An efficient and practical method for the synthesis of mono-N-protected α,ω-diaminoalkanes

Article abstract of DOI:10.1016/S0040-4039(01)00282-9

The large-scale synthesis of mono-N-protected (Cbz, Boc, Ts, and Ns) α,ω-diaminoalkanes (the number of carbon atoms=3, 4, 5 and 6) are accomplished in 81-94% yield by the protection of amine and subsequent reduction of an azido group from α,ω-azido alkyl amines. α,ω-Azido alkyl amines are prepared efficiently by the partial reduction of α,ω-diazidoalkanes which are obtained from the corresponding dibromoalkanes.

Full text of DOI:10.1016/S0040-4039(01)00282-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2709–2711
An efficient and practical method for the synthesis of
mono-N-protected a,v-diaminoalkanes
Jae Wook Lee, Sung Im Jun and Kimoon Kim*
National Creative Research Initiative Center for Smart Supramolecules and Department of Chemistry,
Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31 Hyojadong,
Pohang 790-784, South Korea
Received 21 November 2000; revised 29 January 2001; accepted 16 February 2001
Abstract—The large-scale synthesis of mono-N-protected (Cbz, Boc, Ts, and Ns) a,v-diaminoalkanes (the number of carbon
atoms=3, 4, 5 and 6) are accomplished in 81–94% yield by the protection of amine and subsequent reduction of an azido group
from a,v-azido alkyl amines. a,v-Azido alkyl amines are prepared efficiently by the partial reduction of a,v-diazidoalkanes which
are obtained from the corresponding dibromoalkanes. © 2001 Elsevier Science Ltd. All rights reserved.
Polyamines such as putrescine, spermidine and sper-
mine and their derivatives have attracted considerable
interest in recent years due to their biological functions
and pharmacological properties.1 As well as medicinal
chemistry, these amines have been used in supramolecu-
lar chemistry. For example, they form stable host–guest
complexes with cucurbituril, a synthetic receptor.2 Tak-
ing advantage of this fact, we have been studying
self-assembly of interlocked structures such as rota-
xanes, polyrotaxanes and molecular necklaces using
cucurbituril as a molecular ‘bead’ and diamines and
polyamines as molecular ‘strings’.3 These rotaxanes are
potentially useful in the construction of molecular
switches, memories and machines.3g,4 However, devel-
opment of such rotaxanes with functions requires elab-
orated polyamine-based molecular ‘strings’. In our
efforts to synthesize polyamine-based molecular
‘strings’ we decided to develop an efficient and practical
route to mono-N-protected diaminoalkanes.
Despite many reported methods in the mono-protection
of diamines,5 however, mono-selective protection of
diamines is still difficult and inefficient because of the
concomitant generation of unprotected and diprotected
by-products. Furthermore, these direct mono-protec-
tion methods are not economical because starting mate-
rials a,v-diaminoalkanes and protecting reagents such
as CbzCl and (Boc)2O are expensive. Although an azido
group has been used as a primary amine genitor in
organic synthesis,6 little attention has been paid to the
idea that azidoamines would provide an efficient syn-
thetic route to mono-N-protected diaminoalkanes. Here
a
b
N3
Br
N3
NH2
Br
N3
n
n
n
1
3
2
a : n = 0, b : n= 1
c : n = 2, d: n = 3
HCl
H2N
c
d
N3
NHCbz
NHCbz
n
n
5
4
Scheme 1. Reagents and conditions: (a) NaN3, DMF (H2O), 80°C, 20 h; (b) Ph3P, Et2O/EtOAc –5% HCl, rt, 24 h; (c) CbzCl,
NaOH, THF–H2O, 2 h at 0°C and 3 h at rt; (d) Ph3P, THF (H2O), rt, 24 h, then HCl.
Keywords: mono-protection; a,v-diaminoalkanes; azides; reduction.
* Corresponding author. Fax: 82-54-279-8129; e-mail: kkim@postech.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00282-9

2710
J. W. Lee et al. / Tetrahedron Letters 42 (2001) 2709–2711
Table 1. Synthesis of compounds 2, 3 and 5
reduced to amines using triphenylphosphine in wet
THF. Isolation of the mono-Cbz-protected diamines 5
as a hydrochloride salt is readily accomplished in 85–
95% yields by treatment with conc. HCl (Table 1).11
Compound
n
Yield (%)a
Compound
n
Yield (%)a
2a
2b
2c
2d
3a
3b
0
1
2
3
0
1
97
98
99
99
90
88
3c
3d
5a
5b
5c
5d
2
3
0
1
2
3
67
60
85
86
95
94
Recognizing the advantages of this synthetic approach,
we studied the introduction of other protective groups
to the aminoazides. For example, 4-azidobutylamine 3b
was reacted with (Boc)2O, TsCl and NsCl to give the
corresponding protected aminoazides 6 quantitatively.
The protected amino-azides 6 are reduced to mono-N-
protected diaminoalkanes 7 using triphenylphosphine in
wet THF, which are isolated in 81–90% yields as hydro-
chloride salts by treatment with conc. HCl (Scheme 2).
a Yields of pure, isolated products.
we report efficient preparation of mono-N-protected
diaminoalkanes from diazidoalkanes via azidoamine
(Scheme 1).
Although monoprotected diamines such as 5 and 7
have been widely used in organic synthesis, particularly
polyamine synthesis,1b,1e,12 their synthetic utilities in
supramolecular chemistry are further demonstrated by
our recent syntheses of DNA binding rotaxanes13 and
rotaxane-terminated dendrimers.14 In the former, a
cucurbituril ‘bead’ is threaded on desymmetric
polyamine ‘strings’, while in the latter a cucurbituril
‘bead’ is threaded on each and every terminal
diaminobutane unit of the dendrimers. In both cases,
the key synthetic step involves regioselective monofunc-
tionalization of the diaminoalkane, which was easily
achieved using the monoprotected diaminoalkanes pre-
sented here.
The starting materials, a,v-diazidoalkanes 2 are easily
prepared from the corresponding dibromoalkanes 1.
1,4-Diazidobutane 2b (n=1) is reacted with
triphenylphosphine in ether/ethyl acetate in the pres-
ence of 5% HCl.7 The initially formed azidoamine is
protonated by the acid to migrate into the aqueous
layer. As a result, the over-reduction to diamine is
prevented. After the organic layer is discarded, the
aqueous layer is washed with methylene chloride to
remove the remaining triphenylphosphine oxide and
non-ionic organic components. Addition of a base to
the aqueous layer followed by extraction with methyl-
ene chloride gives azidoamine 3b in 88% yield, which
contains virtually no diamine. Other azidoamines 3a, 3c
and 3d (n=0, 2 and 3, respectively) are also easily
prepared from diazides 2a, 2c and 2d, respectively.8
Eventually we can prepare highly pure azidoamines by
acid–base extractions.9 The yields of azidoamines with
shorter alkyl chains (n=0, 1) are higher than those with
longer chains (n=2, 3). The somewhat lower isolation
yields of the latter may be due to their higher solubili-
ties in methylene chloride used to remove
triphenylphosphine oxide and non-ionic organic
components.
In conclusion, large quantities of mono-N-protected
diaminoalkanes can be easily prepared from azido-
aminoalkanes, which are obtained efficiently by the
desymmetric reduction of diazidoalkanes. No chro-
matography is needed in this procedure. Separation of
the desired products can be achieved by simple acid–
base extractions and crystallization. Thus, this is a
highly efficient, economical and practical method for
preparing mono-N-protected diaminoalkanes. Azido-
aminoalkanes and mono-N-protected diaminoalkanes
should be useful in the preparation of polyamines and
their derivatives, which are important in medicinal
chemistry as well as supramolecular chemistry.
After a protective group is introduced to the amine
group of the azidoamines, the azido group is trans-
formed into a primary amine to produce mono-N-pro-
tected diaminoalkanes. Among many protective groups
we first chose the benzyloxycarbonyl (Cbz) group,
which is stable under basic and most acidic condi-
tions.10 A Cbz group is introduced to azidoamines 3 by
the reaction with CbzCl in THF–H2O in the presence of
NaOH. The Cbz-protected aminoazides 4 are obtained
quantitatively, and can be used in reduction of azide
without further purification. The crude azides 4 are
Acknowledgements
We gratefully acknowledge the Korean Ministry of
Science and Technology (Creative Research Initiative
Program) for support of this work, and Professor P. K.
Bharadwaj for reading the manuscript.
1.1 eq. PG-X
N3
N3
NH2
NHPG
NaOH, THF/H2O
3b
6
PG-X = (Boc)2O, TsCl, NsCl
HCl
H2N
SO2Cl
1.2 eq. PPh3
NsCl =
NHPG
NO2
THF (H2O), rt, 24 h
then HCl
7
Scheme 2. 81% for PG=Boc (7a); 88% for PG=Ts (7b); 90% for PG=Ns (7c).

J. W. Lee et al. / Tetrahedron Letters 42 (2001) 2709–2711
2711
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