1,n-diamines. Part 2: Synthesis of acyclic and heterocyclic N-arylputrescine derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.02.042

In the present Letter we report the use of N-arylputrescines as synthetic intermediates for the preparation of N-acyl-N′-aryltetramethylenediamines 3 and related seven-membered heterocyclic amidines 4. Compounds 1 were synthesized by Cs₂CO

Full text of DOI:10.1016/j.tetlet.2011.02.042

Tetrahedron Letters 52 (2011) 1895–1897
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,n-Diamines. Part 2: Synthesis of acyclic and heterocyclic N-arylputrescine
derivatives
⇑
Jimena E. Díaz, Juan Á. Bisceglia, Ma. Cruz Mollo, Liliana R. Orelli
Departamento de Química Orgánica. Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires. CONICET. 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 the present Letter we report the use of N-arylputrescines as synthetic intermediates for the prepara-
tion of N-acyl-N0-aryltetramethylenediamines 3 and related seven-membered heterocyclic amidines 4.
Received 8 January 2011
Revised 3 February 2011
Accepted 8 February 2011
Available online 13 February 2011
Compounds
1 were synthesized by Cs2CO3/KI-mediated aminolysis of 4-chlorobutyronitrile and
subsequent reduction. N-Acylation of diamines 1 with carboxylic acid anhydrides led selectively to
N-acyl-N0-aryl tetramethylenediamines 3. Microwave-assisted ring closure of such precursors promoted
by PPE allowed for the synthesis of hitherto unreported 1-aryl-2-alkyl-1H-1,4,5,6-tetrahydro-1,3-diaze-
pines 4.
Keywords:
Polyamines
Cyclic amidines
N-Acylation
Ó 2011 Elsevier Ltd. All rights reserved.
Cyclodehydration
Microwaves
1. Introduction
dehydrating agents for the synthesis of N-aryl five- to eight-mem-
bered cyclic amidines.7
Cyclic amidines represent a heterocyclic core of wide pharma-
cological interest. Among them, dihydroimidazoles1 and tetrahy-
dropyrimidines2 are found in many biologically active
compounds. Due to their broad spectrum of biological activity,
such heterocycles have received a great deal of attention in con-
nection to their synthesis. In contrast, only scattered references
on seven-membered cyclic amidines (tetrahydrodiazepines) are
available in the literature. Tetrahydro-1,3-diazepines have been
studied owing to the biological properties of some members, acting
as diuretics, hypoglycemiants, anti-inflammatory, and antispasmo-
dics.3 More recently, some tetrahydro-1,3-diazepines have been
investigated as NMDA receptor antagonists4 and dopamine D4
receptor1b or muscarinic agonists.5 The described syntheses of 2-
alkyl-1H-4,5,6,7-1,3-diazepines involve the reaction of 1,4-butane-
diamine with carboxylic acids and their derivatives.3a–c,6 Due to the
considerably lower nucleophilicity of the arylamino group, appli-
cation of such procedures to N-aryl derivatives would involve dras-
tic reaction conditions, which may result in decomposition of
sensitive substrates. Polyphosphoric acid esters are mild irrevers-
ible dehydrating reagents of the Lewis acid type that activate oxy-
gen and nitrogen functionalities toward nucleophilic attack and, at
the same time, react chemically with water. Ethyl polyphosphate
(PPE) and trimethylsilylpolyphosphate (PPSE) have been used as
Reactions performed under microwave irradiation proceed in
general faster, more cleanly, and with higher yields than with con-
ventional heating.8 Cyclocondensation is one of the most impor-
tant methods for the synthesis of heterocycles, and microwave
heating has found interesting applications in this area.9 In previous
work, we investigated the use of microwave irradiation to enhance
the PPE-promoted synthesis of cyclic amidines.10
The synthetic precursors of N-aryldihydroimidazoles or tetrahy-
dropyrimidines, namelyN-acyl-N0-aryldi(ortri)methylenediamines,
are prepared by acylation of the corresponding N-(x-bro-
moalkyl)amine followed by aminolysis.7a,c This strategy is not
suitable for tetramethylenediamine derivatives, which can alterna-
tively be synthesized by von Braun reaction of N-acylpyrrolidines
with PCl5 followed by aminolysis.7c The overall yields of this
method are moderate, and the limiting step is the synthesis of the
precursorN-(4-chloroalkyl)amides.11 Anadditionalimportantdraw-
back is that the procedure is restricted to N-acyl derivatives without
a
-hydrogens. Thus, N-aryl-N0-acyltetramethylenediamines bearing
primary or secondary alkyl substituents in the acyl moiety are not
available throughthismethodology. In thiscontext, selective N-acyl-
ation of N-arylputrescines 1 seemed an interesting alternativefor the
preparation of compounds 3.
Selectively N-substituted 1,4-diaminobutanes are of biochemi-
cal and pharmacological interest as synthetic analogs of the natural
polyamine putrescine. Several derivatives have been described act-
ing as antibiotics, antineoplastics, antiparasitic agents, and NMDA
or cholinergic modulators.12 In the context of our research on
⇑
Corresponding author. Tel.: +54 11 4964 8250; fax: +54 11 4964 8250.
E-mail addresses: von_orelli@yahoo.com, lorelli@ffyb.uba.ar (L.R. Orelli).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.042

1896
J. E. Díaz et al. / Tetrahedron Letters 52 (2011) 1895–1897
nitrogen compounds,13 N-substituted putrescines represent suit-
able precursors of selectively N,N0-disubstituted tetramethylenedi-
amines and related heterocycles.
Table 1
Synthesis of N-arylputrescines 1 via Scheme 1
Compound 1
Ar
Yielda (% 2)
Yielda (% 1)
a
e
i
4-ClC6H4
4-CH3C6H4
4-BrC6H4
4-FC6H4
72
94
62
66
87
81
83
82
2. Results and discussion
j
In a previous publication we presented some preliminary re-
sults on the synthesis of diamines 1.14 An alternative multistep
synthesis was recently reported,15 although it leads to compara-
tively lower global yields of the diamines and it relies on
N-(4-chloroalkyl)amides as the precursors. In the present work,
N-arylputrescines 1 were thus syntesized by aminolysis of 4-chlo-
robutyronitrile with arylamines followed by reduction (Scheme 1).
The first step involves cesium carbonate-mediated alkylation of
anilines with 4-chlorobutyronitrile in the presence of potassium
iodide, and shows remarkable selectivity toward the N-monosub-
stituted products 2. The whole sequence afforded the desired dia-
mines in good to high yields (Table 1).
a
Yields correspond to pure compounds.
H
(RCO)2O/aq.Na2CO3
NH2
N
R
ArHN
ArHN
0ºC
O
1
3
Scheme 2.
Table 2
Synthesis of compounds 3 via Scheme 2
Aminoamides 3 were synthesized by selective monoacylation of
precursors 1 (Scheme 2).
Compound 3
Ar
R
Yielda (%)
Amine acylation in Schotten–Baumann conditions is usually re-
garded as a click chemistry reaction.16 Such procedure, however,
may lead to diacylation by-products for substrates containing
additional OH, SH, or NHR groups. Thus, specific acylating agents
or catalysts have been developed for aminoalcohols and
aminothiols.17
Acylation of compound 1a was examined under different exper-
imental conditions. Reaction with propionyl chloride led to the
corresponding N,N0-diacyl derivative as the main product, both at
rt or at ꢀ5 °C. In order to improve the selectivity toward the pri-
mary amino group, the less reactive propionic anhydride was em-
ployed as the acylating agent. At rt, the main product was the
expected N-(4-chlorophenyl)-N0-propionyl derivative 3a, accompa-
nied by some diacylation product. Selective N-monoacylation was
achieved working at 0 °C in a biphasic system (Cl3CH/aqueous
Na2CO3). Employing the optimized reaction conditions, we synthe-
sized compounds 3b–j in good to excellent yields and with com-
plete selectivity (Table 2).
a
b
c
d
e
f
g
h
i
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-FC6H4
C2H5
CH3
iso-C3H7
C6H5
CH3
C2H5
iso-C3H7
C6H5
iso-C3H7
iso-C3H7
91
quant
80
quant
quant
93
quant
quant
81
j
quant
a
Yields correspond to pure compounds.
R
Ar
H
N
N
PPE/Cl3CH
N
R
( )n
ArHN
µ
W
( )n
O
3
4
Scheme 3.
Cyclodehydration reactions leading to seven-membered cyclic
amidines usually require prolonged reaction times and/or drastic
conditions under conventional heating.7c Microwave irradiation
in a domestic oven under reflux drastically reduces the reaction
times.10 The use of such instruments, however, suffers from several
drawbacks regarding safety and reproducibility of the experimen-
tal results. In this work we have, therefore, used a Monowave 300
monomode reactor. Cyclodehydration of N-aryl-N0-acyl-1,4-butan-
ediamines 3a–c, e–g, i, j with a chloroformic solution of PPE
(Scheme 3) was carried out in a closed vessel. The reactions were
completed in 8 min at 100 °C. Isolated yields are shown in Table 3.
In order to extend the scope of the method, we synthesized by
the same procedure a pentamethylenic substrate, namely N-isobu-
tyryl-N0-(4-methylphenyl)-1,5-pentanediamine 3k. To our knowl-
edge, very few references on hexahydro-1,3-diazocines are
reported in the literature,10,18 and their synthesis under conven-
tional heating involves even more drastic conditions than for the
seven-membered homologs. In fact, treatment of compound 3k
with PPE under microwave irradiation (8 min at 100 °C) led to
low percentual conversion to 1-(4-methylphenyl)-2-isopropyl-
Table 3
Synthesis of compounds 4 via Scheme 3
Compound 4
n
Ar
R
Yielda (%)
a
b
c
e
f
g
i
j
1
1
1
1
1
1
1
1
2
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-FC6H4
C2H5
CH3
iso-C3H7
CH3
79
85
75
87
71
90
72
63
42
C2H5
iso-C3H7
iso-C3H7
iso-C3H7
iso-C3H7
k
4-CH3C6H4
a
Yields correspond to pure compounds.
1,4,5,6,7,8-hexahydro-1,3-diazocine 4k (Table 3). Longer reaction
times (20 min) or higher temperatures (125 °C) did not improve
the yield and resulted in partial decomposition of the reagent
and development of high pressure within the reaction vessel.
ArNH2
BH3
THF
NH2
Cl
CN
ArHN
CN
ArHN
Cs2CO3
2 KI
DMF
1
2
Scheme 1.

J. E. Díaz et al. / Tetrahedron Letters 52 (2011) 1895–1897
1897
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In conclusion, we have developed a synthetic route to tetrame-
thylenic N-aryl aminoamides 3 and amidines 4, structurally related
to the natural polyamine putrescine. Such compounds are poten-
tially bioactive, and some of them are useful synthetic precursors
of selectively N,N0-substituted 1,4-butanediamines.19 The pro-
posed method employs N-arylputrescines 1 as key synthetic inter-
mediates, and represents an advantageous alternative to
previously described procedures considering yields and number
of steps. Besides, it can be applied for the synthesis of derivatives
with primary and secondary alkyl substituents, not accessible
through the literature method.
Acknowledgments
This work was supported by the University of Buenos Aires and
by CONICET. We are also grateful to Mr. Lucas Monzón and Lic.
Gastón Estruch (SANICO Argentina) for technical collaboration.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.042.
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