Powerful N-monoalkylation of linear tetraamines via bisaminal intermediates

Article abstract of DOI:10.1002/ejoc.200400459

The bisaminals obtained through the condensation of two linear tetraamines with glyoxal or pyruvic aldehyde were selectively alkylated with bromo- or α,ω-dibromoalkanes in good yields at one of the secondary amino functions to give rise to N-monoalkylated tetraamines or linear octaamines. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400459

FULL PAPER
Powerful N-Monoalkylation of Linear Tetraamines via Bisaminal Intermediates
[a]
[a]
[a]
[a]
´
´ `
Geraldine Claudon, Nathalie Le Bris, Helene Bernard, and Henri Handel*
Keywords: Linear tetraamine / Linear octaamine / Glyoxal / Bisaminal / N-Monoalkylation
The bisaminals obtained through the condensation of two
linear tetraamines with glyoxal or pyruvic aldehyde were se-
lectively alkylated with bromo- or α,ω-dibromoalkanes in
good yields at one of the secondary amino functions to give
rise to N-monoalkylated tetraamines or linear octaamines.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
and statistical reactions of the two terminal nitrogen atoms
lead to mixtures of products and lower the yields. These
In the last three decades naturally occurring polyamines drawbacks could be considerably reduced by bringing the
and their synthetic analogues have been widely studied be- two remaining secondary amino functions closer together
cause of their various biological and medical applications, to form a rigid intermediate: in this way, the alkylation of
notably as antineoplastic,[1] antimicrobial[2] and antima- the first nitrogen atom could influence the alkylation of the
larial[3] agents. These studies have highlighted the large po- second one, and thus limit its reactivity (Scheme 1). The
tential of polyamine functionalisation in the generation of properties of the bisaminal intermediates appear to be ap-
important applications. Since the publications of Ganem[4] propriate for such a purpose owing to their geometry.
and Bergeron,[5] few articles covering the main synthetic Moreover, their preparation is quantitative and, after reac-
routes to polyamines have been published. Two recent re- tion, can easily be deprotected.
views have exhaustively reported the methods used in the
synthesis of polyamines and their derivatives.[6,7] Many of
the methods used for the selective N-alkylation of polyam-
ines involve one-pot syntheses which necessitate the tedious
separation of the resulting mixtures,[8] step-by-step ap-
proaches with the complete elaboration of the polyamine
skeleton[9] or multi-step routes that involve classical N-pro-
Scheme 1
tecting groups.[10] Moreover, few examples of the direct and
efficient N-monofunctionalisation of polyamines have been
described with the exception of two methods based on the
temporary triprotection of triamines[11] or tetraamines.[12]
In recent years, the bisaminals of cyclic and linear tetra-
Results and Discussion
amines have been extensively studied. In numerous cases,
Herein, we describe the N-monoalkylation of bisaminals
they have enabled the successful synthesis of tetra-
readily obtained through the condensation of the two linear
azamacrocycles[13Ϫ17] (cyclen, cyclam and homocyclen) and
tetraamines, 1,4,7,10-tetraazadecane and 1,4,8,11-tetraaza-
the N-mono-[18Ϫ20] and N,NЈ-dialkylation[21] of these
undecane, respectively denoted in the literature as 222 (trien
or VE2896) and 232 (NSC19173), with glyoxal and pyruvic
aldehyde. These tetraamines and their N-functionalised de-
rivatives have been extensively studied because of their bio-
macrocycles. The use of bisaminals has also allowed the
synthesis of specific α,ω-dialkylated linear tetraamines.[22]
The selective N-monoalkylation of primary amines of
classically protected linear polyamines (with, for example,
the Ts and Boc groups) is tricky because the independent
logical importance.[23Ϫ25] Hence, it is essential to control
the selective alkylation. Reports concerning the synthesis of
these bisaminals indicate that one or several isomers can be
isolated in variable proportions depending on the exper-
imental conditions.[14,15,26,27] Scheme 2 lists the bisaminals
synthesized under our own conditions.
[a]
´
Laboratoire de Chimie, Electrochimie Moleculaires et Chimie
´
Analytique, UMR CNRS 6521, Universite de Bretagne
Occidentale,
6 Avenue Victor Le Gorgeu, CS 93837, 29238 Brest Cedex 3,
France
Bisaminals 1Ϫ5, eventually used as a mixture of isomers,
were engaged in N-alkylation reactions with benzyl bromide
Fax: (internat.) ϩ 33-2-98017001
E-mail: henri.handel@univ-brest.fr
Eur. J. Org. Chem. 2004, 5027Ϫ5030
DOI: 10.1002/ejoc.200400459
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5027

G. Claudon, N. Le Bris, H. Bernard, H. Handel
FULL PAPER
Scheme 2. Bisaminals obtained under our experimental conditions
or 1-bromopropane as the electrophile (Scheme 3). Under
The proximity of the two secondary amino functions in
our conditions, the reactivity of the first secondary nitrogen the bisaminals is likely to introduce geometrical constraints
atom of these bisaminals, which have all been previously and steric hindrance; these effects added to those induced
used as precursors in cyclisation reactions with dihalo- by the first-linked RЈ substituent, prevent the access of the
alkanes,[16,17,28] showed high selectivity: The reaction of second electrophile equivalent to the free secondary nitro-
1 equiv. of the electrophilic agent with the different bis- gen atom. The nature of the bisaminal bridge does not in-
aminals led, after deprotection performed in hydrazine hy- fluence the course of the reaction since similar results were
drate,[28] to N-monoalkylated compounds and a few dialkyl- obtained with glyoxal or pyruvic aldehyde derivatives.
ated products which were easily removed during the purifi-
Among the dialkylated products obtained, dissymmetri-
cation step. The monoalkylation was easy to perform and cal ones, obtained by reaction with the tertiary amino
was achieved with good yields irrespective of the electroph- groups of the bisaminals, were also detected. This fact pre-
ile (activated or not) and starting bisaminal (single com- cludes the formation of selectively α,ω-dialkylated tetra-
pound or a mixture of isomers). The overall yields for com- amines with 2 equiv. of the electrophile.
pounds 6Ϫ9 are reported in Table 1.
We took advantage of the selective reactivity of these bis-
aminals towards electrophiles to synthesize linear octa-
amines by using bis(electrophilic) reagents. Since compound
3 gave the best monoalkylation yields, it was used in alky-
lation reactions with α,αЈ-dibromo-p-xylene and 1,5-di-
bromopentane. Accordingly, very good yields were also se-
cured for the expected octaamines 10 and 11, respectively
(Scheme 4).
Scheme 3. Selective N-monoalkylation of bisaminals 1Ϫ5
Table 1. N-Monoalkylation of linear tetraamines
Starting tetraamine Bisaminal
Product
No. RЈ
Yield (%)[a]
Scheme 4. Synthesis of two linear octaamines
222
232
1
2
1
2
3
4
5
3
4
5
6
7
8
C6H5CH2 60
63
nPr
62
65
Conclusions
C6H5CH2 86
76
74
76
74
72
In summary, the use of bisaminal intermediates of linear
tetraamines to discriminate between the two terminal nitro-
gen functions constitutes a new and efficient route to the
N-monoalkylation of linear tetraamines. The synthesis of
bisaminals is quasiquantitative, and deprotection, after al-
9
nPr
a
Isolated yield after purification.
5028
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 5027Ϫ5030

N-Monoalkylation of Linear Tetraamines
FULL PAPER
the solution was filtered and the solvent evaporated. Then the resi-
due was dissolved in hydrazine monohydrate (10 mL) and the solu-
tion refluxed for 2 h. Excess hydrazine was removed in vacuo and
the residual oil was taken up in CHCl3 (20 mL); insoluble poly-
hydrazones were discarded. The solvent was evaporated in vacuo
and the residue was purified to obtain the N-mono-alkylated tetra-
amine. The crude product was dissolved in EtOH and the N-
monoalkylated derivative was precipitated as the sulfate salt for 222
derivatives (solution of 5% H2SO4 in EtOH) or as the chloride salt
for 232 derivatives (12  HCl). The solid was washed with EtOH
(3 ϫ 20 mL) and the salt was dissolved in the minimum amount of
water (5 mL). The pH of this solution was raised to 14 (NaOH
pellets) with cooling and after extraction with CH2Cl2 (3 ϫ 20 mL),
drying (MgSO4) and concentrating, the oily residue was found to
be pure and free N-monoalkylated tetraamine. For microanalyses
and NMR studies, 222 derivatives were also isolated as the chlo-
ride salts.
kylation, is facile. It should be easy to extend this process
to other electrophilic reagents and linear tetraamines. The
two linear octaamines described here constitute an interest-
ing application of the method as they are used as starting
materials in the synthesis of large macrocycles. Further in-
vestigations are in progress.
Experimental Section
General: All reagents were of commercial quality and solvents were
dried using standard procedures. 1H and 13C NMR spectra were
recorded with an AC 300 or a DX Avance 400 Bruker spectrometer.
The mass spectra were recorded with a ZABSpec TOF Micro-
Mass spectrometer
Experimental Procedures for the Synthesis of Bisaminals 1؊5
Tetraamine 6: 1H NMR (300.13 MHz, CDCl3, 25 °C): δ ϭ
2.62Ϫ2.78 (m, 12 H, CαH-N), 3.84 (s, 2 H, CH2Ph), 7.26Ϫ7.30 (m,
5 H, CH2Ph) ppm. 13C NMR (75.47 MHz, CDCl3, 25 °C): δ ϭ
41.2 (CαϪNH2), 48.3, 48.8 (3 C), 52.0 (CαϪN), 53.4 (CH2C6H5),
126.4, 127.5, 127.7, 140.0 (C6H5) ppm. HRMS (ESI): calcd. for
C13H25N4: 237.2079 [M ϩ H]ϩ; found: 237.2081.
Bisaminal 1: A solution of 40% aqueous glyoxal (726 mg, 5 mmol)
in EtOH (10 mL) was added to a solution of 222 (730 mg, 5 mmol)
in EtOH (10 mL). The resulting mixture was stirred for 2 h and
then the solvent was removed under reduced pressure. Following
the addition of CH3CN (20 mL) and a few drops of water, the
resulting solution was stirred under reflux overnight. Then, the sol-
vent was evaporated, and the residual oil was taken up in toluene
(20 mL). Insoluble polymers were eliminated by filtration. When
required, this procedure was repeated twice. The filtrate was con-
centrated to give an oily residue composed of the four isomers of
bisaminal 1 in 90% yield (755 mg). The gem-cis isomer was the
major product (about 70%).
Tetraamine 6·4HCl: 13C NMR (100.62 MHz, D2O, 25 °C): δ ϭ 38.2
(CαϪNH2), 45.3, 46.2, 46.5, 47.5, 47.9 (CαϪN), 54.5 (CH2C6H5),
132.2, 132.8 (3C) (C6H5) ppm. C13H28Cl4N4 (382.2): calcd. C 40.85,
H 7.38, N 14.66; found C 40.92, H 7.49, N 14.38.
Tetraamine 7: 1H NMR (400.13 MHz, CDCl3, 25 °C): δ ϭ 0.87 (t,
J ϭ 7.3 Hz, 3 H, CH3), 1.46 (m, 2 H, CH2CH3), 2.50Ϫ2.65 (m, 14
H, CαHϪN) ppm. 13C NMR (100.62 MHz, CDCl3, 25 °C): δ ϭ
10.5 (CH3), 21.9 (CH2CH3), 40.5 (CαϪNH2), 48.1 (3 C), 50.5, 51.2
(2 C) (CαϪN) ppm.
Bisaminal 2: A solution of 40% aqueous pyruvic aldehyde (901 mg,
5 mmol) in EtOH (10 mL) was added to a solution of 222 (730 mg,
5 mmol) in EtOH (10 mL) and stirred at room temperature for 2 h.
After removal of the solvent, the residual oil was purified by treat-
ment with toluene according to the same procedures as those used
for compound 1. Bisaminal 2 was obtained in 90% yield (820 mg)
as a mixture of four isomers of which the gem-cis isomer was the
major one (about 75%).
Tetraamine 7·4HCl: 1H NMR (400.13 MHz, D2O, 25 °C): δ ϭ 0.82
(t, J ϭ 7.1 Hz, 3 H, CH3), 1.57Ϫ1.58 (m, 2 H, CH2CH3), 3.27Ϫ3.38
(m, 14 H, CαHϪN) ppm. 13C NMR (100.62 MHz, D2O, 25 °C):
δ ϭ 13.3 (CH3), 22.1 (CH2CH3), 38.4 (CαϪNH2), 45.7, 46.2 (2 C),
46.5, 47.5, 52.7 (CαϪN) ppm. C9H28Cl4N4 (334.2): calcd. C 32.35,
H 8.45, N 16.77; found C 32.68, H 8.45, N 16.52.
Bisaminal 3: A solution of 40% aqueous glyoxal (726 mg, 5 mmol)
with a few drops of glacial acetic acid in EtOH (10 mL) was added
to a stirred solution of 232 (800 mg, 5 mmol) in EtOH (10 mL).
The solution was refluxed overnight. After evaporation of the sol-
vent and removal of polymers (see details for the preparation of
compound 1), a white solid was obtained in 90% yield (818 mg) as
a single gem-trans isomer.
Tetraamine 8: 1H NMR (400.13 MHz, CDCl3, 25 °C): δ ϭ 1.67 (m,
2 H, CβHϪN), 2.59Ϫ2.79 (m, 12 H, CαHϪN), 3.77 (s, 2 H,
CH2C6H5), 7.29Ϫ7.31 (m,
5
H, C6H5) ppm. 13C NMR
(100.62 MHz, CDCl3, 25 °C): δ ϭ 29.6 (CβϪN), 40.9 (CαϪNH2),
47.4, 47.5, 47.9, 48.6, 51.8 (CαϪN), 53.0 (CH2C6H5), 125.9, 127.2,
127.4, 139.7 (C6H5) ppm. HRMS (ESI): calcd. for C14H27N4:
251.2236 [M ϩ H]ϩ; found: 251.2241. C14H27N4·1.4H2O (276.6):
calcd. C 61.01, H 10.53, N 20.33; found C 61.03, H 10.07, N 20.54.
Bisaminal 4: A mixture of 40% aqueous glyoxal (726 mg, 5 mmol)
in EtOH (10 mL) was added at 0 °C to a solution of 232 (800 mg,
5 mmol) in EtOH (10 mL). The mixture was stirred at this tempera-
ture for 2 h. After evaporation of the solvent and removal of poly-
mers (see details for the preparation of compound 1), an oily resi-
due was obtained in 90% yield (822 mg) as a single gem-cis isomer.
Tetraamine 8·4HCl: 1H NMR (400.13 MHz, D2O, 25 °C): δ ϭ 1.99
(m, 2 H, CβHϪN), 3.03Ϫ3.09 (m, 4 H, CαHϪN), 3.23Ϫ3.26 (m, 4
H, CαHϪN), 3.31 (s, 4 H, CαHϪN), 4.16 (s, 2 H, CH2C6H5), 7.35
(m, 5 H, C6H5) ppm. 13C NMR (75.47 MHz, D2O, 25 °C): δ ϭ
25.5 (CβϪN), 38.2 (CαϪNH2), 45.3, 46.1, 47.1, 47.7, 47.8 (CαϪN),
54.6 (CH2C6H5), 132.2, 132.7, 132.8, 132.9 (C6H5) ppm.
Bisaminal 5: A solution of 40% aqueous pyruvic aldehyde (901 mg,
5 mmol) was added to 232 (800 mg, 5 mmol) according to the same
procedure as described for the synthesis of compound 2 to give the
oily gem-cis bisaminal 5 in 90% yield (880 mg).
1
Tetraamine 9: H NMR (400.13 MHz, CDCl3, 25 °C): δ ϭ 0.87 (t,
J ϭ 7.4 Hz, 3 H, CH3), 1.45 (m, 2 H, CH2CH3), 1.64 (m, 2 H,
CβHϪN), 2.52 (t, J ϭ 7.1 Hz, 2 H, CαHϪN), 2.60 (m, 8 H,
CαHϪN), 2.75 (t, J ϭ 5.8 Hz, 4 H, CαHϪN) ppm. 13C NMR
(100.62 MHz, CDCl3, 25 °C): δ ϭ 11.2 (CH3), 22.6 (CH2CH3), 29.9
(CβϪN), 41.2 (CαϪNH2), 47.7, 47.8, 48.8, 49.0, 51.3, 52.1 (CαϪN)
ppm. HRMS (LSIMS): calcd. for C10H27N4: 203.2236 [M ϩ H]ϩ;
found 203.2234.
Typical Procedure for the Synthesis of N-Monoalkylated Tetra-
amines 6Ϫ11: K2CO3 (6.91 g, 10 equiv.) and the electrophile (1
equiv.) or biselectrophile (0.5 equiv.) were added to a solution of
the bisaminal (5 mmol) in CH3CN. After stirring at room tempera-
ture for 4 h for benzyl bromide or α,αЈ-dibromo-p-xylene, or at 50
°C for 2 d in the case of 1-bromopropane or 1,5-dibromopentane,
Eur. J. Org. Chem. 2004, 5027Ϫ5030
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5029

G. Claudon, N. Le Bris, H. Bernard, H. Handel
FULL PAPER
[5]
[6]
Tetraamine 9·4HCl: 1H NMR (400.13 MHz, D2O, 25 °C): δ ϭ 1.02
(t, J ϭ 7.4 Hz, 3 H, CH3), 1.76 (m, 2 H, CH2CH3), 2.20 (m, 2 H,
CβHϪN), 3.13 (t, J ϭ 7.7 Hz, 2 H, CαHϪN), 3.29 (t, J ϭ 7.7 Hz,
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(100.62 MHz, D2O, 25 °C): δ ϭ 13.1 (CH3), 22.0 (CH2CH3), 25.5
(CβϪN), 38.3 (CαϪNH2), 45.8, 46.1, 47.2, 47.8 (2 C), 52.7 (CαϪN)
ppm. C10H30Cl4N4·0.5H2O (215.4): calcd. C 56.83, H 12.88, N
26.51; found C 56.65, H 12.38, N 26.53.
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CαHϪN), 2.74 (m, 4 H, CαHϪN), 3.72 (s, 4 H, CH2C6H4),
7.18Ϫ7.21 (m, 4 H, C6H4) ppm. 13C NMR (100.62 MHz, CDCl3,
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Acknowledgments
We are grateful to Marie-Paule Friocourt for her invaluable help
[22]
´
and to the Region Bretagne for financial support. We thank the
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the Service Central d’Analyse, CNRS, BP 22, 69390 Vernaison,
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Received July 1, 2004
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 5027Ϫ5030