Bis-imine primary amine protection of the dialkyltriamine, norspermidine

Article abstract of DOI:10.1016/j.tetlet.2012.04.070

This Letter details the particular use of salicylaldehyde (2-hydroxybenzaldehyde) for the regiospecific protection of primary amines in a representative polyamine, norspermidine (N-(3-aminopropyl)propane-1,3-diamine) under mild reaction conditions in high

Full text of DOI:10.1016/j.tetlet.2012.04.070

Tetrahedron Letters 53 (2012) 3301–3304
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Tetrahedron Letters
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Bis-imine primary amine protection of the dialkyltriamine, norspermidine
Adrian S. Culf a,b, , Jennifer A. Melanson b, ,§, Rodney J. Ouellette a,à, Glen G. Briand b,§,
⇑
⇑
a Atlantic Cancer Research Institute, 35 Providence St., Moncton, NB, Canada E1C 8X3
b Dept. of Chemistry & Biochemistry, Mount Allison University, Sackville, NB, Canada E4L 1G8
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter details the particular use of salicylaldehyde (2-hydroxybenzaldehyde) for the regiospecific
protection of primary amines in a representative polyamine, norspermidine (N-(3-aminopropyl)pro-
pane-1,3-diamine) under mild reaction conditions in high yield. The lack of intramolecular hexahydro-
pyrimidine formation allowed for subsequent N2-acylation and N2-alkylation reactions, typical of
polyamine synthetic strategies.
Received 6 January 2012
Revised 11 April 2012
Accepted 17 April 2012
Available online 25 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Polyamine
Imine
Protection
The chemoselective manipulation of dialkyltriamines is useful
for the preparation of metal multidentate ligands,1 molecular
probes2–5 and bio-conjugates across a wide spectrum of potential
applications.6 Examples include cancer diagnostics and ther-
apy;7–9 low molecular mass organic gelators;10,11 dynamic combi-
natorial libraries;12 self-assembled organic nano-structures13,14
and photochromic Schiff base macrocycles.15 Such chemical
manipulations are also useful for total synthesis involving poly-
alkylamines, for example, using spermidine, norspermidine and
sym-homospermidine.6,16
O
O
R
R
R'
R
R
NH2
R'
N
R'
N
H
O
N
H
1o Amine
Carbamate
2o Amide
Schiff base / Imine
Figure 1. Some protecting group options for primary amine function.
H2N
N
H
NH2
From the available amine protection strategies (e.g., carbamate,
amide and imine/Schiff base; Fig. 1) a novel strategy is presented
for the less often utilized bis-imine selective functionalization of
primary amines.6,17 In this Letter, the bis-imine strategy for the
protection of N-(3-aminopropyl)propane-1,3-diamine, also known
as norspermidine, is shown. The attraction of the Schiff base ap-
proach stems from the ease of selective imine formation from pri-
mary alkylamines in the presence of intramolecular secondary and
higher substituted alkylamines under mild reaction conditions.
Unaffected amine functional groups are then available for further
regiospecific procedures pertaining to a particular synthetic target
goal.
Norspermidine /
N1-(3-aminopropyl)propane-1,3-diamine
Figure 2. Representative dialkyltriamine used in this study.
yields and mild reaction conditions. 1-Propylamine and benzalde-
hyde (yielding N-benzylidenepropan-1-amine) were chosen as a
structurally representative monomeric model reaction under:
solvent-free, microwave assisted;18 room temperature;15 acid-
catalyzed; trimethyl orthoformate reagent addition;19 Montmoril-
lonite K10 catalyzed18 and in water,15 methanol15,20 and ethanol14
solvents. These methodologies were selected as they had been
presented in the literature as being facile and high yielding. Prod-
uct was only recovered by simple stoichiometric mixture of reac-
tants in alcohol solution. It was found that the most favourable
conditions were 0.5 M solution (of 1-propylamine) at room tem-
perature overnight in methanol using one equivalent of benzalde-
hyde, as previously demonstrated by other groups.15,20 The 1H
NMR spectrum of the non-purified imine product, N-benzylidene-
propan-1-amine, is provided as part of Supplementary data.
Our investigation began with the optimization of reaction con-
ditions for imine formation utilizing a range of preparative meth-
ods chosen from the literature for their capacity to provide high
⇑
Corresponding authors. Tel.: +1 506 869 2020; fax: +1 506 862 7571 (A.S.C.);
tel.: +1 506 364 2346; fax: +1 506 364 2313 (G.G.B.).
E-mail addresses: adrianc@canceratl.ca (A.S. Culf), gbriand@mta.ca (G.G. Briand).
Present address: Dept. of Chemistry, Dalhousie University, NS, Canada.
Tel.: +1 506 869 2020; fax: +1 506 862 7571.
à
§
Tel.: +1 506 364 2346; fax: +1 506 364 2313.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.070

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A. S. Culf et al. / Tetrahedron Letters 53 (2012) 3301–3304
An aromatic aldehyde, benzaldehyde, was chosen as the pro-
central 2oamine
Ph
tecting reagent due to its additional usefulness as a chromophoric
moiety, being a practical aid in monitoring reaction progress by
TLC and simplifying chromatographic purification by UV detection.
A complication that soon became apparent was the intramolec-
ular 6-endo-trig ring closure to form an isomeric and cyclic 1-
substituted hexahydropyrimidine20 (Fig. 3a). This side reaction
robs the central secondary amine of its capacity to be further
substituted in subsequent chemical transformations (such as alkyl-
ation and acylation, as it is transformed to a tertiary amine) and
renders the initially-added imine protecting group immutable to
subsequent removal. The presence of this cyclized side product
gave rise to a diagnostic signal from its unique methine CH signal
at ca. d 4 ppm in the 1H NMR spectrum, even though the mass
spectrum reports the expected molecular mass due to the isobaric
nature of the linear and cyclic structural isomers (Fig. 3b).
H
MeOH
HN
N
N
Ph
N
N
H
N
Ph
Ph
1H NMR diagnostic methine
CH 4 ppm
m/ z 307.2
m/ z 307.2
Figure 3a. Intramolecular cyclization observed with
a,x-bis(benzylideneimino)
dipropylenetriamine.
Having optimized the reaction conditions for imine formation,
norspermidine was selected as a representative polyamine back-
bone with widespread interest for a range of synthetic targets6
(Fig. 2). Interestingly, this dialkyltriamine has shown innate anti-
tumour activity.21,22
9.0
8.5
8.0 7.5
7.0
6.5 6.0
5.5
5.0
4.5
4.0 3.5
3.0
2.5 2.0
1.5
1.0
0.5
1H
Figure 3b. 1H NMR of undesired cyclic 1-substituted hexahydropyrimidine showing characteristic resonance at ca. d = 4 ppm of methine CH. Reaction of norspermidine with
benzaldehyde.
Table 1
Selection of benzaldehyde for linear bis-imine formation
O
N
N
H
N
H2N
N
H
NH2
X
X
X
Benzaldehyde substituent
% Linear bis-iminea
% Tetrahydropyrimidinea
H
41
95
45
59
5
55
2-OH
3-OH
4-OH
2-OMe
3-OMe
4-OMe
Quinoid structureb
43
26
45
57
74
55
The significance of the emboldened letters are to signify the unique ability of the 2-hydroxybenzaldehyde to yield a linear bis-imine
protected triamine unencumbered by the cyclic hexahydropyrimidine contaminant.
a
Amount of linear bis-imine and cyclic tetrahydropyrimidine determined by integration of 1H NMR signals of CH@N of imine and
methine CH of tetrahydropyrimidine as CDCl3 solutions of crude reaction product mixtures.
b
4-Hydroxybenzaldehyde yielded only the keto tautomer.

A. S. Culf et al. / Tetrahedron Letters 53 (2012) 3301–3304
3303
O
linear
OH
N
N
H
N
H2N
N
H
NH2
MeOH, rt
OH
HO
norspermidine
1
Figure 4. Synthesis of linear a,x-bisimine protected norspermidine, without hexahydropyrimidine contamination.
N
H
N
H
N
H
N
N
H
N
O
O
OH
HO
keto
en1ol
Non -
purified
Purified
Figure 5. Structure and 1H NMR spectra (CDCl3)—top, non-purified crude reaction mixture and bottom, purified by flash chromatography—of the desired
a,x
-bisimine
protected norspermidine.
A series of six substituted benzaldehydes (Table 1) were se-
lected to investigate electronic and steric effects on linear bis-
imine formation in norpsermidine. 1H NMR spectra of each of the
crude reaction mixtures were recorded, as CDCl3 solutions, to
determine the distribution between the desired linear and byprod-
uct cyclic isomer formation. It was immediately evident that a
combination of steric bulk at the ortho-position coupled with an
ability to form an intramolecular hydrogen bond was the essential
pre-requisite for linear bis-imine 1 formation.11,14 (Fig. 4). Salicyl-
aldehyde (2-hydroxybenzaldehyde) was unique in its ability to
form the bis-imine in almost quantitative yield. Notably, the
NMR spectra of crude and purified 1 were essentially identical
pointing to the high yield and cleanliness of this reaction23
(Fig. 5). Keto-enol tautomerism considerations revealed that
4-hydroxybenzaldehyde formed the para-quinoid keto structure
exclusively. Being more symmetrical, the NMR spectra of 1 were
simpler and had fewer peaks. Compare Figures 3b and 5.
In order to demonstrate the synthetic utility of imine protecting
group strategy, molecule 1 was subjected to alkylation and acyla-
tion reactions at the N2-position representative of widely applied
chemical modifications of polyamine backbones.
Molecule 1 was N2-acylated with benzoic anhydride (yielding
2); di-tert-butyl dicarbonate (Boc) 3 and benzyl chloroformate (Z)
4 in anhydrous ethanol with TEA base, stirring at room tempera-
ture overnight. Following chromatographic purification, yields
of 68–91% were obtained. Molecule 1 was also successfully

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A. S. Culf et al. / Tetrahedron Letters 53 (2012) 3301–3304
N2-alkylated with benzyl bromide 5, propargyl bromide 6 and allyl
bromide 7 in anhydrous chloroform with TEA base and potassium
iodide catalyst stirring at room temperature overnight. Following
chromatographic purification, yields of 62–75% were realised.
Deprotection of imine protecting groups from representative
N2-benzoyl and N2-benzyl compounds 2 and 5, respectively, was
effected with 50% (v/v) TFA in dichloromethane by stirring for 2 h
at room temperature. To the best of our knowledge, this is the first
report of TFA deprotection of an imine/Schiff base protecting
group. Purification by reverse phase column chromatography gave
N2-benzyl- and N2-benzoylnorpsermidine, 8 and 9 respectively,
in moderate yield (ca. 60%) thereby validating the bis-imine
protection strategy. All compounds were characterized by 1D and
2D NMR, IR and HR-MS. These spectra are available as Supplemen-
tary data.
NMR spectra revealed some interesting aspects of the structures
of these molecules. The 1H NMR signals of the bis-imine protected
triamine, 1, were very broad. Unexpectedly, the alkyl methylene
13C NMR signals were also broadened (see Supplementary data).
Spectra recorded in d1-chloroform were compared to those re-
corded in less viscous d3-acetonitrile to no avail. The phenolic OH
and amine NH signals were not evident in the NMR spectrum of
1, although the OH hydrogens were observed for all N2-substituted
molecules (2–7) prepared from it. The observed line broadening
was attributed to extensive hydrogen bonding and rapid proton
exchange in solution. The N2-acylated molecules, 2, 3 and 4, also
displayed broadened NMR signals (both 1H and 13C) with distinct
signals for seemingly equivalent atoms. This was attributed to sta-
ble intramolecular hydrogen bond formation. In contrast, the cor-
responding N2-alkylated molecules, 5, 6 and 7 reported highly
resolved signals revealing distinctive spin–spin coupling patterns.
Hydrogen bonding between the phenolic OH functions and the
N2-substituent was not possible in these molecules.
Supplementary data
Supplementary data (chromatography trace, ESI+ MS, NMR and
IR data for bis-imine protected norspermidine, 1 and its N2-substi-
tuted derivatives 2–9) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
070.
References and notes
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23. Typical synthesis procedure: Bis-imine protected norspermidine. To a solution of
In conclusion, it has been demonstrated that the use of salicyl-
aldehyde (2-hydroxybenzaldehyde) as an imine protection reagent
for primary amine functions in a polyamine. This reaction may
have potential utility for imine protection of primary amine groups
and will spur further development of organic polyamine synthesis
and applications.
norspermidine (0.25 mmoles, 33 mg, 35
was added dropwise salicylaldehyde (0.50 mmoles, 61 mg, 53
l
L) in anhydrous methanol (0.4 mL)
lL) at room
temperature under a stream of argon gas. The bright yellow solution was
stirred at room temperature overnight, evaporated and purified by medium
pressure chromatography (MPLC) on a 4 g silica column using a DCM/MeOH
gradient. Reaction was also performed successfully up to 5 mmole scale. Yield:
82% (70 mg) of
a,x
-bis(o-hydroxybenzylideneimino)norspermidine. 1H NMR
(400 MHz, CD3CN, d ppm): CH2 1.77 (m, 4H), 2.60 (M, 4H), 3.59 (m, 4H); CH
6.85 (m, 4H), 7.27 (m, 4H); CH@N 8.37 (m, 2H) Phenolic OH and NH not
observed due to rapid proton exchange. 13C{1H} NMR (101 MHz, CD3CN): CH2
Acknowledgements
32.3, 48.5, 58.2; CH 117.9, 119.9, 132.9, 133.4, 162.6;
C 120.3, 167.0.
We thank the ACRI, Mount Allison University, NBIF and NB SEED
for funding this research. We also acknowledge D. Léger for MS
support and Dr. M. Touaibia for access to NMR instrumentation.
Assignments by COSY, HSQC, HMBC. LR MS (ESI+): 339.5 m/z. Elemental
analysis (calcd): C: 70.53 (70.77); H: 7.19 (7.42); N: 12.15 (12.38). IR (cmÀ1):
3453, 3054, 1633, 1279, 757. Full spectra displayed in Supplementary data.