A novel alkylation procedure using MW irradiation for the synthesis of 1,2,3-trisubstituted 1,4,5,6,7,8-hexahydro-1,3-diazocinium salts from their corresponding 1,2-diaryldiazocines

Article abstract of DOI:10.1016/j.tetlet.2012.01.009

In this work, we describe the synthesis of a series of 1,2,3- trisubstituted-1,4,5,6,7,8-hexahydro-1,3-diazocinium salts (1) by alkylation of the corresponding 1,2-diaryl-1,4,5,6,7,8-hexahydro-1,3-diazocines (2). Compounds 2 were obtained by ethyl polypho

Full text of DOI:10.1016/j.tetlet.2012.01.009

Tetrahedron Letters 53 (2012) 1367–1369
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel alkylation procedure using MW irradiation for the synthesis of
1,2,3-trisubstituted 1,4,5,6,7,8-hexahydro-1,3-diazocinium salts from their
corresponding 1,2-diaryldiazocines
⇑
María A. Ramírez, Gisela M. Ortiz, Alejandra Salerno, Isabel A. Perillo, María M. Blanco
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (1113) Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, we describe the synthesis of a series of 1,2,3-trisubstituted-1,4,5,6,7,8-hexahydro-1,3-diaz-
ocinium salts (1) by alkylation of the corresponding 1,2-diaryl-1,4,5,6,7,8-hexahydro-1,3-diazocines (2).
Compounds 2 were obtained by ethyl polyphosphate-promoted cyclocondensation of N-aroyl-N0-aryl-
pentamethylenediamines (3). Reaction of compounds 2 with alkyl iodides led to 1,2,3-trisubstituted
1,4,5,6,7,8-hexahydro-1,3-diazocinium iodides (1), a new family of cyclic amidinium salts. The best yields
for the alkylation were achieved using a mixture of DCM–DMSO (10:1) as solvent. The reaction times of
both, the cyclocondensation of compounds 3 and the reaction of 2 with alkyl halides, are dramatically
decreased when using microwave irradiation.
Received 5 December 2011
Revised 3 January 2012
Accepted 4 January 2012
Available online 15 January 2012
Keywords:
Cyclic amidinium salts
Cyclic amidines
Ethyl polyphosphate
N-alkylation
Ó 2012 Elsevier Ltd. All rights reserved.
Microwaves
N-Substituted derivatives of pentamethylenediamine (cadaver-
ine) are considered the analogs of natural polyamines.1 Some of
them are compounds of interest due to their biological properties.
N-(p-Tolyl) cadaverine is an active fibrin-stabilizing factor (FSF)
inhibitor2 and N,N0-dibenzyl and N,N0-di(2-chloroethyl) derivatives
show antitumor activity.3,4
Imidazolines8 and their six-9 and seven-membered homologs10
(I, n = 2–4) and the corresponding imidazolinium and tetrahydro-
pyrimidinium salts11 (II, n = 2,3) have been synthesized and used
as synthetic precursors to obtain N-substituted diamines by reduc-
tive cleavage of the heterocyclic ring. However, hexahydrodiazo-
cines (I, n = 5) have not been explored for this purpose. Some of
them have been obtained from the reaction of 1,5-diaminopentane
and an appropriate compound that provides the C-2 of the cycle13
or by cyclocondensation of adequate acyclic precursors.6,14 In con-
trast, to our knowledge, there are no reports of the corresponding
hexahydro-1,3-diazocinium salts (II, n = 5).
In line with our previous studies related to the synthesis of
diamine derivatives of biological interest, here we describe the syn-
thesis of a series of eight-membered cyclic amidinium salts, namely
1,2-diaryl-3-methyl-1,4,5,6,7,8-hexahydro-1,3-diazocinium salts
(1) and their 1,2-diaryl-1,4,5,6,7,8-hexahydro-1,3-diazocines (2)
precursors (Table 1) as potential sources of selectively N,N,N0-tri-
and N,N0-di-substituted pentamethylenediamines, respectively.
To this end, we used N-aroyl-N0-arylpentamethylenediamines 3
as precursors of hexahydrodiazocines 2 (Scheme 1). In our first
approach, we prepared compounds 3 by acylation of N-arylpen-
tamethylenediamines7 (Scheme 1). However, the reaction of
N-phenypentamethylenediamine with benzoyl chloride under
Schotten–Baumann conditions gave poor yields of the desired
compound 3, together with important amounts of unreacted
diamine and the corresponding N,N0-dibenzoyl derivative. The
One of the strategies used for the synthesis of selectively
N-substituted 1,n-diamines starts from acyclic compounds that
provide the polymethylene portion, generally the corresponding
1,n-diamine or some derivative. Thus, for example, N-alkyl or
benzylpentamethylenediamines are obtained by transforming the
amino primary group by means of reductive alkylation using a
carbonyl compound.1,5 On the other hand, the reaction of cadaverine
with reactive chloronitrobenzenes easily leads to the corresponding
N-nitroaryl derivatives.6 In contrast, the synthesis of cadaverines
with other types of N-substitution requires more complex synthetic
strategies. Among these, we have recently described two new routes
for the synthesis of
N-arylpentamethylenediamines.7
An alternative strategy to obtain selectively N-substituted 1,
n-diamines is to use dinitrogenated heterocyclic compounds such
as cyclic amidines8–10 (I), cyclic amidinium salts11 (II), and
aminals12 (III) as precursors (Fig. 1).
⇑
Corresponding author. Tel./fax: +54 11 4964 8250.
E-mail addresses: mercedesblanco2@yahoo.com.ar, mblanco@ffyb.uba.ar
(M.M. Blanco).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.009

1368
M. A. Ramírez et al. / Tetrahedron Letters 53 (2012) 1367–1369
O
(CH2)n
(CH2)n
(CH2)n
Ar1
+
N
N
N
N
N
N
Ar2
(
)
3
R3
R1
(
)
R1
R3
R1
N
H
NH2
a
Cl
N
H
3
X-
R2
R2
R2
b
I
II
III
O
2 (I,n=5)
1 (II,n=5)
Ar1
Ar2
(
)
3
N
H
N
H
Figure 1. Cyclic amidines (I), cyclic amidinium salts (II) and aminals (III).
3
c
Table 1
Compounds 1, 2 and 3 prepared
Compounds
Ar1
Ar2
R
d
I-
+
1a
1b
1c
1d
1e
1f
1g
1h
2a,3a
2b,3b
2c,3c
2d,3d
2e,3e
2f,3f
C6H5
C6H5
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-ClC6H4
C6H5
4-ClC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH2(4-BrC6H4)
CH2C6H5
N
N
N
N
Ar1
Ar1
R
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
3,4-Cl2C6H3
C6H5
3,4-Cl2C6H3
C6H5
C6H5
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
3,4-Cl2C6H3
Ar2
1
Ar2
2
Scheme 1. (a) Ar2COCl/TEA/DCM/ꢀ10 °C. (b) Ar1NH2/ 100 °C. (c) PPE/120 °C or PPE/
HCCl3/70 °C/700 W. (d) RI/DCM–DMSO (10:1)/reflux or RI/HCCl3/90 °C/400 W.
in chloroform solution without the addition of the DMSO. In this
way the reaction times were reduced to 6–15 min and the workup
was easier (85–96%). When we used alkyl chlorides or bromides as
alkylation agents, results were not as satisfactory as those pre-
sented above. We obtained hygroscopic salts that were hard to
purify. Reaction times were longer, both employing conventional
heating and MW irradiation, and yields were lower.
selective acylation of the primary amino group was achieved with
55–60% yields working in homogeneous phase with DCM as sol-
vent and TEA as acceptor of hydrogen chloride at ꢀ10 °C.
The second approach to obtain compounds 3 involved the use of
N-(5-chloropentyl) benzamides obtained from piperidine deriva-
tives by von Braun reaction.15
The reaction, with a two-fold amount of arylamines, led to the
expected compounds 3. The best yields (75–87%) were obtained
when heating at 100 °C in the absence of solvent.
Iodides 1 are stable salts. Infrared spectra confirmed their ionic
structure, as it can be seen from the strong amidinium band at ca.
1600–1620 cmꢀ1. However, they are oils thus evidencing charac-
teristics of ionic liquids.
Comparing 1HNMR spectra of compounds 1 and 2 we found cer-
tain facts. All methylene hydrogen signals of salts 1 are deshielded
with respect to the values of amidines 2. Methylenes adjacent to
The ring closure of compounds 3 was assayed using PPE (ethyl
polyphosphate) and PPSE (trimethylsilyl polyphosphate) under dif-
ferent conditions. Excellent yields (96–99%) were obtained work-
ing with conventional heating with PPE in free-solvent reactions
at 120° for 45–60 min. With the aim to optimize the reaction, we
used microwave irradiation (MW), a valuable technique which
has received increased attention in the last decades.16 In this work,
we used a Microwave Digestion System WX-4000. In chloroform
solution at 700 W (70 °C), we obtained yields similar to the previ-
ous ones in 6–7 min.
As expected because of the nature of cyclic amidines, com-
pounds 2 have nucleophilic character due to the N-3 lone pair.
Reactions with alkyl halides led to the corresponding 1,2,3-
trisubstituted hexahydro-1,3-diazocinium salts 1, highly stabilized
by resonance (Scheme 1). Since the reaction is a typical SN2 dis-
placement, it is adequate for the introduction of primary alkyl
groups. As alkylating reagents we employed methyl iodide, 4-chlo-
robenzyl iodide, and benzyl iodide. Since the solvent plays a major
role in alkylation reactions, varying both speed and nature of the
products,17 different solvents were tested. Using ethanol, acetoni-
trile, acetone, THF, and chloroform we obtained in general very
poor yields of compounds 1 recovering large amounts of the unre-
acted amidine. When the reaction was conducted in DCM solution,
in some cases, we obtained low yields of salt 1, the major product
being the corresponding hexahydrodiazocine hydrohalide. Im-
proved yields were obtained under strictly anhydrous conditions.
Finally, protonation of the amidine could be avoided by using a
mixture of DCM–DMSO (10:1) as solvent. Working at reflux with
conventional heating, 2–4 h was required for total conversion
(71–95%). Using MW irradiation, the reactions were carried out
the N-1 and N-3 were the most affected (Dd = 0.98 and 0.67 ppm,
respectively). The deshielding results from the electron deficiency
of the heterocyclic ring caused by nitrogen quaternization are in
full agreement with the cationic character of the amidinium
system.
In conclusion, we herein report the synthesis of 1,2-diaryl-
1,4,5,6,7,8-hexahydro-1,3-diazocines (2) and their corresponding
1,2,3-trisubstituted diazocinium salts 1, a new family of cyclic
amidinium compounds. The method used to obtain the diazocines
2 involves the PPE-promoted cyclocondensation of N-aroyl-N0-
arylpentamethylenediamines 3. Two alternative routes for the
preparation of compounds 3 are presented. Finally, reaction with
alkyl halides leads to salts 1. We also showed that the reaction
times of both, the cyclocondensation of compounds 3 and the reac-
tion of 2 with alkyl halides, are dramatically decreased when using
microwave irradiation. Compounds 2 and 1 are potential key inter-
mediates for the synthesis of selectively N,N0-di- and N,N,N0-
trisubstituted pentamethylenediamines.
Acknowledgments
This work was financially supported by the Universidad de Bue-
nos Aires and the Agencia Nacional de Promoción Científica y
Tecnológica.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.009.

M. A. Ramírez et al. / Tetrahedron Letters 53 (2012) 1367–1369
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