amounts of unreacted
halides. Fortuitously, reactions involving an equimolar amount
or excess of sulfonyl halides were unaffected since the
unreacted material degraded under the reaction conditions (vide
supra). Interestingly, all reactions were high yielding and
afforded NA-substituted products in high purity. The presence of
electron-withdrawing groups on the arylpiperazine, e.g. 1-(4-
nitrophenyl)piperazine in entries 3, 5, and 9, didn’t appear to
impede reaction. It has been reported previously that the
presence of electron-withdrawing groups in the aryl ring of
arylpiperazines diminishes the nucleophilicity of the secondary
amine.7
Reactions on silica gel were performed without incident and
somewhat surprisingly without salt formation. It is thought that
silica gel scavenges any HCl formed in the reaction, thereby
negating salt formation. When reactions were performed in the
absence of silica gel or by using finely ground glass as the
support none of the desired products were isolated. TLC
analysis of these reactions indicated the absence of product.
However, the presence of a new and more polar baseline spot
was seen, presumably the corresponding amine salt formed in
the presence of HCl generated in situ.
In summary, reactions performed on a TLC plate are a
powerful tool for rapid reaction optimisation. The method is
suitable in particular for microwave assisted reactions since the
plate can be used as an inert support. The technique is applicable
to combinatorial chemistry where reactions often have to be
optimised prior to library synthesis. Moreover it is possible to
combine this technique with bioautographical screening and
analytical methods.8 Use of this technology for the synthesis
and screening of combinatorial libraries will be described in due
course.
1 See for example: M. Perez, C. Fourrier, I. Sigogneau, P. J. Pauwels, C.
Palmier, G. W. John, J.-P. Valentin and S. Halazy, J. Med. Chem., 1995,
38, 3602.
2 M. E. Jung, E. C. Yang, B. T. Vu, M. Kiankarimi, E. Spyrou and J.
Kaunitz, J. Med. Chem., 1999, 42, 3899 and references therein.
3 L. Williams, Proceedings of ECSOC-3, The Third International Elec-
tronic Conference on Synthetic Organic Chemistry, http:/
/www.mdpi.org/ecsoc-3.htm, September 1–30, 1999, ed. E. Pombo-
Villar, R. Neier and S.-K. Lin, CD-ROM edition ISBN 3-906980-04-9, to
be published in 2000 by MDPI, Basel, Switzerland; L. Williams, 6th
Annual Exploiting Molecular Diversity meeting, San Diego, 1999, 4th
Annual High-Throughput Organic Synthesis meeting, San Diego,
1999.
4 For a comprehensive overview of microwave heating in synthesis, see
Microwave-Enhanced Chemistry. Fundamentals, Sample Preparation
and Applications, ed. H. M. Kingston and S. J. Haswell, ACS,
Washington, DC, 1997.
5 K. Undheim and L. Williams, J. Chem. Soc., Chem. Commun., 1994, 883;
L. Williams, S. E. Booth and K. Undheim, Tetrahedron, 1994, 50,
13697.
6 L. Williams, unpublished results.
7 M. Hepperle, J. Eckert and D. Gala, Tetrahedron Lett., 1999, 40, 5655.
8 Patent pending.
Aud Bouzga and Ole Saastad are gratefully acknowledged for
NMR and GCMS analysis.
Notes and references
† All compounds gave satisfactory spectral data.
‡ Typical procedure: 1-(a,a,a-trifluoro-m-tolyl)piperazine (0.25 g, 1.1
mmol) in CH2Cl2 (1 ml) and 2-nitrobenzenesulfonyl chloride (0.24 g, 1.1
Communication a909305b
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Chem. Commun., 2000, 435–436