Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores

Article abstract of DOI:10.1016/j.ejmech.2010.11.037

A variety of 2-(aminomethyl)aziridines was prepared and converted into the corresponding 1,2,3-triaminopropanes through a novel, microwave-assisted and regioselective ring opening by diethylamine in acetonitrile. Antiplasmodial assays revealed antimalaria

Full text of DOI:10.1016/j.ejmech.2010.11.037

European Journal of Medicinal Chemistry 46 (2011) 579e587
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 2-(aminomethyl)aziridines and their microwave-assisted ring
opening to 1,2,3-triaminopropanes as novel antimalarial pharmacophores
,
a
a
b
b
c
Matthias D’hooghe a , Sara Kenis , Karel Vervisch , Carmen Lategan , Peter J. Smith , Kelly Chibale ,
*
,
Norbert De Kimpe a
*
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Medical School, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South Africa
c Department of Chemistry and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 2-(aminomethyl)aziridines was prepared and converted into the corresponding 1,2,3-tri-
aminopropanes through a novel, microwave-assisted and regioselective ring opening by diethylamine in
acetonitrile. Antiplasmodial assays revealed antimalarial activity for 2-[(1,2,4-triazol-1-yl)methyl]azir-
idines and 2-(N,N-diethylaminomethyl)aziridines, as well as for the corresponding 1-(diethylamino)
propanes obtained through ring opening, pointing to the relevance of both the 2-(aminomethyl)aziridine
and the 1,2,3-triaminopropane unit as novel antimalarial pharmacophores.
Received 16 August 2010
Received in revised form
15 October 2010
Accepted 24 November 2010
Available online 1 December 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Aziridines
Aziridinium salts
Ring opening
Triaminopropanes
Antimalarial agents
1. Introduction
glycerol analogues [7e9]. Their aza-derivatives, i.e. 1,2,3-tri-
aminopropanes, however, have not been the subject of antimalarial
With 247 million clinical cases and nearly one million deaths in
2008, mostly among African children, malaria remains a major
issue in health control [1]. Quinoline-containing compounds, such
as the potent and inexpensive chloroquine (CQ) [2e4], have a long
tradition in the treatment of malaria, and systematic modification
has led to a variety of antimalarial drugs with diverse substitutions
around the quinoline ring [5,6]. However, the spread of chloro-
quine-resistant Plasmodium falciparum strains has dashed hopes of
global malaria eradication and has complicated the clinical
management of malaria in endemic areas. Consequently, many
efforts are devoted to the design and synthesis of novel and
structurally diverse compounds with potential antimalarial activity.
screening up to now.
In this paper, the preparation and biological evaluation of novel
2-(aminomethyl)aziridines
described as potential new lead compounds within the framework
of malaria management and treatment.
and
1,2,3-triaminopropanes
is
The aziridine moiety represents one of the most valuable three-
membered ring systems in organic chemistry [10e17], and the
regiocontrolled ring opening of C-substituted aziridines constitutes
a powerful approach toward the preparation of a large variety of
nitrogen-containing target compounds. In contrast to their activated
counterparts, non-activated aziridines have been evaluated to
a limited extent up to now, both from a synthetic and a pharmaco-
logical point of view. Due to the presence of an electron-donating
substituent at nitrogen, the latter aziridines have to be activated
toward aziridinium ion intermediates prior to ring opening [18e31].
Within the present work, the scarcely studied subclass of non-acti-
vated 1-alkyl-2-(aminomethyl)aziridines [32e39] was employed as
asourceofsubstratesforthedevelopmentofanovelentrytowardthe
biologically relevant 1,2,3-triaminopropane unit through a highly
regioselective and microwave-assisted ring opening by diethylamine
in acetonitrile.
Recently, the
b-amino alcohol moiety has been introduced as
a promising antimalarial pharmacophore, and the synthesis of
a number of novel aminopropanols with significant antimalarial
activity has revealed the medicinal importance of this class of
* Corresponding author.
E-mail addresses: matthias.dhooghe@UGent.be (M. D’hooghe), norbert.
dekimpe@UGent.be (N. De Kimpe).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.11.037

580
M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
Table 1
2. Results and discussion
Synthesis of 2-(aminomethyl)aziridines 2aek.
R1R2NH
Reaction
Product (yieldb)
2.1. Synthesis
Entry
Ar
conditionsa
1
2
3
4
5
6
7
8
Ph
Adenine
Adenine
Adenine
Thymine
Thymine
1,2,4-triazole
1,2,4-triazole
1,2,4-triazole
Et2NH
A
A
A
B
B
C
C
C
D
D
D
2a (31%)
2b (51%)
2c (32%)
2d (34%)
2e (26%)
2f (90%)
2g (63%)
2h (54%)
2i (90%)
2j (63%)
2k (64%)
Given the recently disclosed antimalarial properties of amino-
propanols [7e9], and taking structureeactivity relationship studies
with regard to chloroquine into account [40], the elaboration of
a 1,2,3-triaminopropane unit substituted with an aryl group, an
N,N-diethylamino moiety and an azaheteroaromatic nucleus was
envisaged as a potential novel antimalarial pharmacophore. From
a retrosynthetic point of view, 2-(aminomethyl)aziridines can be
regarded as suitable precursors for the preparation of 1,2,3-tri-
aminopropanes through ring opening by amines. Thus, the
synthesis of properly substituted aziridines, bearing an azaheter-
oaromatic group in their side chain, was proposed, which then
could serve as eligible substrates for the preparation of the desired
targets through aziridine ring opening by a nucleophilic amine.
At first, a variety of 2-(aminomethyl)aziridines 2 was prepared
via coupling of different nitrogen nucleophiles with 2-(bromo-
methyl)aziridines 1 [41e43], employing the electrophilicity of the
latter as a convenient handle for their connection to other moieties
[33]. In order to introduce structural diversity within the amino
side chain, aziridines 1 were connected to different classes of
aromatic azaheterocycles such as adenine [44], thymine and 1,2,4-
triazole en route to the corresponding 2-(aminomethyl)aziridines
2aeh (Scheme 1, Table 1). In addition, also diethylamine was used
for the preparation of 2-(N,N-diethylaminomethyl)aziridines 2iek
in order to evaluate the difference between the presence of an
aromatic azaheterocyclic moiety and a simple acyclic amino group
in 1,2,3-triaminopropanes with regard to their biological activity.
The synthesis of 2-[(6-aminopurin-9-yl)methyl]aziridines 2aec
was accomplished upon treatment of 2-(bromomethyl)aziridines 1
with 1 equiv of adenine in DMF at 80 ꢀC for 5 h in the presence of
5 equiv of K2CO3 (Table 1, entries 1e3). Next to the desired N9-
substituted adenines 2aec, isomeric N7-alkylation products were
observed as well in minor amounts (N9/N7 ∼3/1), which is in
accordance with literature data on the N-alkylation of adenine [45].
The premised adenine derivatives 2aec were isolated in pure form
through crystallization. In recent years, the synthesis of function-
alized adenines has gained much interest due to the pronounced
biological activities, such as antitumor and antiviral, associated to
this class of compounds [46e48]. Besides purines, also pyrimidines
are known to be of importance as lead compounds in medicinal
chemistry [48e50]. In that respect, thymine was used as a nucleo-
phile toward the preparation of 2-[(2,4-dioxo-5-methylpyrimidin-
1-yl)methyl]aziridines 2d,e upon treatment of 2-(bromomethyl)
aziridines 1 with one equiv of thymine and one equiv of NaH in
DMF at 80 ꢀC for 3 h (Table 1, entries 4e5). The former aziridines
2d,e were obtained in good crude yields, and were purified by
crystallization from CH2Cl2/Et2O (4/1) in order to obtain analytically
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
Ph
4-ClC6H4
4-MeOC6H4
Ph
9
10
11
4-ClC6H4
4-MeOC6H4
Et2NH
Et2NH
a
Reaction conditions: A ¼ 1 equiv adenine, 5 equiv K2CO3, DMF, 80 ꢀC, 5 h; B ¼ 1
equiv thymine, 1 equiv NaH, DMF, 80 ꢀC, 3 h; C ¼ 5 equiv 1,2,4-triazole, 4 equiv
K2CO3, CH3CN,
D
, 2.5 d; D ¼ 16 equiv Et2NH, MeOH,
D, 1 d.
b
Yield after purification by crystallization or column chromatography.
pure samples (the yields in Table 1 are yields obtained after
purification).
Next to DNA bases, the 1,2,4-triazole moiety was introduced as
an aziridine side chain through reaction of aziridines 1 with 5 equiv
of 1,2,4-triazole [51] in CH3CN under reflux for 2.5 d in the presence
of 4 equiv of K2CO3, affording the corresponding triazoles 2feh in
good yields (Table 1, entries 6e8) [33]. These long reaction times
appeared to be necessary in order to drive the reaction to
completion. Finally, a number of 2-(N,N-diethylaminomethyl)azir-
idines 2iek were prepared in good yields using an excess (16 equiv)
of diethylamine in methanol under reflux for one day (Table 1,
entries 9e11).
Subsequently, 2-(aminomethyl)aziridines 2aek were converted
into novel 1,2,3-triaminopropanes 3aek bearing a diethylamino
group through elaboration of the constrained aziridine moiety. The
interest in this type of compounds stems from the known anti-
malarial activity of aminopropanols on the one hand and the
relevance of a diethylamino unit in potent antimalarial agents (e.g.
chloroquine) on the other hand. With the intention to introduce
a diethylamino group, the ring opening of aziridines 2 by diethyl-
amine was envisaged. Given the necessary activation of non-acti-
vated aziridines prior to ring opening, the use of diethylamine
hydrochloride was contemplated. In this way, protonation of the
aziridine ring provides a highly electrophilic aziridinium interme-
diate which is prone to nucleophilic ring opening. In order to drive
the reaction to completion, and to avoid competition between
chloride- and diethylamine-induced ring opening, a large excess of
Et2NH$HCl (20 equiv) and an additional amount of diethylamine
(10 equiv) was used. Nonetheless, only partial conversion (<80%) of
aziridines 2 was achieved after heating under reflux for 7 days in
acetonitrile under the given reaction conditions. Fortunately, the
poor reactivity of 2-(aminomethyl)aziridines 2 with regard to the
R1R2NH
base
.
Ar
Ar
20 equiv Et2NH HCl
10 equiv Et2NH
Ar
R1
N
NH R1
N
N
N
Et2N
Br
R2
R2
CH3CN, 140 °C, 2 h
microwave (200 Wmax
Table 1
)
1
2a-k (26-90%)
3a-k (13-65%)
Ar
Ar
Ar
Ar
O
N
N
NH
NH
NH
NH
NH2
Et2N
N
Et2N
N
NH
Et2N
N
Et2N
NEt2
N
N
3a-c
3d-e
3f-h
3i-k
N
O
Scheme 1. Synthesis of 2-(aminomethyl)aziridines 2 and their microwave-assisted conversion into 1,2,3-triaminopropanes 3.

M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
581
Et2NH$HCl/Et2NH system under conventional heating was easily
overcome through the application of microwave irradiation. Heat-
ing of the latter aziridines 2 at 140 ꢀC (200 Wmax) in CH3CN resulted
in full and selective conversion to the desired triaminopropanes 3
after 2 h (Scheme 1), which were purified by crystallization or
column chromatography (Al2O3) in order to obtain analytically pure
samples (13e65% yield).
and screened for in vitro cytotoxicity against a mammalian cell-
line, Chinese Hamster Ovarian (CHO), in triplicate on one occasion.
The test samples were prepared to a 2 mg/mL stock solution in
10% DMSO and sonicated to enhance solubility. The samples were
tested as a suspension and stock solutions were stored at ꢁ20 ꢀC.
Further dilutions were prepared on the day of the experiment.
For aziridines 2aeh, bearing an aromatic azaheterocyclic side
chain, the ring opening of intermediate aziridinium ions 4aeh
proceeded with excellent regioselectivity through attack at the
unhindered aziridinium carbon atom (Scheme 2). In the case of
2-(N,N-diethylaminomethyl)aziridines 2iek, however, a mixture of
regioisomers (∼3/2 3iek/6iek) was obtained, with the major
isomers 3iek being formed through ring opening of the initially
formed aziridinium salts 4iek at the less hindered position
(Scheme 2, pathway a). Due to the presence of a nucleophilic
nitrogen atom in the diethylaminomethyl group, rearrangement of
aziridinium salts 4iek to the corresponding 1,1-diethylaziridinium
intermediates 5 occurred as well. Then, ring opening by diethyl-
amine at the unhindered aziridinium carbon atom took place,
giving rise to the formation of 1-(arylmethyl)amino-2,3-bis(dieth-
ylamino)propanes 6 (Scheme 2, pathway b). Only the major
isomers 3iek were isolated in pure form through column chro-
matography on aluminium oxide.
3.1.1. Antiplasmodial assay
Continuous in vitro cultures of asexual erythrocyte stages of P.
falciparum were maintained using a modified method of Trager and
Jensen [52]. Quantitative assessment of antiplasmodial activity in
vitro was determined via the parasite lactate dehydrogenase assay
using a modified method described by Makler [53]. Chloroquine
diphosphate (Sigma) (CQ) was used as the reference drug in all
experiments. A full dose-response was performed for all compounds
to determine the concentration inhibiting 50% of organism growth
(IC50-value).
3.1.2. Cytotoxicity assay
The MTT-assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylte-
trazolium bromide-assay] is used as a colorimetric assay for cellular
growth and survival, and compares well with other available assays
[54,55]. The tetrazolium salt MTT was used to measure all growth
and chemosensitivity. Emetine dihydrochloride (Sigma) was used
as the reference drug in all experiments.
The results of the biological evaluation are summarized in
Table 2 for 2-(aminomethyl)aziridines 2 and in Table 3 for 1,2,3-
triaminopropanes 3.
Although the aziridine moiety was initially not considered as
a template for biological screening, both 2-[(1,2,4-triazol-1-yl)
methyl]aziridine 2h and 2-(N,N-diethylaminomethyl)aziridines
2iek exhibited antiplasmodial activity against the CQS D10 strain of
The observed regioselectivity was confirmed through detailed
spectroscopic analysis of triaminopropanes 3. In addition, the
formation of symmetric compounds 3iek further corroborates the
regiochemical ring opening of aziridinium salts 4 by diethylamine
at the unsubstituted carbon atom.
3. Results and discussion
P. falciparum, with IC50-values between 15.3 and 4.2 mM (Table 2).
3.1. Biological evaluation
Moreover, aziridines 2h and 2iek also showed antimalarial activity
against the CQR Dd2 strain of P. falciparum (IC50-values between
48.3 and 18.0 mM), and low (2iek) or no (2h) cytotoxicity (Table 2).
With regard to the screening of 1,2,3-triaminopropanes 3, all
representatives showed weak to potent antiplasmodial activities
against the chloroquine sensitive (CQS) strain of P. falciparum, with
Both classes of compounds, i.e. 2-(aminomethyl)aziridines 2
and 1,2,3-triaminopropanes 3, were screened for in vitro anti-
plasmodial activity. All samples were tested in triplicate on one
occasion against a chloroquine sensitive (CQS) strain of P. falci-
parum (D10). Additionally, those samples showing promising
antimalarial activity were tested in triplicate on one occasion
against a chloroquine-resistant (CQR) strain of P. falciparum (Dd2)
IC50-values ranging from 214.1 to 2.0
mM (Table 3), with some
degree of cross resistance being displayed by 3h. In particular,
Ar
Ar
.
Ar
Cl
20 equiv Et2NH HCl
H
10 equiv Et2NH
R1
N
R1
N
NH R1
N
N
N
Et2N
R2
CH3CN, 140 °C, 2 h
microwave (200 Wmax
R2
Ar
R2
)
Et2NH
2a-h
4a-h
3a-h
R1R2NH = adenine, thymine, 1,2,4-triazole
Ar
Ar
Cl
H
a
NH
b
N
N
b
a
¨
NEt2
NEt2
Et2N
NEt2
a
¨
Et2NH
3i-k
2i-k
4i-k
Cl
Et
b
Ar
Ar
Et
NEt2
N
HN
NEt2
HN
¨
Et2NH
6i-k
5i-k
Scheme 2. Regioselectivity in the ring opening of 2-(aminomethyl)aziridines 2 using Et2NH$HCl/Et2NH.

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M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
Table 2
IC50-values of 2-(aminomethyl)aziridines 2 tested for in vitro antiplasmodial activity and cytotoxicity.
Compound
Ar
R1R2NH
D10: IC50
(m
M)
Dd2: IC50
(m
M)
CHO: IC50
(
mM)
RIa
SIb
NH2
N
N
2a
Ph
>350
ND
ND
ND
ND
N
H
N
NH2
N
N
2b
2c
4-ClC6H4
>300
ND
ND
ND
ND
ND
ND
ND
ND
N
H
N
NH2
N
N
4-MeOC6H4
266.76
N
H
N
O
HN
NH
2d
2e
4-ClC6H4
137.92
172.16
ND
ND
ND
ND
ND
ND
ND
ND
O
O
HN
NH
4-MeOC6H4
O
N
N
N
2f
Ph
80.74
ND
ND
ND
ND
5.6
ND
ND
ND
HN
HN
HN
N
N
N
2g
2h
4-ClC6H4
4-MeOC6H4
125.97
ND
ND
4.18 (n ¼ 2)
23.17
>400
2i
2j
2k
CQ
Ph
Et2NH
Et2NH
Et2NH
15.25
6.49
48.32
23.74
18.04
0.298
401.67
247.33
193.15
3.2
3.7
2.1
7.5
26.3
38.1
22.6
4-ClC6H4
4-MeOC6H4
8.54 (n ¼ 2)
0.040 (n ¼ 3)
emetine
0.145
ND ¼ not determined. n ¼ number of data sets averaged.
a
RI (Resistance Index) ¼ IC50 Dd2/IC50 D10.
b
SI (Selectivity Index) ¼ IC50 CHO/IC50 D10.
triazoles 3g,h and 1,3-bis(diethylamino)propanes 3j,k exhibited
IC50-values less than 10 mM, exhibited better antiplasmodial
superior antimalarial activities with IC50-values between 8.4 and
activities as compared to the previously reported class of amino-
propanols [8], pointing to the promising potential of aziridines 2
and aminopropanes 3 within the context of the development of
novel antimalarial agents. It is noteworthy that these compounds
were synthesized in racemic form, and it is conceivable that
enantiomerically pure variants could deliver superior activities.
With regard to structureeactivity relationships, substituted
2.0
mM. Furthermore, triazoles 3feh and 1,3-bis(diethylamino)
propanes 3iek were tested against the chloroquine-resistant (CQR)
strain of P. falciparum, again showing antiplasmodial activities.
Interestingly, the in vitro cytotoxicity results showed that only
compounds 3j and 3k have SI’s of 9 and 24, respectively (Table 3),
whereas all other compounds did not show cytotoxicity at the
concentrations tested.
propanes bearing
a 1,2,4-triazole group at the 1-position,
It should be stressed that a number of 2-(aminomethyl)aziri-
dines (e.g. 2h,j,k) and 1,2,3-triaminopropanes (e.g. 3g,h,j,k), with
a 4-chloro- or 4-methoxybenzylamino substituent at the 2-position
and an N,N-diethylamino moiety at the 3-position appear to be of

M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
583
Table 3
IC50-values of 1,2,3-triaminopropanes 3 tested for in vitro antiplasmodial activity and cytotoxicity.
Compound
Ar
R1R2NH
D10: IC50
(m
M)
Dd2: IC50
(m
M)
CHO: IC50
(m
M)
RIa
SIb
NH2
N
N
3a
Ph
214.11
ND
ND
ND
ND
ND
ND
N
H
N
NH2
N
N
3b
3c
4-ClC6H4
78.21
81.91
ND
ND
ND
ND
ND
ND
N
H
N
NH2
N
N
4-MeOC6H4
N
H
N
O
HN
NH
3d
3e
4-ClC6H4
71.68
ND
ND
ND
ND
ND
ND
ND
ND
O
O
HN
NH
4-MeOC6H4
127.80
O
N
N
N
3f
Ph
42.90
6.52
1.98
98.75
13.11
80.90
>300
>300
158.62
2.3
ND
ND
HN
HN
HN
N
N
N
3g
3h
4-ClC6H4
4-MeOC6H4
2.0
41.1
ND
ND
9.1
24.2
3i
3j
3k
Ph
Et2NH
Et2NH
Et2NH
23.67
8.41
6.66
30.16
19.82
13.53
>300
76.37
170.00
1.3
2.4
2.0
4-ClC6H4
4-MeOC6H4
CQ
Emetine
0.030 (n ¼ 6)
0.215 (n ¼ 4)
7.27
0.127 (n ¼ 2)
ND ¼ not determined. n ¼ number of data sets averaged.
a
RI (Resistance Index) ¼ IC50 Dd2/IC50 D10.
b
SI (Selectivity Index) ¼ IC50 CHO/IC50 D10.
particular interest in terms of their antimalarial activity. In addi-
tion, 1,3-bis(diethylamino)propanes bearing a 4-chloro- or 4-
methoxybenzylamino substituent at the 2-position are also of
importance in that respect.
propanes obtained through ring opening by diethylamine. Both the
2-(aminomethyl)aziridine and the 1,2,3-triaminopropane unit can
thus be considered as novel antimalarial pharmacophores.
In conclusion, a novel synthetic protocol was established for the
straightforward conversion of a variety of 2-(aminomethyl)azir-
idines into 1,2,3-triaminopropanes through microwave-assisted
regioselective ring opening by diethylamine using a combination of
Et2NH$HCl and Et2NH in acetonitrile. Furthermore, both 2-(amino-
methyl)aziridines and 1,2,3-triaminopropanes were shown to be of
biological relevance as potential antimalarial agents, in particular
2-[(1,2,4-triazol-1-yl)methyl]aziridines and 2-(N,N-diethylamino-
methyl)aziridines as well as the corresponding 1-(diethylamino)
4. Experimental section
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSEþ)
with CDCl3 as solvent and tetramethylsilane as internal standard.
13C NMR spectra were recorded at 75 MHz (JEOL ECLIPSEþ) with
CDCl3 as solvent and tetramethylsilane as internal standard.
Mass spectra were obtained with a mass spectrometer Agilent
1100, 70 eV. IR spectra were measured with a Spectrum One FT-IR
spectrophotometer. Elemental analyses were performed with

584
M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
a PerkinElmer series II CHNS/O analyzer 2400. Dichloromethane
was distilled over calcium hydride, while diethyl ether was dried
over sodium benzophenone ketyl. Other solvents were used as
received from the supplier. Melting points of crystalline compounds
were measured with a Büchi 540 apparatus. The purity of all new
compounds was assessed by means of NMR analysis (purity > 95%).
4.1.4. 2-(6-Aminopurin-9-yl)methyl-1-[(4-methoxyphenyl)methyl]
aziridine (2c)
Recrystallization from CH2Cl2/Et2O (4/1); yield 32%;
mp ¼ 181.1 ꢀC 1H NMR (300 MHz, CDCl3):
1.63 (1H, d, J ¼ 6.6 Hz),
d
1.87 (1H, d, J ¼ 3.3 Hz), 2.04e2.11 (1H, m), 2.93 and 3.60 (2H, 2 ꢂ d,
J ¼ 12.6 Hz), 3.72 (1H, d ꢂ d, J ¼ 14.3, 8.6 Hz), 3.78 (3H, s), 4.49 (1H,
d ꢂ d, J ¼ 14.3, 3.8 Hz), 5.52 (2H, br s), 6.65e6.70 (2H, m), 6.97e7.01
4.1. Microwave reactions
(2H, m), 7.65 and 8.34 (2H, 2 ꢂ s). 13C NMR (75 MHz, CDCl3):
d 33.1,
37.5, 46.9, 55.3, 63.8, 113.7, 119.4, 129.4, 130.4, 140.7, 149.7, 152.8,
155.6, 158.8. IR (ATR, cmꢁ1): nNH ¼ 3310 and 3121. MS (70 eV): m/z
(%): 311 (Mþ þ 1, 100). Anal. calcd. for C16H18N6O: C 61.92, H 5.85, N
27.08; found: C 61.45, H 5.97, N 26.91.
All microwave reactions were performed in a CEM Focused
MicrowaveTM Synthesis System, Model Discover, with a selectable
power output from 0 to 300 Watt. The reactions were performed in
10 mL thick walled Pyrex reaction vessels closed with a ‘snap-on’
septa cap and equipped with a small stirring bar. The temperature
4.1.5. Synthesis of 1-arylmethyl-2-[(2,4-dioxo-5-methylpyrimidin-
1-yl)methyl]aziridines (2dee)
control uses
a non-contact infrared sensor to measure the
temperature on the bottom of the vessel and is used in a feedback
loop with the on-board computer to regulate the temperature from
25 to 250 ꢀC by adjusting the power output (1 Watt increments).
The pressure control, IntelliVentTM Pressure Control System, uses an
indirect measurement of the pressure by sensing changes in the
external deflection of the septa on the top of the sealed pressure
vessel. Stirring is performed by a rotating magnetic plate located
below the floor of the microwave cavity. Cooling of the vessel (after
the reaction) is performed by a stream of clean air onto the vessel
which decreases the temperature of a 2 mL solution from 150 ꢀC to
40 ꢀC in less than 120 s. A ramp time of maximum 5 min is used
during which the temperature increases from room temperature to
the desired one. This temperature is maintained during the course
of the reaction for the indicated time.
General procedure: To a solution of 1-arylmethyl-2-(bromo-
methyl)aziridine 1 [41e43] (5 mmol) and thymine (5 mmol,
1 equiv) in dimethylformamide (25 mL) was added sodium hydride
(60% in mineral oil; 5 mmol, 1 equiv). After stirring for 3 h at 80 ꢀC,
the solvent was removed under reduced pressure. The residue was
poured into water (10 mL), extracted with chloroform (3 ꢂ 15 mL)
and washed with brine (3 ꢂ 15 mL). The combined organic layers
were dried over anhydrous magnesium sulfate. Filtration of the
drying agent and removal of the solvent in vacuo afforded the crude
products 2dee, which were purified by recrystallization from
dichloromethane/ether (4/1).
4.1.6. 1-(4-Chlorophenyl)methyl-2-[(2,4-dioxo-5-methylpyrimidin-
1-yl)methyl]aziridine (2d)
Recrystallization from CH2Cl2/Et2O (4/1); yield 34%; mp ¼ 149.4 ꢀC
4.1.1. Synthesis of 2-(6-aminopurin-9-yl)methyl-1-(arylmethyl)
aziridines (2aec)
1H NMR (300 MHz, CDCl3):
d
1.64 (1H, d, J ¼ 6.1 Hz), 1.74 (3H, d,
J ¼ 1.1 Hz), 1.86 (1H, d, J ¼ 3.9 Hz), 2.00e2.07 (1H, m), 2.79 (1H, d,
J ¼ 12.1 Hz), 2.86 (1H, d ꢂ d, J ¼ 14.2, 8.8 Hz), 3.87 (1H, d, J ¼ 12.1 Hz),
4.35 (1H, d ꢂ d, J ¼ 14.2, 3.1 Hz), 6.81 (1H, d, J ¼ 1.1 Hz), 7.16e7.21 and
General procedure: To a solution of 1-arylmethyl-2-(bromo-
methyl)aziridine 1 [41e43] (5 mmol) and adenine (5 mmol,
1 equiv) in dimethylformamide (50 mL) was added potassium
carbonate (25 mmol, 5 equiv). After stirring for 5 h at 80 ꢀC, the
solvent was removed under reduced pressure. The residue was
poured into water (25 mL), extracted with CHCl3 (3 ꢂ 25 mL) and
washed with brine (3 ꢂ 25 mL). The combined organic layers were
dried over anhydrous magnesium sulfate. Filtration of the drying
agent and removal of the solvent in vacuo afforded the crude
products 2aec, which were purified by recrystallization.
7.23e7.27 (4H, 2 ꢂ m), 9.42 (1H, br s).13C NMR(75 MHz, CDCl3):
d 12.2,
32.4, 37.5, 51.1, 63.5,110.0,128.6,130.0,133.5,136.9,140.7,151.0,164.2.
IR (ATR, cmꢁ1): nCO ¼ 1698 and 1660, nNH ¼ 3192. MS (70 eV): m/z (%):
306/8 (Mþ þ 1, 100). Anal. calcd for C15H16ClN3O2: C 58.92, H 5.27, N
13.74; found: C 59.31, H 5.46, N 13.46.
4.1.7. 2-(2,4-Dioxo-5-methylpyrimidin-1-yl)methyl-1-[(4-methoxy-
phenyl)methyl]aziridine (2e)
Recrystallization from CH2Cl2/Et2O (4/1); yield 26%; mp ¼ 167.7 ꢀC
4.1.2. 2-(6-Aminopurin-9-yl)methyl-1-(phenylmethyl)aziridine (2a)
Recrystallization from CH2Cl2/Et2O (4/1); yield 31%; mp ¼
1H NMR (300 MHz, CDCl3):
d
1.64 (1H, d, J ¼ 6.6 Hz), 1.67 (3H, s), 1.84
(1H, d, J ¼ 3.3 Hz),1.99e2.05(1H, m), 2.60(1H, d, J ¼ 12.1 Hz), 2.71 (1H,
d ꢂ d, J ¼ 14.3, 9.4 Hz), 3.79 (3H, s), 3.90 (1H, d, J ¼ 12.1 Hz), 4.41 (1H,
d ꢂ d, J ¼ 14.3, 2.7 Hz), 6.73 (1H, s), 6.77e6.79 (2H, m), 7.11e7.14 (2H,
145.2 ꢀC 1H NMR (300 MHz, CDCl3):
d
1.64 (1H, d, J ¼ 6.6 Hz), 1.89
(1H, d, J ¼ 3.3 Hz), 2.07e2.13 (1H, m), 3.06 and 3.63 (2H, 2 ꢂ d,
J ¼ 12.6 Hz), 3.77 (1H, d ꢂ d, J ¼ 14.3, 8.3 Hz), 4.50 (1H, d ꢂ d, J ¼ 14.3,
3.9 Hz), 5.87 (2H, br s), 7.09e7.21 (4H, m), 7.64 and 8.34 (2H, 2 ꢂ s).
m), 8.92 (1H, br s). 13C NMR (75 MHz, CDCl3):
d 12.2, 32.4, 37.8, 51.3,
55.2, 63.8, 109.7, 113.8, 129.9, 130.5, 140.7, 150.9, 159.0, 164.3. IR (ATR,
cmꢁ1): nCO ¼ 1696 and 1660, nNH ¼ 3189. MS (70 eV): m/z (%): 302
(Mþ þ 1, 100). Anal. calcd for C16H19N3O3: C 63.77, H 6.36, N 13.94;
found: C 63.46, H 5.99, N 13.46.
13C NMR (75 MHz, CDCl3):
d 33.2, 37.7, 46.8, 64.4, 119.5, 127.4, 128.2,
128.4, 138.2, 140.7, 149.8, 152.9, 155.6. IR (ATR, cmꢁ1): nNH ¼ 3289
and 3103. MS (70 eV): m/z (%) 281 (Mþ þ 1, 100). Anal. calcd. for
C15H16N6: C 64.27, H 5.75, N 29.90; found: C 64.06, H 5.74, N 29.73.
4.1.8. Synthesis of 1-arylmethyl-2-[(1,2,4-triazol-1-yl)methyl]
aziridines (2feh) [33]
General procedure: To a solution of 1-arylmethyl-2-(bromo-
methyl)aziridine 1 [41e43] (7.78 mmol) and 1,2,4-triazole
(38.9 mmol, 5 equiv) in acetonitril (100 mL) was added potassium
carbonate (31.12 mmol, 4 equiv), after which the resulting
suspension was heated under reflux for 2 days. Afterwards, the
solvent was removed under reduced pressure. The residue was
poured into 75 mL of a 1 M sodium hydroxide solution and
extracted with diethyl ether (3 ꢂ 30 mL). The combined organic
layers were dried over anhydrous potassium carbonate. Filtration
of the drying agent and removal of the solvent in vacuo afforded the
4.1.3. 2-(6-Aminopurin-9-yl)methyl-1-[(4-chlorophenyl)methyl]
aziridine (2b)
Recrystallization from CH2Cl2; yield 51%; mp ¼ 167.6 ꢀC 1H NMR
(300 MHz, CDCl3):
d
1.64 (1H, d, J ¼ 6.1 Hz), 1.91 (1H, d, J ¼ 3.3 Hz),
2.06e2.14 (1H, m), 2.91 and 3.62 (2H, 2 ꢂ d, J ¼ 12.9 Hz), 3.72 (1H,
d ꢂ d, J ¼ 14.3, 8.3 Hz), 4.50 (1H, d ꢂ d, J ¼ 14.3, 3.9 Hz), 5.72 (2H, br
s), 6.97e7.00 and 7.08e7.11 (4H, 2 ꢂ m), 7.64 and 8.34 (2H, 2 ꢂ s).
13C NMR (75 MHz, CDCl3):
d 33.4, 37.7, 46.7, 63.6, 119.4, 128.4, 129.4,
133.1, 136.6, 140.5, 149.6, 152.8, 155.5. IR (ATR, cmꢁ1): nNH ¼ 3311
and 3119. MS (70 eV): m/z (%): 315/7 (Mþ þ 1, 100). Anal. calcd. for
C15H15ClN6: C 57.24, H 4.80, N 26.70; found: C 57.04, H 4.97, N 26.85.

M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
585
crude products 2feh, which were purified by column chromatog-
raphy on silica gel (CHCl3/MeOH 97/3).
2aec (0.89 mmol), diethylamine (17.8 mmol) and diethylamine
hydrochloride (8.9 mmol) were dissolved in acetonitrile (6 mL).
The mixture was heated to 140 ꢀC for 2 h under microwave irra-
diation (200 Wmax). Afterwards, the reaction mixture was
neutralized by means of a saturated sodium bicarbonate solution,
poured into water (15 mL), extracted with diethyl ether (3 ꢂ10 mL)
and washed with brine (3 ꢂ 10 mL). The combined organic layers
were dried over anhydrous potassium carbonate. Filtration of the
drying agent and removal of the solvent in vacuo afforded the crude
products 3aec, which were purified by recrystallization from
CH2Cl2/Et2O (4/1).
4.1.9. 1-(4-Methoxyphenyl)methyl-2-[(1,2,4-triazol-1-yl)methyl]
aziridine (2h)
Rf ¼ 0.17 (CHCl3/MeOH 97/3); yield 54%. 1H NMR (300 MHz,
CDCl3):
d
1.60 (1H, d, J ¼ 6.6 Hz),1.81 (1H, d, J ¼ 3.3 Hz),1.99e2.06 (1H,
m), 3.19 and 3.44 (2H, 2 ꢂ d, J ¼ 12.6 Hz), 3.78 (3H, s), 3.91 (1H, d ꢂ d,
J ¼ 14.2, 7.7 Hz), 4.30 (1H, d ꢂ d, J ¼ 14.2, 4.2 Hz), 6.79e6.83 (2H, m),
7.09e7.13 (2H, m), 7.86 and 7.96 (2H, 2 ꢂ s).13C NMR (75 MHz, CDCl3):
d
32.6, 37.5, 52.6, 55.2, 63.5, 113.9, 129.3, 130.4, 143.1, 151.6, 158.9. IR
(ATR, cmꢁ1): nmax ¼ 2836, 1612, 1511, 1273, 1244, 1176, 1139, 1031, 817,
751, 733, 679. MS (70 eV): m/z (%): 245 (Mþ þ 1, 100). Anal. calcd for
C13H16N4O: C 63.91, H 6.60, N 22.93; found: C 63.78, H 6.67, N 22.78.
4.1.15. 1-(6-Aminopurin-9-yl)-3-diethylamino-2-(phenylmethyl)
aminopropane (3a)
Recrystallization from CH2Cl2/Et2O (4/1); yield 34%;
mp ¼ 114.7 ꢀC 1H NMR (300 MHz, CDCl3): 0.90 (3H, t, J ¼ 7.2 Hz),
1.86 (1H, br s), 2.18e2.51 (6H, m), 3.04e3.09 (1H, m), 3.71 and 3.79
(2H, 2 ꢂ d, J ¼ 13.2 Hz), 4.19 (1H, d ꢂ d, J ¼ 13.9, 5.0 Hz), 4.24 (1H,
d ꢂ d, J ¼ 13.9, 4.7 Hz), 5.59 (2H, br s), 7.23e7.33 (5H, m), 7.96 and
4.1.10. Synthesis of 1-arylmethyl-2-(diethylaminomethyl)aziridines
(2iek)
General procedure: A solution of 1-arylmethyl-2-(bromomethyl)
aziridine 1 [41e43] (6.67 mmol) and diethylamine (106.72 mmol,
16 equiv) in methanol (100 mL) was heated under reflux for 3 days.
Afterwards, the reaction mixture was neutralized by means of
a saturated sodium bicarbonate solution. The resulting suspension
was poured into water (70 mL) and extracted with CH2Cl2
(3 ꢂ50 mL). The combined organic layers weredried overanhydrous
potassium carbonate. Filtration of the drying agent and removal of
the solvent under reduced pressure afforded the crude products
2iek, which were purified by column chromatography on silica gel.
8.37 (2H, 2 ꢂ s). 13C NMR (75 MHz, CDCl3):
d 11.7, 45.7, 46.9, 52.1,
54.7, 55.4, 119.6, 127.0, 128.1, 128.4, 140.2, 142.0, 150.3, 152.9, 155.3.
IR (ATR, cmꢁ1): nNH ¼ 3286, 3228, 3130. MS (70 eV): m/z (%): 354
(Mþ þ 1, 100). Anal. calcd. for C19H27N7: C 64.56, H 7.70, N 27.74;
found: C 64.83, H 7.85, N 27.49.
4.1.16. 1-(6-Aminopurin-9-yl)-2-[(4-chlorophenyl)methyl]amino-
3-diethylaminopropane (3b)
Recrystallization from CH2Cl2/Et2O (4/1); yield 18%; mp ¼ 135.5 ꢀC
1H NMR (300 MHz, CDCl3): 0.92 (6H, t, J ¼ 7.2 Hz), 1.80 (1H, br s),
2.21e2.52 (6H, m), 3.01e3.09 (1H, m), 3.68 and 3.75 (2H, 2 ꢂ d,
J ¼ 13.5 Hz), 4.17 (1H, d ꢂ d, J ¼ 14.1, 5.3 Hz), 4.23 (1H, d ꢂ d, J ¼ 14.1,
4.7 Hz), 5.61 (2H, br s), 7.15e7.18 and 7.23e7.25 (4H, 2 ꢂ m), 7.93 and
4.1.11. 2-(N,N-Diethylamino)methyl-1-(phenylmethyl)aziridine (2i)
Rf ¼ 0.14 (CHCl3/MeOH 95/5); yield 90%. 1H NMR (300 MHz,
CDCl3):
d
0.97 (6H, t, J ¼ 7.2 Hz), 1.40 (1H, d, J ¼ 6.6 Hz), 1.60 (1H, d,
J ¼ 3.3 Hz),1.63e1.70 (1H, m), 2.38e2.62 (6H, m), 3.34 and 3.46 (2H,
2 ꢂ d, J ¼ 13.2 Hz), 7.20e7.39 (5H, m). 13C NMR (75 MHz, CDCl3):
8.37 (2H, 2 ꢂ s). 13C NMR (75 MHz, CDCl3):
d 11.7, 45.9, 47.0, 51.4, 54.6,
d
11.6, 32.7, 38.0, 47.0, 56.2, 64.7, 127.1, 128.4, 139.1. IR (ATR, cmꢁ1):
55.4,119.4,128.5,129.4,132.7,138.6,141.8,150.6,152.9,155.4. IR (ATR,
cmꢁ1): nNH ¼ 3284 and 3132. MS (70 eV): m/z (%): 388/90 (Mþ þ 1,
100). Anal. calcd. for C19H26ClN7: C 58.83, H 6.67, N 25.28; found: C
58.72, H 7.14, N 24.96.
nmax ¼ 2968, 2799, 2360, 2341, 1454, 1348, 1202, 1069, 1028, 757,
731, 697. MS (70 eV): m/z (%): 219 (Mþ þ 1, 100). Anal. calcd. for
C14H22N2: C 77.01, H 10.16, N 12.83; found: C 76.79, H 10.03, N 12.77.
4.1.12. 1-(4-Chlorophenyl)methyl-2-[(N,N-diethylamino)methyl]
aziridine (2j)
4.1.17. 1-(6-Aminopurin-9-yl)-3-diethylamino-2-[(4-methoxy-
phenyl)methyl]aminopropane (3c)
Rf ¼ 0.22 (CHCl3/MeOH 95/5); yield 63%. 1H NMR (300 MHz,
Recrystallization from CH2Cl2/Et2O (4/1); yield 13%; mp ¼ 106.8 ꢀC
1H NMR (300 MHz, CDCl3): 0.91 (3H, t, J ¼ 7.2 Hz), 2.20e2.52 (6H, m),
3.03e3.11 (1H, m), 3.65 and 3.73 (2H, 2 ꢂ d, J ¼ 13.2 Hz), 3.79 (3H, s);
4.19 (1H, d ꢂ d, J ¼ 14.5, 5.2 Hz), 4.23 (1H, d ꢂ d, J ¼ 14.5, 4.4 Hz), 5.85
(2H, br s), 6.81e6.85 (2H, m), 7.14e7.18 (2H, m), 7.97 and 8.37 (2H,
CDCl3):
d
0.99 (6H, t, J ¼ 7.2 Hz), 1.42 (1H, d, J ¼ 6.6 Hz), 1.63 (1H, d,
J ¼ 3.9 Hz), 1.66e1.71 (1H, m), 2.47e2.64 (6H, m), 3.33 and 3.46 (2H,
2 ꢂ d, J ¼ 13.5 Hz), 7.30 (5H, s). 13C NMR (75 MHz, CDCl3):
d 11.41,
32.61, 37.99, 46.89, 56.02, 63.79, 128.44, 129.58, 132.80, 137.55. IR
(ATR, cmꢁ1): nmax ¼ 2970, 1491, 1346, 1202, 1087, 1071, 1015, 806,
732. MS (70 eV): m/z (%): 253/5 (Mþ þ 1, 100). Anal. calcd. for
C14H21ClN2: C 66.52, H 8.37, N 11.08; found: C 66.67, H 8.62, N 10.99.
2 ꢂ s). 13C NMR (75 MHz, CDCl3):
d 11.7, 45.8, 46.9, 51.5, 54.5, 55.3,
55.4,113.8,129.3,119.3,132.2,141.9, 150.6,152.9, 155.4,158.7. IR (ATR,
cmꢁ1): nNH ¼ 3322 and 3159. MS (70 eV): m/z (%): 384 (Mþ þ 1, 100).
Anal. calcd. for C20H29N7O: C 62.64, H 7.62, N 25.57; found: C 62.38; H
7.74; N 25.41.
4.1.13. 2-(N,N-Diethylamino)methyl-1-[(4-methoxyphenyl)methyl]
aziridine (2k)
Rf ¼ 0.07 (CHCl3/MeOH 95/5); yield 64%. 1H NMR (300 MHz,
4.1.18. Synthesis of 2-(arylmethyl)amino-3-diethylamino-1-(2,4-
dioxo-5-methylpyrimidin-1-yl)propanes (3dee)
CDCl3):
d
0.99 (6H, t, J ¼ 7.2 Hz), 1.43 (1H, d, J ¼ 6.1 Hz), 1.60 (1H, d,
J ¼ 3.3 Hz),1.65e1.70 (1H, m); 2.43e2.64 (6H, m), 3.33 and 3.41 (2H,
2 ꢂ d, J ¼ 13.2 Hz), 3.80 (3H, s), 6.84e6.88 (2H, m), 7.25e7.28 (2H,
The procedure for the synthesis of compounds 3aec was applied
for the preparation of 2-(arylmethyl)amino-3-diethylamino-1-(2,4-
dioxo-5-methylpyrimidin-1-yl)propanes 3dee. The crude products
3dee were purified by column chromatography on aluminum oxide
or by recrystallization.
m). 13C NMR (75 MHz, CDCl3):
d 11.5, 32.5, 37.7, 46.9, 55.3, 56.1, 64.1,
113.8, 129.4, 131.2, 158.8. IR (ATR, cmꢁ1): nmax ¼ 2970, 2933, 1612,
1512, 1463, 1300, 1244, 1174, 1035, 819, 730. MS (70 eV): m/z (%):
249 (Mþ þ 1, 100). Anal. calcd. for C15H24N2O: C 72.54, H 9.74, N
11.28; found: C 72.43, H 9.84, N 11.16.
4.1.19. 2-[(4-Chlorophenyl)methyl]amino-3-diethylamino-1-(2,4-
dioxo-5-methylpyrimidin-1-yl)-propane 3d
4.1.14. Synthesis of 1-(6-aminopurin-9-yl)-2-(arylmethyl)amino-3-
diethylaminopropanes (3aec)
Recrystallization from CH2Cl2/Et2O (4/1); yield 18%; mp ¼ 42.1 ꢀC
1H NMR (300 MHz, CDCl3): 0.95 (3H, t, J ¼ 6.9 Hz), 1.90 (3H, s),
2.30e2.54 (6H, m), 2.89e2.94 (1H, m), 3.63e3.77 (4H, m), 7.10 (1H,
General procedure: In a 10 mL thick walled Pyrex reaction
vessel,
2-(6-aminopurin-9-yl)methyl-1-(arylmethyl)aziridine
s), 7.19e7.29 (4H, m), 8.86 (1H, br s). 13C NMR (75 MHz, CDCl3):
d 11.8,

586
M. D’hooghe et al. / European Journal of Medicinal Chemistry 46 (2011) 579e587
12.2, 47.0, 50.9, 51.5, 54.2, 55.3, 109.6, 128.6, 129.4, 132.8, 138.8, 142.2,
151.2, 164.2. IR (ATR, cmꢁ1): nCO ¼ 1706 and 1660, nNH ¼ 3248. MS
(70 eV): m/z (%): 379/81 (Mþ þ 1, 100). Anal. calcd. for C19H27ClN4O2:
C 60.23, H 7.18, N 14.79; found: C 60.55, H 7.42, N 14.57.
(diethylamino)propanes 3iek. The crude products 3iek were
purified by column chromatography on aluminum oxide (CH2Cl2/
MeOH 99/1).
4.1.26. 1,3-Bis(diethylamino)-2-(phenylmethyl)aminopropane 3i
Rf ¼ 0.10 (CH2Cl2/MeOH 99/1); yield 31%. 1H NMR (300 MHz,
CDCl3): 0.98 (12H, t, J ¼ 7.2 Hz), 2.39e2.53 (12H, m), 2.66e2.74
(1H, m), 3.87 (2H, s), 7.28e7.34 (5H, m). 13C NMR (75 MHz, CDCl3):
4.1.20. 3-Diethylamino-1-(2,4-dioxo-5-methylpyrimidin-1-yl)-2-
[(4-methoxyphenyl)methyl]aminopropane 3e
Rf ¼ 0.08 (CH2Cl2/MeOH); yield 65%. 1H NMR (300 MHz, CDCl3):
0.94 (3H, t, J ¼ 7.2 Hz), 1.90 (3H, s), 2.32e2.53 (6H, m), 2.90e2.98
(1H, m), 3.65e3.74 (4H, m), 3.77 (3H, s), 7.13 (1H, s), 6.82e6.85 (2H,
d
12.0, 47.6, 52.0, 52.7, 57.1, 126.9, 128.4, 128.5, 140.8. IR (ATR,
cmꢁ1): nNH ¼ 3295. MS (70 eV): m/z (%): 292 (Mþ þ 1, 100). Anal.
calcd. for C18H33N3: C 74.14, H 11.41, N 14.42; found: C 74.03, H
11.36, N 14.30.
m), 7.13 (1H, s), 7.17e7.20 (2H, m). 13C NMR (75 MHz, CDCl3):
d 11.7,
12.3, 46.9, 50.9, 51.5, 53.8, 55.2, 55.3, 109.5, 113.8,129.4, 132.3, 142.2,
151.7, 158.6, 165.0. IR (ATR, cmꢁ1): nCO ¼ 1674, nNH ¼ 3172 and 3029.
MS (70 eV): m/z (%): 375 (Mþ þ 1, 100). Anal. calcd. for C20H30N4O3:
C 64.15, H 8.07, N 14.96; found: C 63.97, H 8.21, N 14.82.
4.1.27. 2-[(4-Chlorophenyl)methyl]amino-1,3-bis(diethylamino)
propane 3j
Rf ¼ 0.16 (CH2Cl2/MeOH 99/1); yield 25%. 1H NMR (300 MHz,
CDCl3): 0.98 (12H, t, J ¼ 7.2 Hz), 2.37e2.55 (12H, m), 2.59e2.71 (1H,
4.1.21. Synthesis of 2-(arylmethyl)amino-3-diethylamino-1-(1,2,4-
triazol-1-yl)propanes (3feh)
m), 3.83 (2H, s), 7.18e7.29 (4H, m). 13C NMR (75 MHz, CDCl3):
d 11.9,
The procedure for the synthesis of compounds 3aec was
applied for the preparation of 2-(arylmethyl)amino-3-dieth-
ylamino-1-(1,2,4-triazol-1-yl)propanes 3feh. The crude products
3feh were purified by column chromatography on aluminum oxide
(CH2Cl2/MeOH 99/1).
47.5, 51.3, 52.7, 57.1, 128.4, 129.5, 132.4, 139.5. IR (ATR, cmꢁ1):
nNH ¼ 3288. MS (70 eV): m/z (%): 326/8 (Mþ þ 1, 100). Anal. calcd.
for C18H32ClN3: C 66.33, H 9.90, N 12.89; found: C 66.57, H 10.13, N
12.77.
4.1.28. 1,3-Bis(diethylamino)-2-[(4-methoxyphenyl)methyl]amino-
propane 3k
4.1.22. 3-Diethylamino-2-(phenylmethyl)amino-1-(1,2,4-triazol-1-
yl)propane 3f
Rf ¼ 0.19 (CH2Cl2/MeOH 99/1); yield 13%. 1H NMR (300 MHz,
CDCl3): 1.00 (12H, t, J ¼ 7.2 Hz), 2.41e2.58 (12H, m), 2.64e2.81 (1H,
m), 3.80 (3H, s), 3.90 (2H, s), 6.86e6.89 (2H, m), 7.25e7.31 (2H, m).
Rf ¼ 0.54 (CH2Cl2/MeOH 99/1); yield 40%. 1H NMR (300 MHz,
CDCl3): 0.91 (6H, t, J ¼ 6.9 Hz), 2.27 (1H, d ꢂ d, J ¼ 14.2, 6.3 Hz), 2.30
(1H, d ꢂ d, J ¼ 14.2, 8.3 Hz), 2.34e2.48 (4H, m), 3.00e3.08 (1H, m),
3.64 and 3.69 (2H, 2 ꢂ d, J ¼ 13.5 Hz), 4.12 (1H, d ꢂ d, J ¼ 14.0,
5.2 Hz), 4.21 (1H, d ꢂ d, J ¼ 14.0, 4.7 Hz), 7.20e7.36 (5H, m), 7.93 and
13C NMR (75 MHz, CDCl3):
d 11.6, 47.3, 50.5, 52.2, 55.3, 56.3, 113.9,
129.7, 130.3, 158.8. IR (ATR, cmꢁ1): nNH ¼ 3298. MS (70 eV): m/z (%):
322 (Mþ þ 1, 100). Anal. calcd. for C19H35N3O: C 70.98, H 10.97, N
13.07; found: C 71.18, H 11.07, N 13.00.
8.13 (2H, 2 ꢂ s). 13C NMR (75 MHz, CDCl3):
d 11.7, 46.9, 51.9, 52.0,
54.6, 55.2, 127.0, 128.1, 140.1, 144.1, 151.6. IR (ATR, cmꢁ1):
nNH ¼ 3300. MS (70 eV): m/z (%): 288 (Mþ þ 1, 100). Anal. calcd. for
C16H25N5: C 66.86, H 8.77, N 24.37; found: C 66.94, H 8.95, N 24.42.
Acknowledgements
The authors are indebted to the “Institute for the Promotion of
Innovation through Science and Technology e Flanders” (IWT-
Vlaanderen), to the “Fund for Scientific Research e Flanders” (FWO-
Vlaanderen) and to Ghent University (GOA) for financial support.
4.1.23. 2-[(4-Chlorophenyl)methyl]amino-3-diethylamino-1-(1,2,4-
triazol-1-yl)propane 3g
Rf ¼ 0.12 (CH2Cl2/MeOH 99/1); yield 31%. 1H NMR (300 MHz,
CDCl3): 0.93 (6H, t, J ¼ 7.2 Hz,), 2.27 (1H, d ꢂ d, J ¼ 12.8, 6.3 Hz), 2.31
(1H, d ꢂ d, J ¼ 12.8, 8.3 Hz), 2.33e2.53 (4H, m), 3.00e3.08 (1H, m),
3.60 and 3.64 (2H, 2 ꢂ d, J ¼ 13.5 Hz), 4.13 (1H, d ꢂ d, J ¼ 13.9,
5.8 Hz), 4.23 (1H, d ꢂ d, J ¼ 13.9, 4.4 Hz), 7.16e7.23 and 7.26e7.29
(4H, 2 ꢂ m), 7.94 and 8.14 (2H, 2 ꢂ s). 13C NMR (75 MHz, CDCl3):
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