1,n-Diamines. Part 3: Microwave-assisted synthesis of N-acyl-N′- arylhexahydropyrimidines and hexahydro-1,3-diazepines

Article abstract of DOI:10.1016/j.tetlet.2011.07.131

In this Letter we present a method for the synthesis of N-acyl-N′-arylhexahydropyrimidines 1, by ring closure of N-acyl-N′-aryl-1,3-propanediamines 3 with formaldehyde. Cyclodehydrations were performed in aqueous medium under microwave irradiation, and le

Full text of DOI:10.1016/j.tetlet.2011.07.131

Tetrahedron Letters 52 (2011) 5238–5240
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Tetrahedron Letters
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1,n-Diamines. Part 3: Microwave-assisted synthesis
of N-acyl-N0-arylhexahydropyrimidines and hexahydro-1,3-diazepines
⇑
Juan Á. Bisceglia, Jimena E. Díaz, Romina A. Torres, 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
In this Letter we present a method for the synthesis of N-acyl-N0-arylhexahydropyrimidines 1, by ring clo-
sure of N-acyl-N0-aryl-1,3-propanediamines 3 with formaldehyde. Cyclodehydrations were performed in
aqueous medium under microwave irradiation, and led to high yields of the desired compounds in
remarkably short reaction times. The method also allowed for the synthesis of hitherto unreported N-
acyl-N0-arylhexahydro-1,3-diazepines 2. The acyclic tetramethylenic precursors 4 were synthesized by
selective functionalization of N-arylputrescines.
Article history:
Received 5 July 2011
Revised 23 July 2011
Accepted 27 July 2011
Available online 5 August 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Polyamine analogs
Cyclic aminals
N-Formylations
Cyclocondensation
Microwaves
Introduction
tively be synthesized by N-monoacylation of N-arylputrescines.12
Selectively N-substituted 1,4-diaminobutanes are of biochemical
Cyclic aminals are compounds of interest due to their pharma-
cological and chemical properties. The five membered heterocyclic
aminal (imidazolidine) core is found in many bioactive compounds
like antiinflammatory and analgesic agents,1 fungicides, antibacte-
rials, parasiticides, and antivirals.1,2 Six membered cyclic aminals
(hexahydropyrimidines) are also present in biologically active
compounds, acting as analgesics, parasiticides,3 antifungals, and
antibacterials.4 Besides, hexahydropyrimidines also behave as pro-
drugs of pharmacologically active di5 and polyamines.6 Such com-
pounds have recently been applied as pro-perfumes, in the
controlled release of volatile aldehydes and ketones.7 In synthetic
organic chemistry, cyclic aminals are useful as protecting groups
in the selective functionalization of di and polyamines and also
in organocatalytic reactions8 or as auxiliaries in asymmetric syn-
thesis.9 Due to their biological and chemical properties, imidazoli-
dines and hexahydropyrimidines have received a great deal of
attention. Their higher homologs (hexahydro-1,3-diazepines) have
been less studied, maybe due to the intrinsical difficulty of ring clo-
sure reactions leading to seven-membered cyclic aminals.10
The synthetic precursors of N-acyl-N0-arylimidazolidines or
hexahydropyrimidines, namely N-acyl-N0-aryldi (or tri)methylen-
and pharmacological interest as synthetic analogs of the natural
polyamine putrescine. Several derivatives of the parent diamine
have been studied as antibiotics, antineoplastics, antiparasitic
agents, and NMDA or cholinergic modulators.13 On the other hand,
some biologically active 1,3-propanediamine derivatives have also
been reported.14 In previous work, we developed a two-step syn-
thesis of N-arylputrescines, by aminolysis of 4-chlorobutyronitrile
followed by reduction.15 Further functionalization of such interme-
diates led to novel acyclic and heterocyclic N-arylputrescine deriv-
atives.12 In the context of our research on nitrogen
heterocycles,12,16 we were interested in tertiary amides derived
from six and seven membered cyclic aminals (hexahydropyrimi-
dines and hexahydro-1,3-diazepines, respectively). The classical
method for the preparation of aminals involves condensation of a
diamine with an aldehyde or ketone (Scheme 1), and requires the
use of different drying agents17 or the azeotropic distillation of
water,18 in order to shift the equilibrium toward the products.
In a recent report, the synthesis of N-acyl-N0-arylimidazolidines
was achieved in the presence of activated Montmorillonite K-10 in
THFunder microwaveirradiationin a domestic oven.2 An interesting
ediamines, are prepared by acylation of the corresponding N-(x-
bromoalkyl) amine followed by aminolysis.11 This strategy is not
suitable for tetramethylenediamine derivatives, which can alterna-
R3 R4
R3
R4
H
H
N
N
+
R1
N
N
R2
+ H2O
O
(
)
n
R1
R2
(
)
n
⇑
Corresponding author. Tel./fax: +54 11 4964 8250.
E-mail addresses: lorelli@ffyb.uba.ar, von_orelli@yahoo.com (L.R. Orelli).
Scheme 1. Condensation reaction leading to cyclic aminals.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.131

J. Á. Bisceglia et al. / Tetrahedron Letters 52 (2011) 5238–5240
5239
method for the synthesis of acyclic and heterocyclic aminals was
developed by Jurcik et al., which involves heating the reactants in
water for several (3–16) hours.19 The reported examples, however,
only include six and seven-membered heterocycles bearing N-alkyl
substituents. The lower nucleophilicity of the arylamino as well as
the amido groups of compounds 3 and 4 could, in principle, become
a limiting factor for the synthesis of the corresponding cyclic
aminals.
Although organic reactions on water are well known, they are
receiving increasing attention in the last years.20 On the other
hand, reactions performed under microwave irradiation proceed
in general faster, more cleanly, and with higher yields than with
conventional heating.21 The possibility of performing organic reac-
tions in water under microwave irradiation combines the benefits
of short reaction times, easy work-up procedures and the use of a
clean solvent with highly efficient energy transfer.22 These features
prompted us to investigate the microwave-assisted synthesis of
compounds 1 and 2 in water and without catalysts.
cyclic aminals were isolated in good to high yields as the only
product (Table 1). An exception was N-pivaloyl-N0-(4-chloro-
phenyl)- 1,3-propanediamine, which did not react even after long-
er reaction times (5 min at 110 °C). The method was successful
both for aminoamides with electron releasing or moderately elec-
tronegative substituents on the aryl moiety. Interestingly, deriva-
tives 1i,n bearing sterically hindering substituents in the aryl
moiety were also synthesized with high yields (Table 1). In all
cases, compounds 1 were obtained as inseparable mixtures of E/Z
diastereoisomers due to hindered rotation about the (O)C–N
bond.16g
Examination of the experimental results indicates that micro-
wave irradiation per se has the expected effects of reaction rate
acceleration. However, the aqueous medium is also important in
order to achieve optimum yields of the desired products in short
reaction times. This is quite surprising taking into account that
the reaction is reversible and proceeds with the liberation of a stoi-
chiometric amount of water (Scheme 1). The combined effect of
microwaves and aqueous reaction medium is more striking in
the case of the less reactive isobutyramide 1d.
Results and discussion
In view of these encouraging results, we attempted next the
synthesis of the homologous seven-membered cyclic aminals
(Scheme 4), which were not described in the literature. Such com-
pounds are of particular interest as synthetic analogs of the natural
polyamine putrescine. The acyclic precursors (N-acyl-N0-arylpu-
trescines 4) were synthesized by selective N-acylation of N-arylpu-
trescines with carboxylic acid anhydrides (Scheme 3).12
Selective formylation of N-(4-chlorophenyl)putrescine was
achieved employing 4-nitrophenyl formate in THF, and showed
complete selectivity toward the primary amino group (Scheme 3).
Cyclodehydration of aminoamide 4a with aqueous formalde-
hyde in methanol did not take place at room temperature (24 h)
The microwave assisted reaction in aqueous medium, in contrast,
was completed in 2 min at 110 °C (Scheme 4). In such conditions,24
We examined first the reaction between N-(4-chlorophenyl)-N0-
formyl-1,3-propanediamine (3a) and excess formaldehyde (38% in
water) at room temperature, using methanol as the solvent on the
basis of previous work.4,23 In such conditions, the reaction was
completed in 12 h (69%), while heating for 6 h at reflux tempera-
ture lead to lower yield (51%) of the expected product. Cyclization
led to 67% yield when performed in the same solvent, under micro-
wave irradiation in a single mode reactor (5 min at 70 °C). Bearing
in mind a recent report on the synthesis of aminals in aqueous
medium,19 the condensation was attempted by treatment of the
substrate with aqueous formaldehyde under microwave irradia-
tion (Scheme 2). In such conditions, total disappearance of the sub-
strate was achieved in only 1 min at 110 °C yielding 87% of
compound 1a (Table 1). Encouraged by these results, several sub-
strates with increasing steric hindrance in the amide moiety were
reacted in the same conditions.24 In all cases, the corresponding
H
(RCO)2O/aq. Na2CO3 (0ºC) or
N
NH
R
2
ArHN
ArHN
4-NO2C6H4OCHO/THF(-5ºC)
(R=H)
O
O
4
Ar
H
H CO/H O
2 2
N
N
R
ArHN
N
R
Scheme 3. Selective acylation of N-arylputrescines.
O
3a-n
1a-n
Scheme 2. Synthesis of N-acyl-N0-arylhexahydropyrimidines 1.
O
Ar
H
H2CO/H2O
N
N
R
N
R
Table 1
Synthesis of N-acyl-N0-arylhexahydropyrimidines 1a–n
ArHN
µW
O
Compound 1
Ar
R
Yielda,b (%)
Yielda,c (%)
4a-f
2a-f
a
b
c
d
e
f
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
C6H5
H
69d
64d
61d
16d
68d
64d
63d
49d
71d
ND
ND
ND
ND
ND
87
85
80
70
95
93
90
73
95
79
79
89
66
78
Scheme 4. Synthesis of N-acyl-N0-arylhexahydro-1,3-diazepines 2.
CH3
C2H5
iso-C3H7
C6H5
H
Table 2
Microwave-assisted synthesis of N-acyl-N0-arylhexahydro-1,3-diazepines 2a–f
g
h
i
j
k
l
C6H5
CH3
CH3
CH3
H
CH3
C2H5
iso-C3H7
CH3
4-CH3OC6H4
2-ClC6H4
4-FC6H4
4-CH3C6H4
C6H5
Compound 2a
Ar
R
Yieldb (%)
a
b
c
d
e
f
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
C6H5
H
79
84
50
71
77
70
CH3
C2H5
C6H5
CH3
C6H5
m
n
4-FC6H4
2,6-(CH3)2C6H3
4-CH3C6H4
a
B
c
Yields correspond to pure compounds.
rt, 12–24 h.
a
Compounds 2a–f were obtained as inseparable mixtures of E/Z
lW heating.
diastereoisomers.
d
b
Ref. 16g.
Yields correspond to pure compounds.

5240
J. Á. Bisceglia et al. / Tetrahedron Letters 52 (2011) 5238–5240
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as the only product in good yields (Table 2). The reaction is sensi-
tive to steric hindrance both in the aryl and carbonyl groups. In
fact, N-isobutyryl-N0-(4-chlorophenyl)putrescine and N-acyl-N0-
(2-methylphenyl)putrescine did not react even in forcing condi-
tions (5 min at 120 °C). Analogous results were obtained when
N-benzoyl-N0-(4-chlorophenyl)-1,5-pentanediamine12 was treated
with formaldehyde in the same conditions.
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In conclusion, we have developed an efficient synthesis of
N-acyl-N0-arylhexahydropyrimidines, by microwave-assisted cyc-
lodehydration of the corresponding aminoamides in aqueous med-
ium in the absence of catalysts. Hexahydropyrimidines bearing
substituents of variable stereoelectronic nature were obtained
with high yields in short reaction times. The procedure also
allowed for the synthesis of hitherto unreported N-acyl-N0-aryl-
hexahydro-1,3-diazepines, which are potentially bioactive com-
pounds as synthetic analogs of the natural polyamine putrescine.
To our knowledge, this is the first report on such compounds in
the literature.
Acknowledgments
This work was supported by the University of Buenos Aires and
by the CONICET. We are also grateful to María C. Mollo (MS) and to
Lic. Gastón Estruch (SANICO Argentina) for technical collaboration.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.131.
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24. General procedure for the synthesis of compounds 1 and 2: The corresponding
aminoamide (1 mmol) was treated with aqueous formaldehyde (3 mL). The
mixture was irradiated in a microwave reactor (Monowave 300, Anton Paar)
for 1 min (compounds 3a–n) or 2 min (compounds 4a–f) at 110 °C, in a closed
vessel with stirring. The reaction mixture was then treated with a mixture of
dichloromethane (20 mL) and saturated aqueous Na2CO3 (5 ml). The aqueous
phase was extracted with dichloromethane (4 ꢀ 20 mL). The organic phases
were pooled, washed with water, treated with anhydrous Na2SO4 and filtered.
The solvent was eliminated in vacuo. The crude products were purified by flash
column chromatography (Silica Gel, n-hexane/dichloromethane/ethyl acetate
15:85:0 to 0:95:5).
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