Versatile solid-phase synthesis of secondary amines from alcohols. Development of an N-Boc-(o-nitrobenzene)sulfonamide linker

Article abstract of DOI:10.1016/S0040-4039(03)00574-4

The development of a versatile amine releasing linker based on the modified o-nitrobenzene sulfonamide protective group is described. This new N-Boc-o-nitrobenzenesulfonamide (Boc-ONBS) linker enables the elaboration on resin of primary and secondary amines by sequential substitution of the sulfonamide moiety using the Mitsunobu reaction. A 16-member array of secondary and Boc protected primary amines was then prepared using this linker.

Full text of DOI:10.1016/S0040-4039(03)00574-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4153–4156
Versatile solid-phase synthesis of secondary amines from
alcohols. Development of an N-Boc-(o-nitrobenzene)sulfonamide
linker
Miles S. Congreve,a Corinne Kay,a,* Jan J. Scicinski,a Steven V. Ley,b Geoffrey Williams,c
Peter J. Murray,c Stephen C. McKeownd and Stephen P. Watsond
aGlaxoSmithKline, Cambridge Chemistry Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
bDepartment of Chemisty, Lensfield Road, Cambridge CB2 1EW, UK
cOSI Pharmaceuticals, Watlington Road, Cowley, Oxfordshire OX4 6LT, UK
dGlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 14 October 2002; accepted 28 February 2003
Abstract—The development of a versatile amine releasing linker based on the modified o-nitrobenzene sulfonamide protective
group is described. This new N-Boc-o-nitrobenzenesulfonamide (Boc-ONBS) linker enables the elaboration on resin of primary
and secondary amines by sequential substitution of the sulfonamide moiety using the Mitsunobu reaction. A 16-member array of
secondary and Boc protected primary amines was then prepared using this linker. © 2003 Elsevier Science Ltd. All rights reserved.
Amine releasing linkers1 possess the combined advantage
of acting as an anchor point to the solid support as well
as in some cases providing temporary protection for an
otherwise reactive functionality.2 Generally such systems
do not allow modification of the amine groups whilst
immobilised on resin to give more complex amines. We
recently reported a linker3 based on Fukuyama’s o-
nitrobenzenesulfonyl protecting group,4 which releases
primary or secondary amines in good yields and purity.
However, one limitation of this linker system is that it
requires functionalisation of one of the amine substituents
in solution prior to immobilisation on the solid support.
Herein we wish to report a modified linker that remedies
this shortcoming. This Boc-ONBS linker (1) enables
on-bead preparation of both primary (free or Boc-pro-
tected) and secondary amines from alcohol precursors via
the Mitsunobu reaction.
Scheme 1. Reagents and conditions: (a) R1OH, Ph3P, DEAD, THF, rt; (b) DBU, mercaptoethanol, MeCN, rt; (c) TFA, CH2Cl2,
rt; (d) R2OH, Ph3P, DEAD, THF, rt.
* Corresponding author. Tel.: +44-(0)121-359-1100; fax: +44-(0)121-359-3326; e-mail: gwilliams@osip.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00574-4

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M. S. Congre6e et al. / Tetrahedron Letters 44 (2003) 4153–4156
As recently shown by Fukuyama5 the presence of the
Boc protective group ensures that only mono alkylation
occurs under Mitsunobu conditions,6,7 and allows syn-
thesis of either Boc (2) or unprotected amines (3) on
cleavage with a thiol (Scheme 2). Secondary amines (4)
are accessible firstly by removal of the Boc group and
then by performing a second Mitsunobu reaction. The
Boc-ONBS linker (1) was prepared from readily avail-
able starting materials as shown in Scheme 2. The
4-chloro-3-nitrobenzoic acid precursor was converted to
the sulfonyl chloride (5), which was then treated with
ammonia to give primary sulfonamide (6). Attachment
of (6) to aminomethyl polystyrene resin (1 mmol/g)
gave primary sulfonamide resin (7) and Boc protection
gave the required immobilised linker (1) in good overall
yield.
peak splitter). Coupling of the sulfonamide linker (6) to
the amine resin (8)10 and Boc protection afforded ana-
lytical construct (9). This was subsequently derivatised
with o-methoxybenzyl alcohol and 1-naphthyl alcohol,
in the manner described in Scheme 1, enabling synthesis
of a previously characterised secondary amine (11).
After each step of the reaction sequence, analytical
cleavage and MS analysis confirmed a successful trans-
formation, with a final conventional cleavage at the
o-NBS linker affording the amine (11) in good yield
and purity.
The utility of the linker was exemplified in the prepara-
tion of an array of Boc protected primary amines and
secondary amines (Table 1). Following the first Mit-
sunobu reaction four resins (12a–d) were obtained.
Thiolate cleavage11 of a sample of each released the
corresponding Boc protected primary amines (2a–d) in
good yield after flash chromatography. Each of the four
resins were then treated with three diverse alcohols that,
on cleavage, gave the secondary amines (4a–l). Interest-
ingly amine (4i) and (4j) afforded the same product in
similar yield and purity showing the order of reaction
to be unimportant.
The feasibility of using linker (1) to produce amines
was firstly tested using an analytical construct8 (Fig. 1).
Introduction upstream of the chemically orthogonal
Dde linker9 (Linker 1) enabled ‘analytical cleavage’ of
small resin samples10 to release amine-tagged frag-
ments, analysis of which indicated the progress of each
reaction step. These cleaved derivatives (10a–c) con-
tained a secondary amine to ensure reliable ionisation
in ESI positive mode mass spectrometry (a MS sensi-
tiser) and were present as an equimolar isotopic mixture
to produce a diagnostic doublet in the spectrum (MS
In conclusion, we have developed a versatile amine
releasing linker that enables the direct elaboration of
Scheme 2. Reagents and conditions: (a) i. Na2S2, DMSO, EtOH, 2 h, rt, 51%, ii. Cl2, CH2Cl2, AcOH, H2O, 3 h, rt, 62%; (b)
MeOH, ammonia, 2 h, rt, 98%; (c) i. (7), PyBOP, HOBt, DIPEA, DMF, CH2Cl2, 18 h, rt, 100%; (d) (Boc)2O, Et3N, CH2Cl2, 2
h, rt, 100%.
Figure 1. Analytical construct features. The construct contains an analytical enhancer (A) including a 1:1 mixture of hydrogen
and deuterium isotopes to aid MS analysis (peak splitter) and a secondary amine to aid ESI positive mode ionisation (MS
sensitiser). Analytical cleavage (2% hydrazine in DMF) releases the amine-tagged analytical fragment. Conventional cleavage
(thiol, base) releases the target compounds.

M. S. Congre6e et al. / Tetrahedron Letters 44 (2003) 4153–4156
Table 1. Preparation of an array of primary and secondary amines
4155
both primary and secondary amines directly on
resin.
Acknowledgements
This represents a significant advantage over the previ-
ously published o-nitrobenzenesulfonamide linker.
The authors are grateful to Dr. Peter Marshall, for the
provision of LCMS analytical data.

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M. S. Congre6e et al. / Tetrahedron Letters 44 (2003) 4153–4156
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