A new synthetic approach to N,N′-disubstituted 1,n-alkanediamines

Article abstract of DOI:10.1081/SCC-100103257

A general procedure is described for the synthesis of unsymmetrically substituted N-aryl-N′-alkyl (or aryl) 1,n-alkanediamines 1 (n = 2-5) by reduction of ω-alkyl (or aryl) aminoalkanamides 2 with borane. Compounds 2 are easily obtained by aminolysis of the corresponding ω-haloalkanamides 3.

Full text of DOI:10.1081/SCC-100103257

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A NEW SYNTHETIC APPROACH
TO N,N′-DISUBSTITUTED 1,n-
ALKANEDIAMINES
Liliana R. Orelli , María M. Blanco , María B.
García , Mónica E. Hedrera & Isabel A. Perillo
Published online: 16 Aug 2006.
To cite this article: Liliana R. Orelli , María M. Blanco , María B. García , Mónica
E. Hedrera & Isabel A. Perillo (2001) A NEW SYNTHETIC APPROACH TO N,N′-
DISUBSTITUTED 1,n-ALKANEDIAMINES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:5, 685-695,
DOI: 10.1081/SCC-100103257
To link to this article: http://dx.doi.org/10.1081/SCC-100103257
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SYNTHETIC COMMUNICATIONS, 31(5), 685–695 (2001)
A NEW SYNTHETIC APPROACH TO
N,N0-DISUBSTITUTED
1,n-ALKANEDIAMINES
Liliana R. Orelli, Marıa M. Blanco, Marıa B. Garcıa,
Monica E. Hedrera, and Isabel A. Perillo*
Departamento de Quımica Organica, Facultad de
Farmacia y Bioquımica, Junın 956 (1113), Buenos Aires,
Argentina
ABSTRACT
A general procedure is described for the synthesis of
unsymmetrically substituted N-aryl-N0-alky1 (or aryl) 1,n-
alkanediamines 1 (n ¼ 2À5) by reduction of !-alkyl (or aryl)
aminoalkanamides 2 with borane. Compounds 2 are easily
obtained by aminolysis of the corresponding !-haloalkan-
amides 3.
INTRODUCTION
Naturally occurring polyamines are of biochemical interest as they are
involved in cellular proliferation and differentiation processes,1 while some
synthetic analogues behave as potent antibiotics and antineoplastics.2
Among polyamines, 1,n-diamines have been extensively studied as they
are biosynthetic precursors of polyamines. Besides, suitably substituted
* Corresponding author. E-mail: iperillo@ffyb.uba.ar
685
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

686
ORELLI ET AL.
derivatives share some pharmacological features of polyamines,3 or act as
modulators of enzymes involved in their metabolism.4 In particular, N,N0-
disubstituted 1,n-diamines display a variety of pharmacological activities, in
addition to the antitumoral activity reported for some members.3 Thus,
suitably substituted 1,3-propanediamines have been employed as platelet
antiagregants5 and microbicidal agents,6 while higher homologues
(putrescine and cadaverine derivatives) display affinity for cholinergic7
and NMDA8 receptors.
The synthesis of symmetrically N,N0-disubstituted derivatives starting
from 1,n-diamines is generally accomplished through direct alkylation or
by reduction of the corresponding diamides or diimines. Such synthetic
approaches, as well as other methods based on the aminolysis of ꢀ,!-
dihaloalkanes, cannot be successfully employed for the preparation of
unsymmetrically substituted analogues, as both groups in the substrate
have the same reactivity.9 The synthesis of such derivatives was achieved
in the case of di and trimethylene compounds through cyclic intermediates
such as amidines or aminals,10 but those methods lack general applicability
and generally involve N-monosubstituted 1,n-diamines as starting materials,
themselves accessible through multistep synthesis.11
Within this context, in the course of our research on potentially bioac-
tive 1,n-diamines, we developed a synthetic procedure for the preparation
of N-alkyl (or aralkyl)-N0-aryl-1,n-diamines from N-(!-haloalkyl)amides.12
As one of the N-substituents is generated by reduction of an amide, such
procedure was limited to the synthesis of derivatives with primary N-alkyl
(or aralkyl) substituents and could not be employed for unsymmetrically
substituted N-N0-diarylalkylenediamines. To circumvent such limitations,
we present here an alternative sequence for the synthesis of unsymmetri-
cally substituted N-aryl-N0-alkyl (or aryl)-1,n-diamines 1 (Table), which
were not accessible by the above mentioned procedure.
RESULTS AND DISCUSSION
The sequence depicted in Scheme 1 involves acylation of aliphatic or
aromatic amines with !-haloalkanoyl chlorides, followed by aminolysis of
the corresponding !-haloamides 3. The resulting aminoamides 2 are then
reduced with borane/THF to yield the desired 1,n-diamines 1.
For the synthesis of N-aryl-N0-alkyl derivatives, except for 1a, the
sequence that involves aminolysis of the !-haloacyl chloride with alkyl
amines followed by aminolysis of the product with the arylamine was the
most suitable in order to avoid intramolecular dehydrohalogenation of pre-
cursors 3. In all cases, aminolysis of !-haloamides 3 lead to better yields

1,n-ALKANEDIAMINES
687
Table.
Compound 1
n
R1
C6H5
R2
a
b
c
d
e
f
2
CH3
2
C6H5
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-ClC6H4
C6H5
3CH
3
3
3
4
4
5
C6H5
iso-C3H7
C6H5
g
h
tert-C4H9
p-ClC6H4
when carried out in the presence of a second equivalent of the amine as
hydracid acceptor. Optimum conditions for those reactions were found to
be different according to the nature of the reactants. Active ꢀ-chloroaceta-
mides react with aliphatic amines at room temperature in aqueous solu-
tion,13 while reaction with arylamines (less nucleophilic) was carried out
by heating in the absence of solvent for 1 hour at 80ꢀC. For higher homo-
logues (n ¼ 3–5), the best yields were accomplished by heating at 120ꢀC in
Scheme 1.

688
ORELLI ET AL.
solvent free conditions. By employing such reaction conditions it was poss-
ible to minimize some colateral products arising from alkylation and
transamidation of aminoamides 2. As an example, in the aminolysis of N-
methyl-3-bromopropanamide with p-chloroaniline two by-products were
isolated which were identified as N,N-bis[2-(methylaminocarbonyl)ethyl]-
p-chloroaniline (4) and 3-(p-chlorophenylamino)-N-(p-chlorophenyl)propa-
namide 2i (2, R1 ¼ R2 ¼ p-ClC6H4, n ¼ 3), arising respectively from
alkylation and thermal transamidation of the main product 2c (Scheme 2).
Scheme 2.
CONCLUSIONS
The synthetic strategy presented in this work is applicable for the
preparation of unsymmetrically substituted N-alkyl (or aryl)-N0-aryl di,
tri, tetra and pentamethylenediamines, not accessible by reduction of the
corresponding N-acyl-N0-aryl-ꢀ,!-alkanediamines.12 The procedure is
methodologically simple, involves easily available starting materials and
leads to high yields of the desired products. The method can in principle
be extrapolated to N-tri and tetrasubstituted derivatives.
EXPERIMENTAL
Melting points were determined with a Buchi capillary apparatus
1
and are uncorrected. H NMR spectra were recorded on a Bruker MSL
300 MHz spectrometer, using deuteriochloroform as the solvent. Chemical
shifts are reported in ppm (ꢁ) relative to TMS as an internal standard. D2O
was employed to confirm exchangeable protons (ex.). Splitting multiplicities

1,n-ALKANEDIAMINES
689
are reported as singlet (s), broad signal (bs), doublet (d), double doublet
(dd), triplet (t), double triplet (dt), quartet (q), pentet (p) and multiplet (m).
Mass spectra (EI) were recorded with a GC-MS Shimadzu QP-1000 spectro-
meter operating at 20 eV. TLC analyses were carried out an aluminium
sheets Silica Gel 60 F254 using chloroform-methanol (9:1), ethyl acetate-
methanol (20:1) or diethyl either-isopropylamine (10:1) as the solvent.
Flash column chromatographies were performed on Silica Gel 60
(0.040–0.063mm). Reagents, solvents and starting materials were purchased
from standard sources and purified according to literature procedures.
N-Alkyl (or aryl)-!-haloalkanamides 3 were synthesized by acylation
of the corresponding amines with !-haloalkanoyl chlorides following litera-
ture procedures.
Compound 2a was described in the literature.13
!-Aryl (or alkyl)aminoalkanamides 2b–h. General Procedure
A mixture of the corresponding !-haloamide 3 (5 mmol) and the ary-
lamine (10 mmol) was heated for 1 hour at 80ꢀC (for compound 2b) or 120ꢀC
(for compounds 2c–h). The reaction mixture was treated with boiling water
(20 ml), the mixture was allowed to cool and the aqueous layer was elimi-
nated. The crude products were purified by flash column chromatography.
2-(p-Chlorophenylamino)-N-phenylacetamide (2b)
The product had mp 118ꢀC (92%).
MS: m/z ¼ 260 (Mþ . ).
1H NMR: ꢁ ¼ 8.49 (1H, bs, ex., NHCO), 7.50 (2H, d, C6H5 2 ortho H),
7.31 (2H, t, C6H5 2 meta H), 7.17 (2H, d, p-ClC6H4 2 meta H), 7.11 (1H, t,
C6H5 para H), 6.59 (2H, d, p-ClC6H4 2 ortho H), 4.46 (1H, bs, ex., NHCH2),
3.86 (2H, s, CH2).
Anal. calcd. for C14H13ClN2O: C 64.50, H 5.03, N 10.74; found: C
64.35, H 5.15, N 10.82.
3-(p-Chlorophenylamino)-N-methylpropanamide (2c)
The product had mp 99ꢀC (67%).
MS: m/z ¼ 212 (Mþ . ).
1H NMR: ꢁ 7.12 (2H, dd, p-ClC6H4, 2 meta H), 6.55 (2H, dd, p-
ClC6H4, 2 ortho H), 5.67 (1H, bs, ex., NHCO), 4.39 (1H, bs, ex., NHAr),
3.42 (2H, t, ArNHCH2), 2.80 (3H, s, CH3), 2.45 (2H, t, CH2CO).

690
ORELLI ET AL.
Anal. calcd. for C10H13ClN2O: C 56.47, H 6.16, N 13.17; found: C
56.60, H 6.20, N 13.25.
Two other compounds were isolated from the crude product, which
were purified by column chromatography and identified as 3-(p-chloro-
phenylamino)-N-(p-chlorophenyl)propanamide 2i and N,N-bis-[2-(methyl-
aminocarbonyl)ethyl]-p-chloroaniline 4.
3-(p-Chlorophenylamino)-N-(p-chlorophenyl)propanamide (2i)
This compound was obtained as an oil.
MS: m/z ¼ 308 (Mþ . ).
1H NMR: ꢁ ¼ 7.65 (1H, bs, ex., NHCO), 7.40 (2H, dd, p-
ClC6H4NHCO, 2 meta H), 7.24 (2H, dd, p-ClC6H4NHCO, 2 ortho H), 7.12
(2H, dd, p-ClC6H4NHCH2, 2 meta H), 6.60 (2H, dd, p-ClC6H4NHCH2,
2 ortho H), 3.50 (2H, t, CH2CH2CO), 2.62 (2H, t, CH2CH2CO).
Anal. calcd. for C15H14Cl2N2O: C 58.27, H 4.56, N 9.06; found: C
58.48, H 4.48, N 9.20.
N,N-Bis[2-(methylaminocarbonyl)ethyl]-p-chloroaniline (4)
This compound was obtained as an oil.
MS: m/z ¼ 297 (Mþ . ).
1H NMR: ꢁ ¼ 7.16 (2H, dd, p-ClC6H4, 2 meta H), 6.70 (2H, dd, p-
ClC6H4, 2 ortho H), 5.93(2H, bs, ex., NHCO), 3.55 (4H, t, C H2CH2CO),
2.79 (6H, s, CH3), 2.40 (4H, t, CH2CO).
Anal. calcd. for C14H20ClN3O2: C 56.47, H 6.77, N 14.11; found: C
56.39, H 6.84, N 14.21.
3-(p-Chlorophenylamino)-N-phenylpropanamide (2d)
The product had mp 107ꢀC (63%).
MS: m/z ¼ 274 (Mþ . ).
1H NMR: ꢁ ¼ 7.54 (1H, bs, ex., NHCO), 7.46 (2H, d, C6H5 2 ortho H),
7.26–7.34 (3H, m, C6H5 2 meta and para H), 7.13(2H, dd, p-ClC6H4 2 meta
H), 6.58 (2H, dd, p-ClC6H4 2 ortho H), 4.20 (1H, bs, ex., NHAr), 3.51 (2H,
t, CH2CH2CO), 2.63(2H, t, CH CH2CO).
2
Anal. calcd. for C15H15ClN2O: C 65.57, H 5.50, N 10.20; found: C
65.72, H 5.59, N 10.09.

1,n-ALKANEDIAMINES
691
3-(p-Chlorophenylamino)-N-isopropylpropanamide (2e)
The product had mp 99ꢀC (60%).
MS: m/z ¼ 240 (Mþ . ).
1H NMR: Á ¼ 7.11 (2H, dd, p-ClC6H4 2 meta H), 6.53(2H, dd, p-
ClC6H4, 2 ortho H), 5.38 (1H, bs, ex., NHCO), 4.20 (1H, bs, ex., NHAr),
4.05 (1H, m, CH(CH3)2), 3.41 (2H, t, ArNHCH2), 2.40 (2H, t, CH2CO),
1.13(6H, d, CH(C H3)2).
Anal. calcd. for C12H17ClN2O: C 59.87, H 7.12, N 11.64; found: C
59.95, H 7.20, N 11.53.
4-(p-Methylphenylamino)-N-phenylbutanamide (2f)
The product had mp 73ꢀC (65%).
MS: m/z ¼ 268 (Mþ . ).
1H NMR: ꢁ ¼ 7.60 (1H, bs, ex., NHCO), 7.45 (2H, d, C6H5, 2 ortho
H), 7.10-7.35 (3H, m, C6H5 2 ortho and para H), 6.98 (2H, d, p-CH3C6H4 2
meta H), 6.60 (2H, d, p-CH3C6H4 2 meta H), 4.30 (1H, bs, ex., NHAr), 3.83
(2H, t, CH2NH), 2.60 (2H, t, CH2CO), 2.35 (3H, s, CH3), 2.15 (2H, m,
CH2CH2CH2).
Anal. calcd. for C17H20N2O: C 76.09, H 7.51, N 10.44; found: C 76.00,
H 7.60, N 10.34.
4-(p-Chlorophenylamino)-N-tert-butylbutanamide (2g)
This compound was obtained as an oil (68%).
MS: m/z ¼ 268 (Mþ . ).
1H NMR: ꢁ ¼ 7.03(2H, d, p-ClC6H4, 2 meta H), 7.00 (2H, d, p-
ClC6H4, 2 ortho H), 5.50 (1H, bs, ex., NHCO), 4.00 (1H, bs, ex., NHAr),
3.05 (2H, t, CH2NH), 2.15 (2H, t, CH2CO), 1.85 (2H, m, CH2CH2CH2), 1.30
(9H, s, CH3).
Anal. calcd. for C14H21ClN2O: C 62.56, H 7.87, N 10.42; found: C
62.75, H 7.95, N 10.37.
5-(Phenylamino)-N-(p-chlorophenyl)valeramide (2h)
This compound was obtained as an oil (60%).
MS: m/z ¼ 302 (Mþ . ).

692
ORELLI ET AL.
1H NMR: ꢁ ¼ 7.50 (1H, bs, ex. NHCO), 7.45 (2H, d, p-ClC6H4 2 ortho
H), 7.28 (2H, d, p-ClC6H4, 2 meta H), 7.18 (2H, t, C6H5 2 meta H), 6.71
(1H, t, C6H5 para H), 6.61 (2H, d, C6H5 2 ortho H) 3.16 (2H, t, CH2NHAr),
2.40 (2H, t, CH2CONH), 1.85 (2H, p, CH2CH2NHAr), 1.80-1.68 (2H, m,
CH2CH2CONH).
Anal. calcd. for C17H19ClN2O: C 67.43, H 6.32, N 9.25; found: C
67.55, H 6.40, N 9.13.
N-Alkyl (or aryl)-N0-aryl-1,n-alkanediamines. General Procedure
Compounds 2 (5 mmol) were treated with borane in dry tetrahydro-
furane (20 ml saturated solution) and heated under reflux in a nitrogen
atmosphere for 4 hours. The solvent was evaporated in vacuo and the resi-
due boiled with 20% hydrochloric acid (20 ml) for 2 hours. The acid solution
was diluted with water (5 ml) and made alkaline (pH ¼ 12) with sodium
hydroxide pellets. The mixture was extracted with chloroform (3 ꢁ 20 ml)
and the organic layer was washed with water and dried with anhydrous
sodium sulphate. The solution was concentrated in vacuo and the crude
products were purified by column chromatography on Silica Gel.
Compound 1a was described in the literature.14
N-(p-Chlorophenyl)-N0-phenylethylenediamine (1b)
This compound had mp 121ꢀC (87%).
MS: m/z ¼ 246 (Mþ . ).
1H NMR: ꢁ ¼ 7.35–7.59 (5H, m, C6H5), 7.10 (2H, dd, p-ClC6H4 2 meta
H), 6.71 (2H, dd, p-ClC6H4 2 ortho H), 5.00 (2H, bs, ex., NH), 3.52 (4H, s,
CH2CH2).
Anal. calcd. for C14H15ClN2: C 68.15, H 6.13, N 11.35; found: C
68.32, H 6.07, N 11.43.
N-(p-Chlorophenyl)-N0-methyl-1,3-propanediamine (1c)
This compound was obtained as an oil (81%).
MS: m/z ¼ 198 (Mþ . ).
1H NMR: ꢁ ¼ 7.10 (2H, dd, 2 meta H), 6.51 (2H, dd, 2 ortho H), 3.45
(1H, bs, ex., NHAr), 3.15 (2H, t, CH2NHAr), 2.71 (2H, t, CH2NHCH3),
2.42 (3H, s, N-CH3), 1.81 (2H, p, CH2CH2CH2), 1.29 (1H, bs, ex., NHCH3).

1,n-ALKANEDIAMINES
693
Anal. calcd. for C10H15ClN2: C 60.45, H 7.61, N 14.10; found: C
60.72, H 7.70, N 14.01.
N-(p-Chlorophenyl)-N0-methyl-1,3-propanediamine (1d)
This compound was obtained as an oil (85%).
MS: m/z ¼ 260 (Mþ . ).
1H NMR: ꢁ ¼ 7.19 (2H, dt, C6H5 2 meta H), 7.13(2H, dd, p-ClC6H4 2
meta H), 6.73(1H, dt, C H5 para H), 6.62 (2H, dd, C6H5 2 ortho H), 6.53
6
(2H, dd, p-ClC6H4 2 ortho H), 3.68–3.74 (2H, bs, ex., NHAr), 3.21–3.39
(4H, m, CH2CH2CH2), 1.93(2H, p, CH CH2CH2).
2
Anal. calcd. for C15H17ClN2: C 69.09, H 6.57, N 10.74; found: C
69.21, H 6.63, N 10.61.
N-(p-Chlorophenyl)-N0-isopropyl-1,3-propanediamine (1e)
This compound was obtained as an oil (81%).
MS: m/z ¼ 226 (Mþ . ).
1H NMR: ꢁ ¼ 7.10 (2H, dd, 2 meta H), 6.50 (2H, dd, 2 ortho H), 4.30
(1H, bs, ex., NHAr), 3.15 (2H, t, CH2NHAr), 2.78 (1H, m, CH(CH3)2), 2.73
(2H, t, CH2NHC3H7), 2.20 (1H, bs, ex., NHC3H7), 1.78 (2H, p,
CH2CH2CH2), 1.06 (6H, d, CH(CH3)2).
Anal. calcd. for C12H19ClN2: C 63.56, H 8.45, N 12.35; found: C
63.50, H 8.55, N 12.24.
N-Phenyl-N0-(p-tolyl)-1,4-butanediamine (1f)
This compound was obtained as an oil (76%).
MS: m/z ¼ 254 (Mþ . ).
1H NMR: ꢁ ¼ 7.10 (2H, t, C6H5, 2 meta H), 7.00 (2H, d, p-CH3C6H4 2
meta H), 6.60–6.40 (3H, t, C6H5, 2 ortho and para H), 6.50 (2H, d, p-
CH3C6H4 2 ortho H), 4.25 (2H, bs, ex., NH), 3.23 (4H, t, CH2N), 2.20
(3H, s, CH3), 1.98 (4H, m, CH2CH2CH2CH2).
Anal. calcd. for C17H22N2: C 80.27, H 8.72, N 11.01; found: C 80.20,
H 8.76, N 11.13.
N-tert-Butyl-N0-(p-chlorophenyl)-1,4-butanediamine (1g)
This compound was obtained as an oil (74%).
MS: m/z ¼ 254 (Mþ . ).

694
ORELLI ET AL.
1H NMR: ꢁ ¼ 7.05 (2H, dd, 2 meta H), 6.50 (2H, dd, 2 ortho H), 4.30
(2H, bs, ex., NHAr), 3.05 (2H, t, CH2NHAr), 2.15 (2H, t, CH2NHC4H9),
1.65–1.45 (4H, m, CH2CH2CH2CH2), 1.10 (9H, s, CH3).
Anal. calcd. for C14H23ClN2: C 65.99, H 9.10, N 10.99; found: C
66.13, H 9.17, N 10.87.
N-(p-Chlorophenyl)-N0-phenyl-1,5-pentanediamine (1h)
This compound was obtained as an oil (74%).
MS: m/z ¼ 288 (Mþ . ).
1H NMR: ꢁ ¼ 7.18 (2H, t, C6H5, 2 meta H), 7.11 (2H, d, p-ClC6H4 2
meta H), 6.71 (1H, t, C6H5 para H), 6.61 (2H, dd, C6H5 2 ortho H), 6.52 (2H,
d, p-ClC6H4 2 ortho H), 3.53 (2H, bs, ex., NH) 3.16-3.07 (4H, m, NHCH2),
1.70–1.62 (4H, m, CH2CH2NH), 1.56-1.48 (2H, m, CH2CH2CH2CH2CH2).
Anal. calcd. for C17H21ClN2: C 70.70, H 7.33, N 9.70; found: C 70.85,
H 7.40, N 9.58.
ACKNOWLEDGMENTS
This work was financially supported by the University of Buenos
Aires and by CONICET. We are grateful to Mr. Fernando Niemevz for
the preparation of some synthetic intermediates.
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Received in the U.S.A. June 12, 2000