Click chemistry on solid support: Synthesis of a new REM resin and application for the preparation of tertiary amines

Article abstract of DOI:10.1016/j.tet.2004.05.099

1,3-Dipolar cycloaddition was employed for the synthesis of a highly practical REM resin. Exploiting this concept, the resulting triazolylmethyl acrylate (TMA) resin was used for an efficient parallel synthesis of tertiary amines by Michael addition, subs

Full text of DOI:10.1016/j.tet.2004.05.099

Tetrahedron 60 (2004) 8699–8702
Click chemistry on solid support: synthesis of a new REM resin
and application for the preparation of tertiary amines
*
¨
Stefan Lober and Peter Gmeiner
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
Received 14 November 2003; accepted 4 May 2004
Available online 10 August 2004
Abstract—1,3-Dipolar cycloaddition was employed for the synthesis of a highly practical REM resin. Exploiting this concept, the resulting
triazolylmethyl acrylate (TMA) resin was used for an efficient parallel synthesis of tertiary amines by Michael addition, subsequent
quarternization and cleavage by means of b-elimination.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
for the immobilization of a variety a different SPOS handles,
we intended to exploit the methodology for the construction
of further linkers.
Solid phase organic synthesis (SPOS) has become an area of
huge interest in the field of organic and medicinal
chemistry.1 In contrast to solid phase peptide synthesis
(SPPS), the application of SPOS comprises a broad variety
of different organic reactions. There is an increasing
demand to establish a great number of linking strategies in
order to translate reaction types from solution to solid
phase.2 Ideally, the linker should be traceless, recyclable
and easily attachable to a polystyrene based backbone.
Typically, SPOS handles are connected to aminomethyl
substituted polystyrene via a carboxylic function resulting
in a secondary amide bearing a free NH that can be crucial
for some reaction conditions during the SPO synthesis. On
the other hand, linker immobilization by ether formation
albeit leading to a widely inert functionality is hard to
monitor. Thus, there is still need for the development of new
linking strategies.
Recently, J. R. Morphy and co-workers introduced the new
acrylate- and vinylsulfone-based linkers 1 and 2, which are
in fact regenerative Michael acceptors (REM) being useful
for the efficient synthesis of tertiary amines.6–8 At this,
addition of a secondary amine followed by quarternization
of the resulting Michael product and subsequent cleavage
led to the desired tertiary amines. Following this REM
Very recently, we reported on the construction and
application of a new family of backbone amide linkers
(BAL) that were accessible by 1,3-dipolar cycloaddition of
azidomethyl polystyrene and a propargyl or propargyloxy
substituted arene carbaldehyde (Scheme 1) when the
triazole formation was high yielding and conveniently
monitored by IR spectroscopy.3
The resulting click linkers were applied for the parallel
synthesis of dopaminergic carboxamides. As we were
convinced that this click chemistry strategy4,5 is suitable
Keywords: Click chemistry; REM Resin; 1,3-Dipolar cycloaddition; SPOS.
*
Corresponding author. Tel.: þ49-9131-8529383; fax: þ49-9131-
Scheme 1. Synthesis and application of click chemistry derived BAL and
REM resins.
8522585; e-mail address: gmeiner@pharmazie.uni-erlangen.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.099

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S. Lober, P. Gmeiner / Tetrahedron 60 (2004) 8699–8702
8700
strategy, the acrylate 1 and the Wang resin based analog 3
were applied for the synthesis of d-opioid receptor
ligands,9 b-peptoides,10 potential If channel blockers11 and
Gly T2 transporter ligands (Scheme 2).12
Scheme 2. Commercially available REM resins.
2. Results and discussion
In conjunction with our efforts in the discovery of highly
selective dopamine receptor modulators, we are especially
interested in tertiary amines being known as a valuable
pharmacophoric functions. Thus, we decided to choose a
REM based methodology for the extension of our studies on
the application of click chemistry for the immobilization of
linking units. In detail, we started from azidomethyl
substituted polystyrene 4, which was easily prepared by
nucleophilic substitution of Merrifield resin with NaN3.13
The subsequent 1,3-dipolar cycloaddition with commer-
cially available propargyl acrylate14 was conducted in
DMF/THF in the presence of DIPEA and catalytic amounts
of Cu(I)I leading to the triazolylmethyl acrylate (TMA)
resin 5 (Scheme 3). Addition of benzylmethylamine
proceeded smoothly in DMF at room temperature. Subse-
quent alkylation of the aminopropionate 6a with 2,6-
dichlorobenzyl bromide was followed by base induced
cleavage leading to the tertiary amine 7a in 68% yield based
Figure 1. IR monitoring of solid phase reactions. All spectra range from
2300 to 1500 cm21. (i) Resin 4 with azido band at 2096 cm21 (A); (ii)
sample after 5 h reaction time of 4 with propargyl acrylate still showing an
azido band at 2096 cm21 (A) and a signal for the acrylic ester moiety at
1732 cm21 (B); (iii) sample after 10 h reaction time of 4 with propargyl
acrylate displaying the acrylic ester signal at 1732 cm21 (B) and complete
disappearance of the azido group; (iv) resin 6a with a slightly shifted ester
signal at 1735 cm21 (C).
1
on the loading of 5. H NMR analysis of the final product
indicated a purity .95%. It is worthy of note that the use of
a regenerated resin 5 for another identical reaction cycle
resulted in the formation of 7a in almost equal yield (66%).
Figure 1 documents a diagnostic IR analysis when both
the azido and the ester CvO functionality reveal strong
IR absorption. The progression of the cycloaddition can
be monitored conveniently and precisely. After 5 h of
reaction time, the signal of the azido group (2096 cm21
)
has been distinctly shrunk whereas a carbonyl band
(1732 cm21) becomes visible. Another 5 h of reaction
time leads to a complete disappearance of the N3-signal.
The 1,4-addition of an amine results to a slight shift the
carbonyl band, whereas the E1cb elimination regener-
ated the acrylate resin showing IR absorption at
1732 cm21 (not shown).
In order to evaluate our new TMA resin and to compare it to
the off-the-shelf REM support 1, we accomplished a parallel
synthesis of six tertiary amines. In detail, the Michael
acceptor 5 was treated with tetrahydroisochinoline or
phenylpiperazine to give the Michael products 6b and 6c,
respectively. Subsequent alkylation with allyl bromide,
p-nitrobenzyl bromide or methyl bromoacetate followed by
Hofmann elimination gave the tertiary amines 7b–f,
respectively.
Scheme 3. (a) NaN3, DMSO, 70 8C, 48 h; (b) propargyl acrylate, Cu(I)I,
DMF, THF, DIPEA, 35 8C, 10 h; (c) benzylmethylamine, DMF, rt, 16 h; (d)
2,6-dichlorobenzyl bromide, DMSO, rt, 16 h; (e) TEA, DMF, rt, 16 h.

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S. Lober, P. Gmeiner / Tetrahedron 60 (2004) 8699–8702
8701
Employing phenylpiperazine as a secondary amine and
methyl bromoacetate an electrophile, the reaction led to the
4-bromophenylpiperazine 8 when LCMS indicated a
product of high purity and the mass signals of m/z¼313
(Mþ1þ) and 315 (Mþ3þ) revealed the typical isotope
AM 360 (360 MHz) spectrometer. IR spectra were recorded
on a Jasco FT/IR 410 spectrometer. Micro analyses were
performed by Beetz, Mikroanalytisches Laboratorium,
Kronach, Germany.
1
pattern of bromine. H NMR spectra indicated an AA’BB’
3.1.1. Azidomethyl polystyrene (4).13 Merrifield resin
(1.0 g, 2.0 mmol/g) was agitated in a PFA vessel with NaN3
(0.65 g, 10 mmol) in DMSO (10 mL) at 70 8C for 48 h.
After being cooled to room temperature, the suspension was
filtered through the vessel frit and the resin was rinsed
alternately with MeOH (5£20 mL) and CH2Cl2 (5£20 mL)
and dried in vacuo to give 4 as a colorless resin. FTIR
coupling pattern for the protons of the phenyl moiety. Being
known that 2-haloacetonitriles can act as efficient halogen-
ating reagents,15 we assume that the excess of bromoacetate
reacted analogously, in this case.
For all SPOS products investigated, the yields were
satisfying and comparable to those described in the
literature based on resin 1 (Table 1). LCMS analysis
employing reversed phase chromatography in combination
with UV (220 nm) and ESI-ion trap detection indicated
excellent purities (.92%).
(KBr-pellet) 2096 cm21
.
3.1.2. Triazolymethyl acrylate (TMA) resin (5). Azido-
methyl polystyrene (4) was agitated in a PFA vessel with
proparyl acrylate14 (1.1 g; 10 mmol), CuI (7.6 mg;
0.04 mmol) DIPEA (1.0 mL, 7.7 mmol) in DMF (4 mL)
and THF (4 mL) at 35 8C. The progression of the reaction
was monitored by IR spectroscopy. After disappearance of
the signal at 2096 cm21, the suspension was filtered through
the vessel frit and the resin was rinsed alternately with
pyridine (5£20 mL), MeOH (5£20 mL) and CH2Cl2
(5£20 mL) and dried in vacuo to give 5 as a light brown
resin. Combustion analysis of nitrogen indicated a loading
of 1.63 mmol/g.
In conclusion, a convenient and practical construction of a
triazolylmethyl acrylate (TMA) resin employing 1,3-dipolar
cycloaddition as the key immobilization step facilitates an
efficient parallel synthesis of differently substituted tertiary
amines. Application for a combinatorial approach to
selective dopamine receptor modulators is currently in
progress.
3.1.3. Benzyl-(2,6-dichlorobenzyl)-methylamine (7a).
TMA resin (5) (100 mg) was agitated with benzylmethyl-
amine (200 mg, 1.65 mmol) in DMF (2 mL) for 16 h at
ambient temperature. The suspension was filtered through
the vessel frit and the resin was rinsed alternately with
MeOH (5£5 mL) and CH2Cl2 (5£5 mL) and dried in vacuo.
The resulting resin 6a was treated with a solution of 2,6-
dichlorobenzyl bromide (200 mg, 0.83 mmol) in DMSO
(4 mL) and agitated for 16 h at ambient temperature. After
being filtered, the resin was washed with MeOH (3£5 mL)
and CH2Cl2 (3£5 mL) and TEA (0.2 mL, 14 mmol) in DMF
3. Experimental
3.1. General
Solvents and reagents were purified and dried by standard
procedures or purchased in pure, dry quality from Fluka or
Sigma-Aldrich. All reactions were performed under nitro-
gen atmosphere in a Synthesis 1 synthesizer (Heidolph
Instruments) equipped with PFA reaction vessels. LCMS
analyses were done with a Bruker Esquire2000 using ESI in
positive mode. 1H NMR spectra were recorded on a Bruker
Table 1. Parallel synthesis using TMA resin
Compound
HX¼
R¼
Yielda (%) (purity, %)b
Ref.6 yield (%) (purity, %)
7b
7c
7d
7e
7f
8
Tetrahydro-isochinoline
Tetrahydro-isochinoline
Tetrahydro-isochinoline
N-Phenyl-piperazine
N-Phenyl-piperazine
N-Phenyl-piperazine
Allyl
82 (95)
77 (92)
75 (92)
79 (93)
53 (91)
62d (96)
88 (.90)
63 (.90)
73c (.90)
75 (.90)
47 (.90)
—
p-Nitrobenzyl
CH2CO2Me
Allyl
p-Nitrobenzyl
CH2CO2Me
a
Calculated on the loading of 5 (1.63 mmol/g).
b
c
d
Determined by LCMS using MeOH/aq. 0.1 N HCO2H gradient system on RP-18 material and ESI-ion trap mass spectrometry.
Results for ethyl ester derivative.
Yield of the brominated phenylpiperazine 8.

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S. Lober, P. Gmeiner / Tetrahedron 60 (2004) 8699–8702
8702
1
(2 mL) was added. Stirring at ambient temperature for 6 h
was followed by filtration of the solvent, whereas the resin
was washed with DMF (2 mL) and CH2Cl2 (3£5 mL). The
combined filtrates were washed with a saturated solution of
NaHCO3 and evaporated to dryness to give 32 mg (68%) of
Methyl (4-(4-bromophenyl)-piperazin-1-yl)-acetate (8). H
NMR (CDCl3, 360 MHz): d (ppm)¼2.73 (t, 4H), 3.21 (t,
4H), 3.29 (s, 2H), 3.74 (s, 3H), 6.76–6.81 (m, 2H), 7.31–
7.36 (m, 2H); ESI-MS (m/z) 313, 315 (Mþ1þ).
1
7a as a colorless solid. H NMR (CDCl3, 360 MHz): d
(ppm)¼2.18 (s, 3H), 3.62 (s, 2H), 3.84 (s, 2H), 7.13 (t, 1H),
Acknowledgements
7.21–7.36 (m, 7H); ESI-MS (m/z) 276 (Mþ1þ).
The BMBF and the Fonds der Chemischen Industrie
is acknowledged for financial support. We thank
¨
Mrs R. Hofner-Stich and Mrs M. Hertel for skillful technical
assistance during the experimental work.
3.1.4. Parallel synthesis of tertiary amines (7b–f) and (8).
Tertiary amines 7b–f and 8 were synthesized following the
procedure described for 7a starting in each case from
100 mg of 5. Yields are given in Table 1. Compounds were
characterized by LCMS analysis using Agilent Zorbax
Eclipseq XDB-C8 (5 mm) and MeOH/0.1 N aq. formic acid
gradient system (50:50 to 95/5) in combination with ES
ionization and ion trap detection in positive mode and by 1H
NMR as follows.
References and notes
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N-Allyl-1,2,3,4-tetrahydroisochinoline (7b). 1H NMR
(CDCl3, 360 MHz): d (ppm)¼2.75 (t, 2H), 2.91 (t, 2H),
3.18 (d, 2H), 3.63 (s, 2H), 5.19 (d, 1H), 5.26 (d, 1H), 5.90–
6.01 (m, 1H), 6.99–7.13 (m, 4H); ESI-MS (m/z) 203
(Mþ1þ).
2. For review see: James, I. W. Tetrahedron 1999, 55, 4855.
¨
3. Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003,
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1128.
2-(4-Nitrobenzyl)-1,2,3,4-tetrahydroisochinoline (7c). 1H
NMR (CDCl3, 360 MHz): d (ppm)¼2.77 (t, 2H), 2.92 (t,
2H), 3.65 (s, 2H), 3.78 (s, 2H), 6.96–7.15 (m, 4H), 7.56–
7.61 (m, 2H), 8.17–8.21 (m, 2H); ESI-MS (m/z) 269
(Mþ1þ).
5. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless,
K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192.
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Methyl-(1,2,3,4-tetrahydroisochinolin-2-yl)-acetate (7d).
1H NMR (CDCl3, 360 MHz): d (ppm)¼2.87–2.97 (m,
4H), 3.43 (s, 2H), 3.75 (s, 3H), 3.80 (s, 2H), 6.98–7.14 (m,
4H); ESI-MS (m/z) 206 (Mþ1þ).
1-Allyl-4-phenylpiperazine (7e). 1H NMR (CDCl3,
360 MHz): d (ppm)¼2.59–2.63 (m, 4H), 3.06, (d, 2H),
3.19–3.23 (m, 4H), 5.15–5.26 (m, 2H), 5.84–5.96 (m, 1H),
6.82–6.94 (m, 3H), 7.22–7.28 (m, 2H); ESI-MS (m/z) 203
(Mþ1þ).
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1-(4-Nitrobenzyl)-4-phenylpiperazine (7f). 1H NMR
(CDCl3, 360 MHz): d (ppm)¼2.60–2.65 (m, 4H), 3.19–
3.24 (m, 4H), 3.66 (s, 2H), 6.84–6.95 (m, 3H), 7.24–7.29
(m, 2H), 7.53–7.57 (m, 2H), 8.17–8.22 (m, 2H); ESI-MS
(m/z) 298 (Mþ1þ).
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14. Propargyl acrylate was purchased from Sigma-Aldrich.
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