Microwave-enhanced synthesis of cyclic amidines

Article abstract of DOI:10.1016/j.tetlet.2006.05.042

We present a simple and efficient microwave based protocol for the synthesis of heterocyclic amidines by PPE promoted cyclodehydration of N-aryl-N′-acylalkylenediamines. The method is general for five- to eight-membered heterocycles and affords high yield

Full text of DOI:10.1016/j.tetlet.2006.05.042

Tetrahedron Letters 47 (2006) 4857–4859
Microwave-enhanced synthesis of cyclic amidines
a
*
´
M Beatriz Garcıa, Romina A. Torres and Liliana R. Orelli
Department of Organic Chemistry, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina
Received 30 March 2006; revised 3 May 2006; accepted 8 May 2006
Available online 30 May 2006
Abstract—We present a simple and efficient microwave based protocol for the synthesis of heterocyclic amidines by PPE promoted
cyclodehydration of N-aryl-N0-acylalkylenediamines. The method is general for five- to eight-membered heterocycles and affords
high yields of the desired products in remarkably short reaction times.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Cyclic amidines represent an heterocyclic core of wide
pharmacological interest. Among them, dihydroimid-
azoles1 and tetrahydropyrimidines2 are found in many
biologically active compounds. In addition, some
derivatives have been employed as chiral ligands or aux-
iliaries.3 In connection to this, we recently reported the
synthesis and stereochemical study of some atropiso-
meric tetrahydropyrimidine derivatives, potentially use-
ful in stereoselective synthesis.4 Due to their broad
spectrum of biological activity, dihydroimidazoles and
tetrahydropyrimidines have received a great deal of
attention in connection to their synthesis. In contrast,
only scattered references on seven and eight-membered
cyclic amidines (tetrahydrodiazepines and hexa-
hydrodiazocines, respectively) are available in the
literature.
has been employed in microwave assisted Biginelli reac-
tions,8 while PPSE was used for dihydroimidazole syn-
thesis by a combination of solid phase and microwave
techniques.9 Reactions performed under microwave
irradiation proceed in general faster, more cleanly and
with better yields than under conventional heating.10
Such characteristics, along with the possibility of
employing this reaction for high throughput preparation
of such compounds, prompted us to investigate the use
of microwave irradiation in the synthesis of cyclic ami-
dines by PPE promoted cyclodehydration of N-aryl-
N0-acylalkylenediamines. Among the synthesized deriv-
atives, tetrahydropyrimidines 1a,b,f were evaluated as
antihelminthic agents.
In this work we have used a domestic microwave oven
(Sanyo EM-D2013) adapted for reflux heating.11
A
Cyclocondensation is one of the most important meth-
ods for the synthesis of heterocycles. These reactions
usually require long reaction times, high temperatures
and catalyst with Lewis or strong BrØnsted acidity.5
In particular, ring closure of a,x-alkanediamine deriva-
tives leading to cyclic amidines usually requires strongly
acidic dehydrating reagents or high temperatures.6 Such
conditions may result in partial or total decomposition
of sensitive substrates. In previous work we employed
polyphosphoric acid esters PPE (ethyl polyphosphate)
and PPSE (trimethylsilylpolyphosphate) as mild dehy-
drating agents for the preparation of tetrahydropyrimi-
dines.7 The main limitation of this procedure is that long
reaction times are often required, resulting in lower
yields of the products in some cases. Recently, PPE
chloroform solution of PPE was employed as dehydrat-
ing agent.12 Reactions were thus conducted at chloro-
form reflux temperature under atmospheric pressure.
We first examined cyclodehydration of N-(4-chloro-
phenyl)-N0-benzoyl-1,3-propanediamine. Under inter-
mittent microwave irradiation,13 compound 1a was
obtained in less than 2 min with high yield (entry 1),
while conventional heating requires 2 h for the reaction
to be completed.14 Similar results were obtained when a
fivefold amount of substrate was employed (entry 2). At
a lower irradiation power (entry 3), only partial conver-
sion to the product was achieved after 1 h, while
employment of a higher potency (320 W) resulted in vio-
lent boiling of the reaction mixture even with inter-
mittent heating (Table 1).
*
Employing the optimum irradiation power, we synthe-
Corresponding author. Tel.: +54 1149 648250; fax: +54 1196
48250; e-mail: lorelli@ffyb.uba.ar
sized tetrahydropyrimidines 1b–f (entries 4–8). No
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.042

4858
Ma B. Garcı´a et al. / Tetrahedron Letters 47 (2006) 4857–4859
Table 1.
R
O
Ar
N
N
PPE
MW
Ar
N
N
R
n
H
H
n
1
Entry Compd 1 Ar
R
n
Microwave irradiation
Conventional heating
Reaction time (min) Pot. (W) Yield (%) Reaction time (h) Yield (%)
1
a
a
a
b
c
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H5
4-NO2C6H4
4-NO2C6H4
C6H5
C6H5
C6H5
C2H5
C2H5
1
1
1
1
1
1
1
1
0
0
0
2
2
2
3
3
1.30
1.30
60
240
240
160
240
240
240
240
240
240
240
240
240
240
320
320
320
98
97
46
92
97
97
91
79
97
93
97
93
89
84
83
79
2
2
2
5
5
5
5
5
5
96a
96a
96a
79
83
86
82
73
95
89
85
79
84
77
39
—
2b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1.30
1.30
2.00
2.00
1.30
1.30
2.00
2.00
2.30
2.30
6.50
6.00
6.00
d
e
C(CH3)3
2,4,6-TriCH3C6H2 C2H5
C6H5
f
C2H4C6H5
C6H5
C(CH3)3
C6H5
C2H5
C6H5
C(CH3)3
C6H5
gc
h
ic
j
2-NO2C6H4
2-NO2C6H4
1-C10H7
2-NO2C6H4
4-BrC6H4
1-C10H7
5
5
12
12
12
2d
—
k
l
m
n
C6H5
4-CH3C6H4
C6H5
a Ref. 14.
b 5 mmol of the precursor and 30 mL of PPE were employed.
c Ref. 6c.
d Ref. 6b.
difference regarding reaction times was observed for
derivatives with electron withdrawing groups in the N-
aryl moiety. Instead, higher reaction times were required
for compounds with steric hindrance either in the aryl or
the R substituents (entries 6 and 7). Analogous results
were obtained for dihydroimidazoles 1g–i (entries 9–
11). In all cases, reaction times were significantly short-
ened and yields improved if compared to conventional
heating. Tetrahydropyrimidines 1a,b,f were investigated
as antihelminthic agents, showing moderate activity.15
amidines, which does not require specialized equipment.
The method is general for five- to eight-membered het-
erocycles with different substitution patterns and affords
high yields of the desired products in remarkably short
reaction times. The reaction conditions are sufficiently
mild to be employed for the construction of the hetero-
cyclic amidine system in more complex molecules, and
suitable for high throughput synthesis of the
compounds.
In a typical experiment, a mixture of the corresponding
N-aryl-N0-acylalkylenediamine (1 mmol) and a chloro-
form solution of PPE (6 ml) was reacted in the micro-
wave oven at the indicated potencies, alternating 10 s
of irradiation and 10 s without irradiation.13 After
reaching room temperature, the resulting solution was
extracted with water (5 · 6 ml). The aqueous phases
were pooled, filtered and made alkaline in an ice bath
and the mixture extracted with chloroform (2 · 30 ml).
The organic layer was washed with water (5 ml), dried
over sodium sulfate and filtered. The solvent was
removed in vacuo. The crude products were purified by
flash chromatography. The structure of all compounds
To widen the scope of the method, we applied it to the
preparation of seven- and eight-membered cyclic ami-
dines, which usually require prolonged reaction times
or more drastic conditions under conventional heat-
ing.6b,16 Such compounds were specially interesting
because only very few papers report on the microwave-
assisted synthesis of seven-membered heterocyclic
rings,5 and none on their higher homologues. Tetra-
hydrodiazepines 1j–l were obtained employing the same
irradiation power but longer reaction times than the
lower homologues, and showed an analogous depen-
dence on steric hindrance (entries 12–14). Under the
conditions described in the literature for N-nitroaryl
derivatives (neat PPE, conventional heating at 120 ꢁC,
2 h),6b hexahydrodiazocine 1m was obtained in 39%
yield. Employing microwave heating, compounds 1m,n
were obtained in 6 min with satisfactory yields (entries
15 and 16). Interestingly, no intermolecular condensa-
tion products were obtained for compounds 1j–n.
1
was confirmed by H NMR and 13C NMR analyses.
Spectral data of new compounds are given as Supple-
mentary data.
Acknowledgements
This work was supported by the University of Buenos
Aires (B-105 Grant) and CONICET (postdoctoral
fellowship M.B.G.). We are grateful to N. P. Link and
In conclusion, we have developed a simple and efficient
microwave based protocol for the synthesis of cyclic

Ma B. Garcı´a et al. / Tetrahedron Letters 47 (2006) 4857–4859
4859
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