Solid-phase synthesis of unsymmetrical ureas through the use of Kenner safety-catch linker

Article abstract of DOI:10.1016/S0040-4039(02)02656-4

A new strategy for the solid-phase synthesis of unsymmetrical ureas is described. Upon treatment of Kenner safety-catch linker with an isocyanate, followed by TMSCHN₂ or iodoacetonitrile and an amine, the corresponding unsymmetrical ureas are released in solution.

Full text of DOI:10.1016/S0040-4039(02)02656-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 811–814
Solid-phase synthesis of unsymmetrical ureas through the use of
Kenner safety-catch linker
Daniela Fattori,* Piero D’Andrea and Marina Porcelloni
Chemistry Department, Menarini Ricerche, S.p.A., Via Tito Speri 10, 00040 Pomezia, (Rome), Italy
Received 17 September 2002; revised 20 November 2002; accepted 21 November 2002
Abstract—A new strategy for the solid-phase synthesis of unsymmetrical ureas is described. Upon treatment of Kenner
safety-catch linker with an isocyanate, followed by TMSCHN2 or iodoacetonitrile and an amine, the corresponding unsymmetrical
ureas are released in solution. © 2003 Elsevier Science Ltd. All rights reserved.
Ureas are often found in biologically active
compounds1 and a number of methods have been pub-
lished for their solid-phase synthesis.2 To the best of
our knowledge, none of these methods takes advantage
of the safety-catch linkers chemical versatility. Consid-
ering our interest in the solid-phase synthesis of drug-
like compounds and on the basis of our previous
experience in the use of the Kenner safety-catch linker,3
we developed a novel method for producing unsymmet-
rical ureas which exploits this linker and it is easy
applicable on combinatorial libraries.
which is sensitive to nucleophiles and can then be
cleaved with amines or thiols.
We reasoned that building on the Kenner sulfonamide
resin a sulfonyl urea could allow the preparation of
ureas rather than amides or thioesters, following activa-
tion and fragment release. To confirm our hypothesis
two batches of sulfonyl urea resins 3 and 4 were
prepared from commercial 4-carboxyphenylsulfon-
amide and 4-sulfonamido butyric polystyrene resins6 1
and 2 by treatment with phenylisocyanate.7 A series of
The Kenner acylsulfonamide safety-catch linker4 (or its
Ellman modification)5 is largely used for the solid-phase
preparation of amides4 and thioesters.3a The
acylsulfonamido bond is completely stable to basic and
acidic conditions and a large variety of chemical manip-
ulations can be performed ‘prior activation’. Activation
is accomplished with TMSCHN2 or iodoacetonitrile to
provide the corresponding N-alkylacylsulfonamide,
experiments was set-up to establish optimal cleavage
conditions (Table 1 and Scheme 1).
Resins 3 and 4 were activated both with TMSCHN2
and iodoacetonitrile. Cleavages were performed with
1.2 equiv. of p-methoxybenzylamine in 1.5 mL of sol-
vent for 12 h and amine excess was scavenged with
isocyanate resin. In vacuo distillation of the solvents
afforded crude products that were analyzed by HPLC,
MS and 1H NMR. Resin 3 gave the best results
through activation with TMSCHN2 and the use of
DMF as cleavage solvent (Fig. 1). Result of entry 4 can
* Corresponding author. Tel.: +39-06-91184522; fax: +39-06-9106137;
e-mail: dfattori@menarini-ricerche.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02656-4

812
D. Fattori et al. / Tetrahedron Letters 44 (2003) 811–814
Table 1. Optimization of cleavage conditions8
Entry
Resin
Solvent
T (°C)
Activating group
Yield(%)a
Purity(%)b
1
2
3
4
5
6
7
3
3
3
3
4
4
4
THF
DMF
THF
THF
DMF
THF
DMF
rt
rt
60
rt
rt
rt
rt
Me
Me
Me
CH2CN
Me
60
89
66
69
42
55
60
90
97
95
77
74
91
87
CH2CN
Me
a Effective yield.9
b HPLC trace 220 nm.10
Scheme 1.
be explained as deriving from an incomplete alkylation
of the resin, as happens in the acylsulfonamides case.
Differences in between DMF and THF were less
enhanced when activating with the cyanomethyl group
(entries 6 and 7). In the same conditions the unalkyl-
ated precursors 3 and 4 released no material.
In order to explore the limits of this methodology, the
set of amines 6–12 was submitted to the cleaving condi-
tions of entry 2 and the resulting products were ana-
lyzed. Primary and secondary amines reacted equally
well and crude product were of good to excellent qual-
ity (Table 2).
Aniline was much less reactive: with both resins 3 and
4 activated either with TMSCHN2 or iodoacetonitrile
and cleaved at rt or 60°C in both DMF and THF,
yields were very poor. The best result was obtained
heating resin 3 in DMF for 3 h at 60°C (42% yield, 73%
purity) in the presence of 1.2 equiv. of aniline, followed
by aqueous acidic work-up. Contrary from what was
Figure 1. HPLC trace (220 nm) of the crude 5 obtained in
entry 2 (Table 1).

D. Fattori et al. / Tetrahedron Letters 44 (2003) 811–814
813
Table 2. Phenyl ureas from amines 6–12
observed in the case of acylsulfonamides, with sulfonyl-
ureas the cyanomethyl group is not very efficient in
enhancing reactivity.
Amine
Urea
Yield (%)a
Purity (%)b
6
7
8
9
10
11
12
6a
7a
8a
78
100
100
77
91
90
97
90
93
92
93
82
91
The method was also applicable to the less reactive
alkyl isocyanates or to the hindered ortho substituted
phenyl isocyanates. When resin 1 was reacted with
benzyl, isopropyl or orthophenyl substituted iso-
cyanates and then submitted to optimized cleavage
conditions, the corresponding ureas (13–17) were
obtained in good to moderate yields (Table 3).
9a
10a
11a
12a
83
a Effective yield.9
b HPLC trace 220 nm.10
In conclusion, we have demonstrated that the Kenner
safety-catch linker can be used for the preparation of
unsymmetrical di- and trisubstituted ureas. Isocyanate
loading on the resin seems to be a crucial point: the
more acidic resin 112 gives better yields than resin 2;
aliphatic isocyanates require longer loading times and
give low yields. This method is especially interesting for
the preparation of libraries, since it allows chemical
elaboration of the molecule prior to urea release, does
not need any further work-up and does not require
particularly sensitive or harsh conditions.
Table 3. Aliphatic and o-phenylsubstituted isocyanates
Loading methods alternative to the isocyanate one,
which would avoid non-commercial isocyanates prepa-
ration and allow the synthesis of tetrasubstituted
unsymmetrical ureas, are under study and will be
reported in due time.
Supplementary material
HPLC chromatograms, MS and 1H NMR for com-
Urea
Yield (%)a
Purity (%)b
pounds 5, 6a–12a, 13–17 are available from the author.
13
14
15
16
17
42
62
62
100
74
92
69
87
91
98
Acknowledgements
We are grateful to C. A. Maggi and F. Animati for
continuous support to the work and to A. Cartoni, S.
Mauro and A. Ettorre for analytical assistance.
a Effective yield.9
b HPLC trace 220 nm.10

814
D. Fattori et al. / Tetrahedron Letters 44 (2003) 811–814
with THF, DCM, THF, diethyl ether and dried in vacuo.
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8. A batch of activated resin was treated with 1.2 equiv. of
p-methoxybenzylamine in 1.5 mL of solvent for 12 h.
Then, 2 equiv. of isocyanate resin were added together
with 2 mL of THF and the resulting mixture was shaken
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vacuo (Genevac HT-4 apparatus) afforded the desired
crude compounds.
9. Effective yield: a weighted batch of sulfonamido resin
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