New synthetic route for selectively substituted 1,n-diamines. Synthesis of N-aryl tetra- and pentamethylenediamines

Article abstract of DOI:10.1016/j.tetlet.2010.07.075

A general procedure for the synthesis of N-aryltetra- and pentamethylenediamines 1 by acid hydrolysis of N-aryl-N'-acylalkylenediamines 2 under microwave irradiation is described. The precursors 2 are obtained by amination of the corresponding N-(x-haloal

Full text of DOI:10.1016/j.tetlet.2010.07.075

Tetrahedron Letters 51 (2010) 5000–5002
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New synthetic route for selectively substituted 1,n-diamines. Synthesis
of N-aryl tetra- and pentamethylenediamines
María A. Ramirez a, María V. Corona a, Maria M. Blanco a, Isabel A. Perillo a, Williams Porcal b,
Alejandra Salerno a,
*
a Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Junin 956, 1113 Buenos Aires, Argentina
b Laboratorio de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay
a r t i c l e i n f o
a b s t r a c t
Article history:
A general procedure for the synthesis of N-aryltetra- and pentamethylenediamines 1 by acid hydrolysis of
N-aryl-N’-acylalkylenediamines 2 under microwave irradiation is described. The precursors 2 are
Received 24 June 2010
Revised 12 July 2010
Accepted 13 July 2010
Available online 17 July 2010
obtained by amination of the corresponding N-(
x
-haloalkyl)benzamides with aromatic amines 3.
Ó 2010 Elsevier Ltd. All rights reserved.
1,n-Diamines and their derivatives have been well studied for
presenting pharmacological activities common to natural poly-
amines1 as well as for their usefulness as synthetic intermediates.
Ethylene- and trimethylenediamines are interesting for their abil-
ity to complex metal ions,2 whereas N-substituted derivatives of
the higher homologs, putrescine, and cadaverine inhibit cell prolif-
eration.3,4 Therefore, the synthesis of selectively substituted 1,n-
diamines represents a field of interest.
and thus result in N,N0-diarylated compounds. Other multistep
syntheses have been developed starting from different precur-
sors.10–12
The above-mentioned methods have been generally applied
to the synthesis of N-aryl derivatives of ethylene- and trimethylen-
ediamine. Instead, methods for the synthesis of N-aryltetra- and
pentamethylenediamines have been scarcely studied. A general
approach for the preparation of these compounds implies the
The synthesis of symmetrically substituted N,N0-dialkyl-1,n-dia-
mines is relatively easy. The most common methods use the corre-
sponding 1,n-diamine as a precursor and imply the derivatization
of the primary amino groups by either direct alkylation with the
halogenated derivatives or transformation in amides or imines
and further reduction.4 These methods cannot adapt to the prepa-
ration of N,N’-asymmetrically substituted diamines since both the
amino groups in the substrate have the same reactivity. Therefore,
the preparation of these compounds presents synthetic difficulties
and limits the number and type of accessible derivatives, thus
requiring more complex synthetic strategies. Among others,
N-monosubstituted 1,n-diamines are adequate precursors for
asymmetric N,N’-disubstituted derivatives. Convenient synthetic
routes to N-alkyl- and benzyl-substituted linear diamines have
already been described;5 however, their N-aryl derivatives are
not yet readily available.
The classical method for obtaining N-aryl-1,n-diamines starting
from diamine is the aryl halide amination, which is limited to pre-
cursors with strong electron-withdrawing groups.6–8A variation of
this method that does not require reactive aryl halides as precur-
sors uses transition metals as catalysts, and has been particularly
applied for the synthesis of N-aryltrimethylenediamines.9
However, in other cases these reactions require high temperatures,
synthesis of x-arylaminoalkanonitriles and the generation of the
primary amino group by reduction of the corresponding cyano
group. In 1958, this method was used to obtain N-phenylpentame-
thylenediamine13 and, later, in 1972, Nilsson obtained N-p-tolyl-
pentamethylenediamine, an active fibrin-stabilizing factor (FSF)
inhibitor.14 More recently, N-phenyltetramethylenediamine was
obtained in a low yield (43%) by N-arylation of 1,4-diaminobutane
using a dicyclopentadienyl iron complex of chlorobenzene contain-
ing phenolphthalein bridges.15
Our group has previously developed the synthesis of N-aryleth-
ylene- and trimethylenediamines by amination of 2-bromoethyl-
and 3-bromopropylamine with aromatic amines.10 However, since
the necessary precursors for the preparation of the corresponding
tetra- and pentamethylenediamines are not easily available, we
designed an alternative synthetic route.
In this Letter, we describe a new method to obtain N-aryltetra-
and pentamethylenediamines 1 by the hydrolysis of the corre-
sponding N-aryl-N’-acylalkylenediamines 2 (Scheme 1) which
was optimized employing microwave irradiation, a valuable tech-
nique which accelerates chemical reactions and minimizes thermal
decomposition of the products.16
Compounds 2 were synthesized by the amination of N-(x-
haloalkyl)amides 3, which provide the tetra- and pentamethylen-
ediamine moiety. This method depends on the availability of
compounds 3, whose synthesis was optimized by von Braun degra-
dation of N-acylpyrrolidine and piperidine.17
* Corresponding author. Tel./fax: +54 (11) 49648250.
E-mail address: asalerno@ffyb.uba.ar (A. Salerno).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.075

M. A. Ramirez et al. / Tetrahedron Letters 51 (2010) 5000–5002
5001
Table 2
(CH2)n
Conversion of 2 ? 1 using 50% aq H2SO4
Compound Conventional heating Microwave irradiation (150 °C, 500 W)
N
PCl5
(
)
n
Cl
NHCOR2
R1NH2
2
1
Time (h) Yields (%) Time (min)
Yields (%)
C=O
R2
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
7
38
40
41
37
40
41
40
36
39
40
41
39
10
8
9
7
7
8
10
9
82
77
78
76
78
74
79
75
78
79
77
78
3
12.5
10
11
11
7.5
10
11
8.5
9.5
15
11
n= 2,3
H2SO4
MW
R1HN
NH2
R1HN
NHCOR2
(
)
n
(
)
n
1
2
9
j
k
l
j
a
a
10
15
9
Scheme 1.
Table 1
Compounds 1 and 2 prepared
and the reaction product 1e was isolated as was indicated in the
conventional procedure.19
Compounds
n
R1
R2
1
2
The general results indicate that irradiating the samples to a po-
tency (500 W, 150 °C), the reaction times are dramatically reduced,
from 7–12.5 h (conventional heating) to 7–15 min, the formation
of the by-products is minimized, and the yields increase.
N-Arylalkylenediamines 1a–j were obtained as oils and spectro-
scopically characterized by MS (EI), IR, 1H, and 13C NMR.
With the aim to determine the nature of the most appropriate
acyl residue for this synthetic sequence, other two compounds 2
were assayed. Thus, N-pivaloyl and N-2,4-dichlorobenzoyl deriva-
tives 2k,l (Table 1) were synthesized and subjected to acid hydro-
lysis. We observed that the times required for the hydrolysis and
the yields obtained did not present advantages over the benzoyl
derivative (Table 2).
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
2
2
2
2
2
3
3
3
3
3
2
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2,4-Cl2C6H3
ter-C4H9
4-CH3C6H4
4-ClC6H4
4-NO2C6H4
3,4-Cl2C6H3
C6H5
4-CH3C6H4
4-ClC6H4
4-NO2C6H4
3,4-Cl2C6H3
C6H5
j
a
a
j
k
l
C6H5
The main limitation of the method was observed in the case of
aryl groups having acid-labile substituents. Thus, the hydrolysis of
alkoxyphenyl derivatives 2 (R1 = 4-CH3OC6H4, 3,4,5-(CH3O)3C6H2;
R2 = C6H5; n = 2, 3) afforded a complex mixture of non-identified
products. On the other hand, the method can be used for com-
pounds with aryl groups containing substituents susceptible to
reduction, such as halogens and nitro. This represents an advan-
tage with respect to the method previously described in the liter-
ature,12,13 in which the primary amine is generated by the
reduction of the cyano group.
In conclusion, we report a novel synthetic approach for the syn-
thesis of N-aryltetra- and pentamethylenediamines 1 of biological
and biomedical interest by acid hydrolysis of N-aryl-N0-acylalky-
lenediamines 2. We have also shown that microwave irradiation
is essential for fast, clean, and high-yielding reactions.
The aminolysis of
R2 = C6H5) with aromatic amines led to the expected N-benzoyl-N0-
arylalkylenediamines 2a–j (Table 1), accompanied with N,N-bis(
benzamidoalkyl)arylamines in variable amounts. In order to mini-
mize the bis derivative formation, the reaction was assayed under
different conditions (in toluene, without a solvent and at different
temperatures), reaching the best results when heating at 100–
120 °C in the absence of the solvent (yields 75–87%).18
Hydrolysis reactions of compounds 2a–j were studied in acid
and alkaline media heating under reflux. Using 20% aq NaOH, the
reactions were not completed after 18 h of heating, and the ex-
pected N-arylalkylenediamines 1a–j were obtained in low yields
(20–35%) together with the starting material and tar by-products.
The acid hydrolysis was tested with different concentrations of
aq H2SO4. The best results were obtained using 50% aq H2SO4,
affording diamines 1a–j after 7–12.5 h of heating, although with
moderate yields (36–41%) (Table 2).19
x-chlorobutyl(pentyl)benzamides 3 (n = 2, 3;
x
-
Acknowledgments
With the aim to enhance the reaction yields and decrease the
reaction times, the acid hydrolysis was optimized using microwave
irradiation. The reactions were carried out in a Reactor Microwave
Digestion System WX-4000, EU chemical instruments.
This work was financially supported by the Universidad de Bue-
nos Aires and the Agencia Nacional de Promoción Científica y
Tecnológica.
The reactions required relatively high temperatures. At 110 °C
(300 W), no conversion to the hydrolysis products was observed,
whereas at 120–130 °C (400 W) the reactions required relatively
longer times (50–60 min) resulting in low yields due to product
decomposition. At 150 °C (500 W), the hydrolysis products were
obtained in high yields (74–82%) leading to complete hydrolysis
within 7–10 min (Table 2).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.075.
References and notes
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cavity. The reaction mixture was subjected to microwave irradia-
tion at a power 500 W (150 °C) for 7 min. After allowing the mix-
ture to cool to room temperature, the reaction vessel was opened
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18. General procedure for synthesis of compounds 2: A mixture of the appropriate N-
(x-chloroalkyl)benzamide 3 (0.02 mol) and the corresponding arylamine
(0.04 mol) was heated for 1 h under reflux in an oil bath at 120 °C. After
cooling, the crude material was treated with hot water (10 mL) in order to
extract the arylamine hydrochloride, and then heated for 5 minutes with 10%
HCl (10 mL) and filtered before cooling. The filtrate was alkalinized with 10%
NaOH to pH 14. The product was filtered, dried, and recrystallized from
cyclohexane.
19. General procedure for the under conventional heating synthesis of N-
aryltetra(penta)methylenediamines 1. A solution of the appropriated N-aryl-N0-
acylalkylenediamine (2) (1 mmol) in 50% P/V aqueous H2SO4 (15 mL) was
heated at reflux for 7–13 h and monitored by TLC. When the reaction was
completed, the solution was made alkaline with 50% aqueous NaOH in an ice
bath and extracted with methylene chloride (3 ꢀ 5 mL). The organic layers
were pooled, washed with water, dried, and evaporated in vacuo affording the
corresponding compounds
1 as oils which were purified by column
chromatography (chloroform/methanol 8:2 to 1:1).