Synthesis of polymeric supports with spacer-modified triazene linkers: Aldol and Grignard reactions of immobilized nortropinone

Article abstract of DOI:10.1016/S0040-4039(03)00345-9

Four new polymeric supports with 3- and 6-carbon atom spacers and triazene linkers derived from meta- and para-aminophenol were synthesized from commercial Merrifield polymer. The supports could be used for immobilization of secondary amines in SPOS. A new strategy based on the use of diethylamine triazenes as masked precursors for the generation of polymer-supported diazonium ions was used. The performance of the new linkers was tested on Grignard and aldol reactions of solid-phase immobilized nortropinone. The new supports with C₃-T2 linkers gave products with better yields and purities than the classical T2 supports or the supports with the C₆-T2 linkers.

Full text of DOI:10.1016/S0040-4039(03)00345-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2441–2444
Synthesis of polymeric supports with spacer-modified triazene
linkers: aldol and Grignard reactions of immobilized
nortropinone
Ryszard Lazny* and Aneta Nodzewska
Institute of Chemistry, University of Bialystok, Al. Pilsudskiego 11/4, 15-443 Bialystok, Poland
Received 30 December 2002; revised 27 January 2003; accepted 7 February 2003
Abstract—Four new polymeric supports with 3- and 6-carbon atom spacers and triazene linkers derived from meta- and
para-aminophenol were synthesized from commercial Merrifield polymer. The supports could be used for immobilization of
secondary amines in SPOS. A new strategy based on the use of diethylamine triazenes as masked precursors for the generation
of polymer-supported diazonium ions was used. The performance of the new linkers was tested on Grignard and aldol reactions
of solid-phase immobilized nortropinone. The new supports with C3-T2 linkers gave products with better yields and purities than
the classical T2 supports or the supports with the C6-T2 linkers. © 2003 Elsevier Science Ltd. All rights reserved.
The development of solid-phase organic synthesis
(SPOS) methodology has been driven by the growing
importance of combinatorial chemistry methods in the
process of drug development.1 The triazene based
linkers2 are one of the recent and fast growing additions
to SPOS methodology. The so-called T2 linker origi-
nally introduced for anchoring secondary amines2a has
been used for synthesis of a number of different classes
of compounds (amides, thioureas, ureas, hydrazines,
alcohols, esters, guanidines, sulfoximines and alkyl
halides).2b We planed to use a triazene linker for immo-
bilization of nortropinone, an important scaffold in
medicinal chemistry, followed by reactions involving
use of lithium amide bases and organomagnesium
reagents. However we found that n-butyllithium or
Grignard reagents complex or react with triazenes giv-
ing only low yields of products of addition to the
carbonyl group of the triazene protected amino ketones
(e.g. nortropinone).3 Reactions of LDA with triazenes
were also reported recently.4 Therefore, we decided to
synthesize modified triazene linkers. Herein, we report
simple syntheses of supports with triazene linkers
modified with 3- and 6-carbon atom spacers and a new
strategy for the generation of supported diazonium
ions, i.e. directly from triazenes.
Model studies in solution: In order to evaluate the
stability of the new linkers under the conditions of
lithium amide deprotonation, five model triazenes were
synthesized (Scheme 1). The triazenes 1a and 2a were
stirred with LDA in THF at −78°C for 6 h without any
detectable decomposition. However, triazenes 1b and 2b
showed slight decomposition at this temperature and all
triazenes significantly decomposed after 8 h at 0°C.
Similar treatment of these triazenes with a Grignard
reagent (EtMgBr) at 0°C did not cause any detectable
decomposition. The recent reports of based-induced
fragmentation of 1-aryl-3,3-dibenzyltriazenes4 forced us
to re-examine our preliminary results. In our hands,
however, no alkylation of diethylamine triazene 3 or
models 1a and 2a after reaction with n-BuLi in THF
for 2 h at −78°C followed by treatment with methyl
iodide could be observed. We could not detect any
product of addition of lithiated diethylamine triazene 3
to the aldehyde after treatment of 3 with n-BuLi for 2
Keywords: amines; polymer support; solid-phase synthesis; triazenes.
* Corresponding author. Tel.: +48-85-745-7580; fax: +48-85-745-7581;
e-mail: lazny@uwb.edu.pl
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00345-9

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R. Lazny, A. Nodzewska / Tetrahedron Letters 44 (2003) 2441–2444
h at −78°C followed by addition of benzaldehyde and
quenching. These observations suggest that the triazenes
without benzyl groups should be stable under the typical
conditions of lithium amide deprotonation and to Grig-
nard reagents.
polystyrene by the Williamson reaction (Scheme 2). The
amino groups of the resulting polymers 6 (isolated in the
form of hydrochlorides) were transformed into diazo-
nium ions upon treatment with t-BuONO at −18°C in
dichloromethane5 directly before anchoring the test
amine (4-methylpiperidine, 9). For the preparation of
spacer-modified, p-aminophenol-derived supports a dif-
ferent strategy was used. The sensitivity of ethers of
p-aminophenol to light and oxygen made the preparation
of the para analogues more difficult and inefficient.
Therefore, the amines prepared by reduction of nitro
alcohols 10 were protected in the form of triazenes 11
(Scheme 3). These triazenes, which served as masked
diazonium ions, were very easily and effectively
Preparation of polymers: The amines were anchored to
a T2-type polymeric support via reaction with a polymer
bound diazonium ion. An aminophenol was typically
used as the diazonium ion precursor.2a We prepared
m-aminophenol-derived precursors of the triazenes with
added spacers 6 by alkylation of m-aminophenol with
3-chloropropan-1-ol or 6-bromohexan-1-ol followed by
binding the resulting amino alcohols 5 to chloromethyl-
Scheme 2.
Scheme 3.

R. Lazny, A. Nodzewska / Tetrahedron Letters 44 (2003) 2441–2444
2443
attached to a Merrifield polymer7 (as indicated by the
high-loading of diethylamine on 12; practically quantita-
tive substitution of Cl by triazene8). Simple washing of
the triazene gel 12 with a cold 10% TFA solution in
dichloromethane regenerated the diazonium salt, which
was ready to anchor a new amine. The overall exchange
of amines was accomplished with barely detectible,
within experimental error, lowering of loadings. The
loadings of the test amine (4-methylpiperidine, 9) immo-
bilized on the new polymers 12 (94 and 98% of the
theoretical value) were significantly better than the load-
ings on the known supports5,6 without spacers 14 and 15
(64 and 69% of the theoretical value). In general the
approach based on the direct preparation of triazenes on
solid-phase gives polymers with lower loadings than the
new strategy based on pre-loading of triazenes 11 pre-
pared in solution and exchange of amines on solid-phase.
In addition, the polymer bound triazenes 12 act as
masked polymer-supported diazonium ions, have a good
shelf life, and thus can be alternatives to the thermally
stable polymer bound 4-chlorobenzenediazonium tetra-
fluoroborate (the so-called T2* linker).2c
to adduct 17, as indicated by the ratio of product to
substrate after cleavage of the linker with 10% TFA in
dichloromethane. Under the same conditions, Grignard
addition reactions on polymers with the meta-T2 and
para-T2 linkers gave 53 and 56% conversion, respec-
tively. Surprisingly the performance of the meta-C6 and
para-C6 linkers was different (37 and 57% conversion,
respectively). A complication of the aldol reaction of the
triazene protected nortropinone is the formation of
bisaldol 19.3 The supported aldol reaction also gave the
best results on the polymer with the para-C3 linker
giving product 18 without bisaldol impurity 19, con-
trary to the other two supports where the amount of
bisaldol 19 was significant (para-C0 20%, para-C6 33%).
Analogous results were obtained for aldol reactions on
the meta isomer. The observations indicate that the
optimal linkers have the so-called C3 spacer (1,3-
propanediol derived) regardless of the ring substitution
pattern.
In summary, a new and efficient approach for prepara-
tion of resins with spacer bound diazonium ions that are
masked (and thus stabilized) in the form of triazenes has
been developed.9 The three carbon atom spacer modified
linkers gave better yields and purities of products of aldol
and Grignard reactions of immobilized nortropinone.
Polymer-supported reactions: In order to compare the
performance of the classical linkers (the so-called meta-
T2, para-T2) and the new supports (meta-C3-T2, meta-
C6-T2, para-C3-T2 and para-C6-T2) two illustrative
reactions on immobilized nortropinone were investigated
(Scheme 4, Table 1). Anchoring of nortropinone (8-
azabicyclo[3.2.1]octan-3-one) to the polymeric supports
under previously found conditions gave polymers 16. The
Grignard addition of ethylmagnesium bromide showed
the best performance on the meta-C3 and para-C3
supports giving 69 and 71% conversion of nortropinone
Acknowledgements
The authors are grateful to the University of Bialystok
(BST-125 and BW-173) and the State Committee for
Scientific Research, Poland (Grant No. 3 T09A 03617)
Scheme 4.
Table 1. Conversion of the Grignard and the aldol reactions on different supports
Support 16
Loadinga of nortropinone (mmol/g)
Conversion in Grignard reaction (%)
Conversion in aldol reaction (18:19, %)b
meta-C0
meta-C3
meta-C6
para-C0
para-C3
para-C6
0.62
0.57
0.29
0.42
0.52
0.27
53
69
37
56
71
57
65:24
76:12
71:19
60:20
77:B5
60:33
a Loading determined from mass of nortropinone·HCl obtained after cleavage with TFA and conversion of the TFA salt to the HCl salt.
b Determined by 1H NMR analysis of cleaved products.

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R. Lazny, A. Nodzewska / Tetrahedron Letters 44 (2003) 2441–2444
for financial support. We also thank Dr. L. Siergiejczyk
for assistance in recording NMR spectra.
K. H.; Balasubramanian, S. Org. Lett. 2001, 3, 53–56.
7. Procedure for the preparation of resin 12a and exchange of
the triazene bound amine: Sodium hydride (0.88 g, 60%
suspension in oil, 22 mmol) was added to a stirred solution
of 11a (5.522 g, 22 mmol) in dry THF (30 mL). After the
hydride dissolved, Merrifield polymer (4 g, Novabiochem,
1% PS-DVB, 200–400 mesh, 1.1 mmol/g) was added and
the mixture was heated at 55°C for 72 h with intermittent
stirring. Then the polymer was washed repeatedly with
water–MeOH, MeOH, DCM, water–DMF, DMF, DCM,
MeOH, and was dried under a vacuum to give a light
yellow powder (4.676 g, 0.89 mmol of Et2NH/g, quantita-
tive substitution). 13C NMR (CDCl3): l 156.9, 143.6,
121.3, 114.8, 66.9, 65.3, 46.0, 29.8, 13.0. The resin 12a
(0.300 g) was swollen in DCM, cooled to 0°C and washed
with a chilled 10% TFA in DCM (3 mL, 10 min), DCM,
10% TFA in DCM (3 mL, 10 min) and DCM (5×4 mL).
Then the cold (−18°C) solution of 9 (10 equiv.) in DCM
was added and the suspension was shaken and slowly
warmed up to rt. After washing, the resulting gel was
treated with 10% TFA in DCM and the cleaved amine was
converted to the hydrochloride and dried to give pure
9·HCl (0.034 g, 0.84 mmol/g).
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