A new versatile linker for the solid-phase synthesis of secondary amines

Article abstract of DOI:10.1016/S0040-4039(02)02478-4

A novel linker for the solid-phase synthesis of secondary amines based on an intramolecular cyclization was developed. The linker allows for a stepwise built-up of the secondary amines on the support. The feasibility was demonstrated in the parallel synthesis of a small set of different secondary amines.

Full text of DOI:10.1016/S0040-4039(02)02478-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 149–152
A new versatile linker for the solid-phase synthesis of
secondary amines
Heiko Glatz and Willi Bannwarth*
Institut fu¨r Organische Chemie und Biochemie, Universita¨t Freiburg, Albertstraße 21, D-79104 Freiburg, Germany
Received 29 October 2002; accepted 31 October 2002
Abstract—A novel linker for the solid-phase synthesis of secondary amines based on an intramolecular cyclization was developed.
The linker allows for a stepwise built-up of the secondary amines on the support. The feasibility was demonstrated in the parallel
synthesis of a small set of different secondary amines. © 2002 Elsevier Science Ltd. All rights reserved.
Solid-phase synthesis has gained widespread acceptance
in combinatorial chemistry related to drug discovery in
order to accelerate lead generation and lead optimiza-
tion.1 Synthesis on a solid support shows a number of
advantages as compared to solution chemistry. The
most salient one is the possibility to apply excesses of
reagents and removing them without involving time-
consuming separation techniques. A prerequisite to
widen the scope of reactions on solid support is the
continuous development of suitable linker molecules
with the desired properties.
were attached as such to the solid-phase and were
cleaved again after chemical modifications.8,9 Herein,
we describe a new method which allows for the de novo
synthesis of secondary amines on the solid support.
In this approach the release of the secondary amines
from the solid support proceeds via intramolecular
cyclization. The basis for this work was led by a paper
published by Fichert and Massing.10 The adaptation of
their strategy to solid support offers the possibility of a
straightforward parallelization and guarantees a high
level of purity of released secondary amines.
An interesting class of molecules in drug discovery are
amines. Secondary amines represent especially potent
pharmacophores and are thus present in numerous
biologically active compounds.2 Furthermore, amines
are often useful intermediates in synthetic organic
chemistry.3 An overview on different synthetic strate-
gies for their preparation was published recently.4 Up
to now a number of linker systems for the solid-phase
synthesis of secondary amines have been reported.
As solid support material we selected aminomethyl-
polystyrene. However, before performing the reaction
steps on solid support, the whole reaction sequence was
evaluated in solution according to Scheme 1. Benzyl-
amine was used as substitute for the aminomethyl-
resin.
In contrast to Massing’s route, commercially available
trimellitic anhydride 1 was used which bears an addi-
tional carboxyl function for the later attachment to
solid support. This was converted to the corresponding
imide in a melting reaction using ammoniumcarbonate
at 280°C in a yield of 80%.11 The protection of the
imide using tritylchloride and Hu¨nig’s base in CH3CN
under reflux furnished 2 in a modest yield (40%), prob-
ably due to sterical hindrance. Coupling to benzylamine
and subsequent removal of the trityl protecting group
with TFA in the presence of Et3SiH as scavenger
yielded 3 in 91%. The introduction of the first residue
proceeded via a Mitsunobu reaction in a yield of 83%.
Ring opening following a NaBH4-reduction gave rise to
two regioisomers with a total yield of 93% for both
They are mainly based on well known protecting
groups for amino functions (BOC and Z),5,6 which were
adapted to their application in solid-phase synthesis.
Alternatively, the Rink-amide linker was employed, as
demonstrated for the synthesis of pharmacologically
interesting arylethanolamines.7 However, all described
protocols suffer from the limitation that the amines
Keywords: linker for solid-phase synthesis; combinatorial chemistry;
secondary amines.
* Corresponding author. Tel.: +49(0)7612036073; fax: +49(0)76-
12038705; e-mail: willi.bannwarth@organik.chemie.uni-freiburg.de
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02478-4

150
H. Glatz, W. Bannwarth / Tetrahedron Letters 44 (2003) 149–152
isomers. The synthesis was continued with purified
isomer 5. The hydroxyl function was protected as 3,4-
dihydropyranyl ether with catalytic amounts of p-tolu-
ene sulfonic acid. The tetrahydropyranylether
protection was chosen because of its stability towards
the basic conditions of the ensuing alkylation step
employed for the introduction of the second residue.
After the alkylation with KOtBu in THF 6 was
obtained in 80% yield. Finally, after cleavage of the
THP-protecting-group, the amine was released as
ammonium salt.
Instead of the THP-group alternative protecting groups
can be employed and can be adapted to the chemistry
Scheme 1.
Scheme 2.

H. Glatz, W. Bannwarth / Tetrahedron Letters 44 (2003) 149–152
151
Table 1.
for further synthetic modifications of the desired sec-
ondary amines.
After the successful feasibility study, the approach was
adapted to the synthesis on solid support. At the same
time the synthesis of a small library of secondary
amines was envisaged. The reactions on the solid-phase
material were monitored by FT-IR spectroscopy. The
actual synthetic route is outlined in Scheme 2.
Aminomethyl-functionalized polystyrene resin (loading:
0.85 mmol/g, 1% cross-linked) was used as support
material. After each reaction step the resin was rinsed
three times with DMF–water (50:50), DMF, CH2Cl2
and Et2O. For some conversions the reaction condi-
tions of solution chemistry had to be modified. The
attachment of the linker molecule to the solid support
was performed using TBTU12 and Hu¨nig’s base in
CH2Cl2. The completeness of the coupling reaction was
verified by a Kaiser test.13,14 The removal of the trityl
group had to be performed with a mixture of TFA/
CH2Cl2 (50/50 v/v) to guarantee a sufficient swelling of
the resin and consequently a good accessibility of the
reactive sites. Triethylsilane was added as scavenger.
The NH bond of the unprotected imide-resin 9 showed
a strong band at 3190 cm−1 for the imide-NH and one
at 3333 cm−1 for the amide-NH. After alkylation of the
imide-NH via Mitsunobu reaction resin 10 disclosed a
single band at 3333 cm−1, whereas the imide NH-band
at 3190 cm−1 had disappeared. The subsequent reduc-
tion step was performed with LiBH4 instead of NaBH4
and the solvent mixture was changed to THF/water
20:1 because of the better swelling properties compared
with the isopropanol–toluene–water mixture applied in
the synthesis in solution. Water was added since the
evaluation in solution manifested faster reduction rates
in the presence of water. Resin 11 showed a characteris-
tic broad absorption band between 3100 and 3600 cm−1
for the hydroxyl-function, whereas the CꢀO band at
1773 cm−1 had vanished. The introduction of the pro-
tecting group was performed at 0°C in CH2Cl2 and the
ensuing alkylation procedure was modified in that way
that KOtBu was removed with a syringe after an hour
before a solution of the alkylating agent in THF was
added. Reaction overnight yielded 12 and FT-IR
revealed, that the NH-band and the OH-band had
totally disappeared. The removal of the protecting
group and subsequent cyclization were performed in a
one-pot procedure in a mixture of TFA/THF/water
(4/2/1) at 60°C for 24 h. TFA was used instead of acetic
acid because of its higher volatility. Work-up yielded
the secondary amines as yellow oils with overall yields
ranging from 6 to 49% and high HPLC purities. The
synthesized amines are outlined in Table 1. In the case
of 3-phenylpropylallylamine the overall yield of 49%
corresponds to a yield of 85% per step. The lowest
overall yield of 6% in the case of 3-phenylpropyl-3-
fluorobenzylamine relates to a 60% yield per step start-
ing from resin 9.
desired amines in acceptable yields and high HPLC-
purities.
Acknowledgements
We would like to thank F. Reinbold and M. Schonhard
for NMR measurements and C. Warth and Dr. J.
Wo¨rth for mass spectrometry measurements. We would
also like to thank Novabiochem, Switzerland for a free
gift of resin.
References
1. Bannwarth, W. In Combinatorial Chemistry: A Practical
Approach; Bannwarth, W.; Felder, E., Eds.; Wiley-VCH:
Weinheim, 2000; pp. 47–95 and references cited therein.
2. Silverman, R. B. The Organic Chemistry of Drug Design
and Drug Action; Academic Press: New York, 1992; pp.
361–413 and references cited therein.
In summary, we have developed a new linker system for
the de novo synthesis of secondary amines on solid
support. It allows for a straightforward synthesis of the

152
H. Glatz, W. Bannwarth / Tetrahedron Letters 44 (2003) 149–152
3. Buehler, C. A.; Pearson, D. E. Survey of Organic Synthe-
CH2Cl2 and Et2O and dried under high vacuum to give
13.6 g of 10. This was suspended in 150 ml THF and 7.5
ml H2O and 400 mg (18 mmol) LiBH4 were added. After
shaking at rt for 12 h another 400 mg (18 mmol) LiBH4
was added and shaking was continued for 12 h. Work-up
(see above), which comprised an additional washing step
with water, gave 12.4 g of intensive yellow resin 11. To a
suspension of 5 g of 11 in 100 ml anhydrous CH2Cl2 4 ml
(44 mmol) 3,4-dihydro-2H-pyran and 840 mg (4 mmol)
of p-TsOH were added at 0°C and the mixture was
shaken at 0°C for 24 h. After workup, 5.1 g of protected
resin were obtained. Protected resin (1 g) was suspended
in 10 ml anhydrous THF in a Schlenk-flask and 526 mg
(5 mmol) KOtBu dissolved in THF were added. After 1 h
the base was removed with a syringe and fresh THF (10
ml) and 5 mmol of the alkylating reagent were added.
The flask was shaken for 24 h at rt. After workup 1.1–1.2
g of resin 12 was obtained. This was suspended in 15 ml
TFA, 7.5 ml THF and 3.5 ml H2O. After shaking for 24
h at 60°C the resin was filtered off and the filtrate was
evaporated and taken up in CH3CN and evaporated
again (three times). After drying under high vacuum the
brownish oil was dissolved in water and extracted with
Et2O (three times). After addition of 2 ml of 2 M NaOH
the aqueous phase was again extracted with Et2O (three
times). Drying over MgSO4, filtration and subsequent
evaporation of the organic phase yielded the secondary
amines as yellow highly viscous substances.
sis; Wiley-Interscience: New York, 1970; Vol. 1, pp.
413–523.
4. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2001, 57, 7785–7811.
5. Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36,
1589–1592.
6. Hernandez, A. S.; Hodges, J. C. J. Org. Chem. 1997, 62,
3153–3157.
7. Purandare, A. V.; Poss, M. A. Tetrahedron Lett. 1998, 39,
935–938.
8. Conti, P.; Demont, D.; Cals, J.; Ottenheijm, H. C. J.;
Leysen, D. Tetrahedron Lett. 1997, 38, 8465–8468.
9. Scialdone, M. A.; Shuey, S. W.; Soper, P.; Hameno, Y.;
Burns, D. M. J. Org. Chem. 1998, 63, 4802–4807.
10. Fichert, T.; Massing, U. Tetrahedron Lett. 1998, 39,
5017–5018.
11. Aronov, A. M.; Gelb, M. H. Tetrahedron Lett. 1998, 39,
4947–4950.
12. Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1927–1930.
13. Kaiser, E.; Colescott, R. L.; Bassinger, C. D.; Cook, P. J.
Anal. Biochem. 1970, 34, 595.
14. General procedure: To 12.1 g of resin 9 (9 mmol loading)
150 ml anhydrous THF, 6.7 g (26 mmol) PPh3, 26 mmol
of R1OH and 7.4 ml (38 mmol) DIAD were added and
the suspension was shaken for 48 h. Then the resin was
filtered off, rinsed three times with DMF, DMF/H2O,