Synthesis and antileishmanial activity of 1,3-bis(aryloxy)propan-2-amines

Article abstract of DOI:10.1007/s00044-017-1805-1

We describe herein the antileishmanial activity of 1,3-bis(aryloxy)propan-2-amines, prepared in four simple steps from epichlorohydrin. Among the evaluated compounds, three (4o, 4q, and 4r) displayed considerable activity against Leishmania amazonensis promastigote forms, with IC₅₀ values below 10 μM. We also analyzed the effects of the nature and the position of ring substituent on activity. Two amines (4m and 4o) showed excellent profiles in the treatment of L. amazonensis-infected macrophages, reducing the parasite burden by more than 95% in tested concentrations.

Full text of DOI:10.1007/s00044-017-1805-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1805-1
ORIGINAL RESEARCH
Synthesis and antileishmanial activity of 1,3-bis(aryloxy)propan-2-
amines
Stefânia N. Lavorato1 Mariana C. Duarte2,3 Daniela P. Lage3
●
●
●
Carlos A. P. Tavares4 Eduardo A. F. Coelho2,3 Ricardo J. Alves1
●
●
Received: 16 October 2016 / Accepted: 10 February 2017
© Springer Science+Business Media New York 2017
Abstract We describe herein the antileishmanial activity of
1,3-bis(aryloxy)propan-2-amines, prepared in four simple
steps from epichlorohydrin. Among the evaluated com-
pounds, three (4o, 4q, and 4r) displayed considerable
activity against Leishmania amazonensis promastigote
forms, with IC50 values below 10 µM. We also analyzed the
effects of the nature and the position of ring substituent on
activity. Two amines (4m and 4o) showed excellent profiles
in the treatment of L. amazonensis-infected macrophages,
reducing the parasite burden by more than 95% in tested
concentrations.
Introduction
Leishmaniasis is a tropical neglected disease caused by
several species of Leishmania protozoa, transmitted by the
bite of the infected phlebotomine sandflies. The disease is
an important public health problem in many countries, with
an annual incidence of approximately 1.3 million new
cases. It is also estimated that 310 million people live in
areas at risk of infection, spread through Latin America,
Africa, Asia and southern Europe (WHO 2016). Nowadays,
there is no effective vaccine in preventing the disease. In
addition, the available chemotherapy is not ideal for the
treatment, due to high toxicity and/or costs of these drugs,
the need of parenteral administration for long periods and
recent cases of parasites resistance (Menezes et al. 2015;
Sundar and Chakravarty 2015). Therefore, the search for
new drugs to treat leishmaniasis is needed.
●
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Keywords Leishmania amazonensis Leishmaniasis
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Cytotoxicity Bisaryloxypropanamines Antileishmanial
activity
In the literature, one can find a variety of symmetrical
compounds with antileishmanial activity (Pandharkar et al.
2014; Cassamale et al. 2016; Souza et al. 2004; Silva Filho
et al. 2008; Braga et al. 2014; Mello et al. 2014; Leal et al.
2013; Cardona et al. 2013; Girault et al. 2000; Rasmussen
et al. 2000), as shown in Fig. 1a. Generally, they present
simple structures, composed by two aromatic moieties
linked together by a spacer (Fig. 1b). The main structural
differences among these substances are the nature and
substitution pattern of aromatic moiety and the size and
nature of the spacer. The aromatic moieties of these com-
pounds are usually substituted. The most common explored
substituents are amidine and methoxy groups, since they are
present in well-documented antileishmanial compounds,
like pentamidine, DB766, and curcumin (Pandharkar et al.
2014; Rasmussen et al. 2000). Nevertheless, Braga and
colleagues (2014) showed that symmetrical compounds
bearing other aryl substituents, like nitro and methyl groups
* Ricardo J. Alves
ricardodylan@farmacia.ufmg.br
1
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia,
Universidade Federal de Minas Gerais, Avenida Antônio Carlos,
6627, Belo Horizonte, MG 31.270-901, Brazil
2
Departamento de Patologia Clínica, COLTEC, Universidade
Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo
Horizonte, MG 31.270-901, Brazil
3
Programa de Pós-Graduação em Ciências da Saúde: Infectologia e
Medicina Tropical, Faculdade de Medicina, Universidade Federal
de Minas Gerais, Avenida Professor Alfredo Balena, 190, Belo
Horizonte, MG 30130-100, Brazil
4
Departamento de Bioquímica e Imunologia, Instituto de Ciências
Biológicas, Universidade Federal de Minas Gerais, Avenida
Antônio Carlos, 6627, Belo Horizonte, MG 31.270-901, Brazil

Med Chem Res
Fig. 1 a Antileishmanial symmetrical compounds described previously in the literature; b The main structural features of antileishmanial
symmetrical compounds; c Basic structure of 1,3-bis(aryloxy)propan-2-amines
can also contribute to antileishmanial activity. Heterocycles
(Pandharkar et al. 2014; Cassamale et al. 2016; Souza et al.
2004; Silva Filho et al. 2008), dienones (Braga et al. 2014;
Mello et al. 2014) and alkyl chains (Leal et al. 2013; Car-
dona et al. 2013) are common spacers found in these
compounds. In general, the spacers contain 2 to 11 atoms
and a polar group is usually present at the central part of the
structure (Fig. 1b). Spacers containing oxygen atom, like
furan, tetrahydrofuran and carbonyl are central polar groups
commonly found in these compounds (Pandharkar et al.
2014; Cassamale et al. 2016; Souza et al. 2004; Silva Filho
et al. 2008; Braga et al. 2014; Mello et al. 2014). On the
other hand, few studies reported on the presence of amino
group in the spacer (Girault et al. 2000).
antileishmanial activity of twenty one 1,3-bis(aryloxy)pro-
pan-2-amine derivatives, which differ in the nature and
position of the substituents on the aromatic rings.
Results and discussion
Chemistry
The 21 1,3-bis(aryloxy)propan-2-amines were prepared in a
straightforward manner as shown in Scheme 1. Briefly, the
reaction of epichlorohydrin with appropriately substituted
phenol or naphthol in aqueous sodium hydroxide at 60 °C
gave alcohol derivatives 1a–1u (Zhao et al. 1996). Metha-
nesulfonates 2a–2u were then obtained by treatment of 1a–
1u with methanesulfonyl chloride in dry pyridine (Lee et al.
1992). Next, reaction of 2a–2u with sodium azide in DMF
at 80 °C provided azido derivatives 3a–3u (Ermeydan et al.
2010). Finally, the reduction of azido group was carried out
in two ways, depending on aryl substituent. Except for
compounds 3d, 3e, and 3f, bearing nitro group, the reduc-
tion was performed by catalytic hydrogenation (Pd/C) in
THF or MeOH (Ebner et al. 2008). As nitro groups are
reduced in this condition, compounds 3d, 3e, and 3f were
converted to their corresponding amines, without any
We recently published a work on the trypanocidal
activity
of
several
symmetrical
1,3-bisarilox-
ypropanolamines (Lavorato et al. 2015), whose general
structure is shown in Fig. 1c. These compounds have the
main structural features (as shown in Fig. 1b) of those of the
antileismanial compounds depicted in Fig. 1a. To the best of
our knowledge, there are no studies on the potential of this
class as antileishmanial agents, which can be prepared in
four simple steps from the reaction of inexpensive epi-
chorohydrin with appropriately substituted aryloxy com-
pounds. In the present work, we describe the

Med Chem Res
Scheme 1 Synthesis and global
yields of 1,3-bis(aryloxy)
propan-2-amines. Reagents and
conditions: (i) NaOH, H2O, 60 °
C, 14 h; (ii) MsCl, py, rt, 4 h;
(iii) NaN3, DMF, 80 °C, 24 h;
(iv) a H2/Pd-C, THF or MeOH,
4 h or DTT, TEA, MeCN, 3 h, b
conc. HCl, MeOH
damage to nitro groups, using dithiothreitol in acetonitrile,
using triethylamine as base (Blaukopf et al. 2012). All
amines were isolated as hydrochloride salts 4a–4u. The
global yields for all compounds are shown in Scheme 1.
We also evaluated the cytotoxicity of 1,3-bis(aryloxy)
propan-2-amines to macrophages derived from female
BALB/c mice to determine the safety of these compounds
against mammalian cells. The results were expressed as
CC50 values, which correspond to the concentration of each
compound required to inhibit 50% of the macrophages
viability. The results are shown in Table 1. The selective
index (SI) for the active compounds presented in Table 1
correspond to the ratio between CC50 and IC50 values.
Usually, a SI value higher than 10 is recommended to
ensure the safety of an antileishmanial substance (Pires et al.
2013). In this study, compounds 4e (m-NO2), 4q (m-Cl),
and 4r (p-Cl) presented the safest biological profiles,
showing a SI value above eight, displaying a moderate
selectivity against the parasites.
In vitro antileishmanial activity and cytotoxicity
evaluation
Amino salts 4a–4u were evaluated for their in vitro antil-
eishmanial activity against stationary promastigote forms of
L. amazonensis. The results were expressed as the com-
pound concentration needed to inhibit 50% of Leishmania
viability (IC50) and are shown in Table 1. In this assay, only
compounds 4d (o-NO2) and 4g (o-COOCH3) were found to
be inactive, indicating that bis-aryl compounds with this
new spacer display a potential antileishmanial application.
The IC50 values of active compounds ranged from 2.9
to 46.8 µM and the most potent bisarylamines were 4o
(p-CH3), 4q (m-Cl) and 4r (p-Cl), showing IC50 values
below 10 µM.
Structure–activity relationship
Structure–activity relationship studies enable the determi-
nation of how structural aspects influence the biological

Med Chem Res
Table 1 The in vitro
antileishmanial activity and
cytotoxicity of synthesized
compounds 4a–4u
Compounds IC50 (µg/mL) SD
IC50 (µM) SD CC50 (µg/mL) SD
CC50 (µM) SD SI
4a
4b
4c
8.19 0.88
5.07 0.74
6.24 0.39
24.8 2.7
15.4 2.2
18.9 1.2
38 11
24 11
116 34
73 35
33 11
–
4.7
4.8
1.7
–
11
4
4d
4e
Inactive
Inactive
–
–
3.91 0.69
4.04 0.60
10.6 1.9
10.9 1.6
32
24
3
5
87
7
8.3
6
4f
65 14
4g
4h
4i
Inactive
Inactive
–
–
7.66 0.88
4.59 0.28
15.90 1.07
13.39 3.60
7.16 1.22
4.10 1.24
8.42 0.12
1.67 0.24
4.26 1.21
1.83 1.25
1.02 0.04
5.29 0.66
6.13 1.12
8.46 0.72
0.2 0.0
19.3 2.2
11.6 0.7
46.8 3.1
29
32
17
1
3
3
74
81
49
4
8
8
3.8
7
4j
1.1
2.4
4.1
3.8
2.2
7.5
5.7
8.4
8.4
6.6
2.2
1.9
4.9
4k
4l
39.4 10.6 33 10
96 28
21.1 3.6
13.3 4.0
27.3 0.4
5.4 0.8
30
16
19
13
24
15
9
0
1
3
5
4
0
1
5
3
0
0
87
51
1
2
4m
4n
4o
4p
4q
4r
61 10
41 15
69 11
12.2 3.5
5.2 3.6
44
24
1
4
2.9 0.1
4s
18.9 2.4
16.1 2.9
22.3 1.9
0.22 0.00
35
14
16
1
125 17
4t
36
42
1
8
1
0
4u
AmpB
IC50 50% inhibitory concentration on L. amazonensis promastigotes, CC50 50% cytotoxicity concentration
on murine macrophages, SI selective index (CC50/IC50), AmpB Amphotericin B, positive control
activity of a compound. Based on these studies, rational
structural modifications can be proposed to obtain new
compounds with desirable properties and increased potency
(Testa and Kier 1991). The present work provides us with
initial information on the structure-activity relationship of
studied compounds. The most active compounds were meta
or para-substituted, indicating that the biological activity
could be influenced by substituent position. Regarding the
influence of the nature of the substituent on activity, it is
known that the introduction of a substituent affects mole-
cular properties of an unsubstituted compound, like lipo-
philicity and electronic aspects. The lipophilic character of a
compound can be measured by its calculated partition
coefficient (ClogP), which increases as the hydrophobic
character of a substituent and, consequently, the hydro-
phobicity of a compound increases. The electronic differ-
ences among structurally related compounds, like the
amines studied in this work, can be estimated by the elec-
tronic contribution of their substituents, represented by the
substituent Hammet constant (σR). Positive values of σR
mean that the group has an electron withdrawing effect,
whereas negative values mean that the group has an electron
donating effect. In this connection, the molecular para-
meters ClogP and σR of each evaluated 1,3-bis(aryloxy)
propan-2-amines were calculated and are shown in Table 2.
Regarding para-substituted bisarylamines, we observed
that the hydrophobicity contribution of the ring substituent
appears to contribute to biological activity profiles of this
compound series. The most active para-substituted com-
pounds were those with higher ClogP values, that is, those
bearing hydrophobic substituents, such as p-CH3 (4o) and
p-Cl (4r). On the other hand, the least active were those
with lower ClogP values or bearing hydrophilic sub-
stituents, such as p-CN (4c) and p-OCH3 (4l). This indicates
a tendency towards increase of antileishmanial activity as
the lipophilicity of the para-substituted compound increa-
ses. More lipophilic compounds are more able to cross
parasite membranes, which contributes to a higher con-
centration of the compound at the site of action, which
could explain their greater activity. Moreover, this activity
may be related to a better ligand-putative target interaction
(Rutkowska et al. 2013). The correlation between lipophi-
licity and antileishmanial activity of compounds with a
variety of substituents has also been previously described
by others (Jorda et al. 2011; Musonda et al. 2009; Valder-
rama et al. 2005; Booth et al. 1987), indicating the impor-
tance of this physicochemical property for activity.
For ortho-substituted compounds, the same tendency
was observed. Compounds 4m and 4p, bearing hydro-
phobic o-CH3 or o-Cl groups, respectively, and the

Med Chem Res
Table 2 Molecular properties
of compounds 4a–4u
a
f
Compound
R
σR
ClogPb
MWc (Da)
HBDd
HBAe
nRB
PSAg (Å2)
4a
4b
4c
4d
4e
4f
2-CN
–
1.95
1.11
1.95
1.67
2.55
2.27
2.30
2.38
2.75
2.13
2.07
2.41
3.40
3.40
3.40
3.57
4.14
3.85
2.48
4.94
4.94
293.33
293.33
293.33
333.30
333.30
333.30
359.38
359.38
359.38
303.36
303.36
303.36
271.36
271.36
271.36
312.20
312.20
312.20
243.31
343.43
343.43
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
5
5
5
9
9
9
7
7
7
5
5
5
3
3
3
3
3
3
3
3
3
6
6
92.08
92.08
92.08
136.14
136.14
136.14
97.10
97.10
97.10
62.96
62.96
62.96
44.49
44.49
44.49
44.49
44.49
44.49
44.49
44.49
44.49
3-CN
0.56
0.66
–
4-CN
6
2-NO2
3-NO2
4-NO2
2-COOCH3
3-COOCH3
4-COOCH3
2-OCH3
3-OCH3
4-OCH3
2-CH3
8
0.71
0.78
–
8
8
4g
4h
4i
10
10
10
8
0.37
0.45
–
4j
4k
4l
0.12
−0.27
–
8
8
4m
4n
4o
4p
4q
4r
4s
4t
6
3-CH3
−0.07
−0.17
–
6
4-CH3
6
2-Cl
6
3-Cl
0.37
0.23
0
6
4-Cl
6
H
6
2,3-Benzo
3,4-Benzo
–
6
4u
a
–
6
σR: Hammet’s electronic constant; obtained from Hansch and Leo (1979);
b
c
d
e
f
ClogP, calculated partition coefficient, calculated using ACD/ChemSketch software (acdlabs.com);
MW molecular weight,
HBD hydrogen-bond donors, the sum of OHs and NHs,
HBA hydrogen-bond acceptors, the sum of Os and Ns,
nRB number of rotatable bonds, calculated using Molinspiration (molinspiration.com);
PSA polar surface area, calculated using Molinspiration (molinspiration.com)
g
unsubstituted 4s were more potent than compounds 4a and
4j, with hydrophilic o-CN or o-OCH3 groups as ring sub-
stituent. Moreover, compounds bearing hydrophilic o-NO2
or o-COOCH3 groups (4d and 4g) were inactive, reflecting
the effect of hydrophobic contribution of ring substituent.
On the other hand, for meta-substituted compounds, we
observed that the electronic effect of ring substituent has a
greater influence on activity. Apart from compounds 4k (m-
OCH3) and 4q (m-Cl), the greater the substituent electron
withdrawing effect, the greater the antileishmanial activity.
Therefore, the amino salt 4e, bearing electron withdrawing
m-NO2 group, was 3-fold more active than amino salt 4n,
bearing electron donating m-CH3 group. These findings
indicate that aromatic rings with low electron density are
important for a stronger antileishmanial effect in this series.
The hydrophobic character of ring substituent also appears
to be important and could explain why compound 4q (m-Cl)
was more active than 4e (m-NO2) and 4b (m-CN), despite
the stronger electron withdrawing effect of these groups,
and why 4n (m-CH3) was more active than 4k (m-OCH3).
Barral et al. (1991) showed that L. amazonensis can cause
not only the cutaneous form, but also the visceral form of
leishmaniasis. The current treatment of visceral leishmaniasis
consists of parenteral medication, commonly painful and
uncomfortable to the patients, resulting in a decrease of
therapy adhesion. This drawback can be solved using the most
convenient oral route of administration. So, the development
of orally active antileishmanial agents may contribute to
increase the treatment success. An interesting and widely
accepted way to predict if a compound is more likely to
present a good oral absorption and permeation is appling
Lipinski’s rule of five (Lipinski et al. 2001). According to this
rule, an orally active compound generally presents a molecular
weight less than 500 Da; a logP value less than 5; a number of
hydrogen-bond donors less than 5 and a number of hydrogen-
bond acceptors less than 10. Veber et al. (2002) also suggested
that compounds with less than 10 rotatable bonds (nRB) and a
polar surface area less than 140 Å2 are more likely to present a
good oral bioavailability. As shown in Table 2, none of the
evaluated 1,3-bis(aryloxy)propan-2-amines violates the

Med Chem Res
criteria previously described, indicating their potential to be
orally absorbed.
amastigotes, since this assay is more representative of the
natural infection. We selected the seven most potent amines
(4e, 4f, 4i, 4m, 4o, 4q, and 4r) and evaluated the reduction
of the percentage of infected macrophages and the number
of amastigotes per macrophage in the presence of each
selected compound in concentrations ranging from 2.5 to
15 µg/mL. Due to the high toxicity to macrophages, even at
the lowest concentration of our protocol (2.5 µg/mL),
compound 4r (p-Cl) could not be evaluated.
The presence of pan-assay interference compounds,
known as PAINS, in chemical libraries is another feature to
be analyzed. In general, PAINS present false positive results
in different biological assays due to their promiscuous
behavior. They can act by different mechanisms, such as
aggregation, redox activity, metal complexation, according
to their chemical structure (Glasser and Holzgrabe 2016).
Considering the important interference of these compounds
in biological assay results, we proceeded with in silico
assays to evaluate the occurrence of PAINS among our
compounds. Therefore, we have selected two web-servers
that can identify potential PAINS in screening libraries: The
PAINS Remover (http://cbligand.org/PAINS/) (Baell and
Holloway 2010) and FAFDrugs3 (http://fafdrugs3.mti.univ-
paris-diderot.fr/) (Lagorce et al. 2011) to evaluated the three
most active compounds against L. amazonensis promasti-
gotes [4o (p-CH3), 4q (m-Cl) and 4r (p-Cl)] and the other
four compounds evaluated in the assay of L. amazonensis-
infected macrophages [4e (m-NO2), 4f (p-NO2), 4i
(p-COOCH3) and 4m (o-CH3)].
As shown in Fig. 2, the results of the treatment of L.
amazonensis-infected macrophages with the selected com-
pounds indicate a dose-dependent response, as the percen-
tage of infected macrophages and the number of
amastigotes per macrophage decrease as the concentration
of the compound increases, when compared with control.
However, when amines 4e, 4f, and 4i were used at the
lowest concentration (2.5 µg/mL), no significant difference
in activity was observed, when compared to control. Thus,
for these three amines only the activity observed at con-
centrations ranging from 5.0 to 15.0 µg/mL, are shown. The
ability of the selected bisarylamines in killing the parasites
in Leishmania-infected macrophages was evaluated by
comparing the percentage of recovered amastigotes per
treated macrophage in the absence (control) and in the
presence of each selected compound (Fig. 2). Except for
compound 4f (p-NO2), the other selected bisarylamines
reduced the percentage of amastigotes in infected macro-
phages by more than 50%, when tested at a concentration of
5 µg/mL. Moreover, all compounds reduced the amastigote
forms per infected macrophage by more than 90% in rela-
tion to untreated controls in, at least, one of the evaluated
concentrations. Compounds 4m (o-CH3), 4o (p-CH3), and
4q (m-Cl) reduced the parasite burden by 50% or more at
the concentration of 2.5 µg/mL. However, only compounds
4m (o-CH3) and 4o (p-CH3) reduced parasites inside mac-
rophages by more than 90% at 5 µg/mL, being the most
promising antileishmanial compounds in the present study.
Interestingly, compound 4m (o-CH3), which presents,
among the selected compounds, the highest IC50 against
promastigote forms, was one of those with the best antil-
eishmanial profile against L. amazonensis intra-macrophage
forms, highlighting the importance of this assay in drug
discovery of antileishmanial compounds.
To analyze these seven compounds using The PAINS
Remover, we submitted to the web-server their structure data
as SMILES format, generated using the web-server Online
SMILES Translator and Structure File Generator (https://
cactus.nci.nih.gov/translate/). None of the evaluated com-
pounds were filtered out by the filter of The PAINS Remover,
indicating there is no potential PAINS in this group.
To confirm the results, we analyzed the compounds using
FAFDrugs3. We submitted to the web-server a sdf format file
containing the structure data of the compounds. We selected
the options “Filter undesirable substructures moieties”,
“Retrieve covalent inhibitors”, “Filter Pan Assay Interference
Compounds (PAINS) Filter A”, “Filter Pan Assay Interference
Compounds (PAINS) Filter B” and “Filter Pan Assay Inter-
ference Compounds (PAINS) Filter C” as filters. The results
indicate the absence of PAINS and covalent inhibitors among
the evaluated compounds. Although PAINS filters did not
recognize any compound as so, it is important to note that the
nitro compounds were evaluated as “intermediate molecules”
due to the presence of low risk nitro and nitrobenzene groups
in their structures. The nitro and nitrobenzene groups are
usually recommended as unsuitable for screening libraries,
but they were not included in the functional groups databank
used to the development of these two PAINS filter web-server
(Baell and Holloway 2010; Lagorce et al. 2011).
We also evaluated the effect of the compounds on the
reduction of the percentage of L. amazonensis-infected mac-
rophages in comparison with non-treated and infected cells
(Fig. 2). Once again, compounds 4m (o-CH3) and 4o (p-CH3)
were those with the best results. At a concentration of 10 µg/
mL, both compounds reduced the percentage of infected
macrophage by more than 95% when compared with the
controls. Compounds 4e (m-NO2) and 4f (p-NO2) were also
able to reduce the infection in the phagocytic cells showing
similar results, although in higher concentration (15 µg/mL).
Treatment of Leishmania amazonensis-infected
macrophages
Studies were extended to evaluate the antileishmanial
activity of selected compounds against intra-macrophage

Med Chem Res
Fig. 2 Effect of selected compounds on the percentage of infected macrophages a and on the number of amastigotes per macrophage b

Med Chem Res
Conclusion
drying and concentration (method 2); or by extraction
procedure as previously described, followed by silica
gel column chromatography (Hexanes/EtOAc 9:1 v/v)
(method 3).
In summary, we report herein the synthesis and biological
activity of 1,3-bis(aryloxy)propan-2-amines, a novel class
of antileishmanial compounds. The nature and position of
substituent in the aromatic ring was shown to affect the
antileishmanial activity and the physicochemical contribu-
tion of each substituent to biological activity. Three com-
pounds, 4o (p-CH3), 4q (m-Cl), and 4r (p-Cl), displayed a
considerable toxicity against L. amazonensis promastigotes,
with IC50 values lower than 10 µM. Regarding the cyto-
toxicity assay, the bisarylamines 4e (m-NO2), 4q (m-Cl),
and 4r (p-Cl) were the compounds with higher selective
index (SI > 8). Amines 4m (o-CH3) and 4o (p-CH3) showed
the best profiles in the treatment of L. amazonensis-infected
macrophages.
Altogether, in this study the potential of 1,3-bis(aryloxy)
propan-2-amine derivatives as antileishmanial agents was
disclosed for the first time. The synthesis of novel analogs
as well as studies on the mechanism of action of these
compounds are underway and the results will be published
in due course.
1,3-Bis(2-cyanophenoxy)propan-2-ol (1a)
Using the general procedure above and the work up method
1, a white solid was obtained in 63% yield. mp: 141–141.8 °
C; IR (ATR) vmax 3499, 2957, 2228, 1597, 1487, 1448,
1287, 1104, 1023, 749 cm−1; 1H NMR (CDCl3, 200 MHz):
δ = 7.60–7.54 (4H, m, H-3′, H-5′); 7.10–7.01 (4H, m, H-4′,
H-6′); 4.52–4.49 (m, 1H, H-2); 4.35 (4H, d, J = 5.0 Hz,
H–1); 3.06 (1H, s, OH); 13C NMR (CDCl3, 50 MHz): δ =
160.1 (C, C-1′), 134.9 (CH, C-5′); 133.8 (CH, C-3′); 121.7
(CH, C-4′); 116.6 (C, CN); 112.8 (CH, C-6′); 102.3 (C, C-
2′); 69.2 (CH2, C-1); 68.2 (CH, C-2).
1,3-Bis(3-cyanophenoxy)propan-2-ol (1b)
Using the general procedure above and the work up method
1, a white solid was obtained in 63% yield; mp: 92.5–93.6 °
C; IR (ATR) vmax 3503, 3090, 3044, 2927, 2234, 2225,
1607, 1576, 1477, 1252, 1129, 1142, 1027, 781, 677 cm−1
;
Materials and methods
Experimental
1H NMR (CDCl3, 200 MHz,): δ = 7.45–7.18 (8H, m, H-3′,
H-4′, H-5′, H-6′), 4.45 (1H, s, H-2), 4.19 (4H, d, J = 4.4 Hz,
H-1), 2.76 (1H, s, OH); 13C NMR (CDCl3, 50 MHz): δ =
158.6 (C, C-1′), 130.8 (CH, C-5′), 125.4 (CH, C-4′), 119.9
(CH, C-6′), 118.7 (C, CN), 117.8 (CH, C-2′), 113.5 (C, C-
3′), 69.1 (CH2, C-1), 68.6 (CH, C-2).
All reagents were obtained from commercial suppliers and
used without further purification. Melting points were
determined on Microquímica MQAPF 301 apparatus. The
1H and 13C NMR spectra were obtained on a Bruker
Avance DPX-200 spectrometer. The proton and carbon
chemical shifts (δ) are given with respect to TMS. IR
spectra were recorded on a Spectrum One, Perkin-Elmer
ATR system. Column chromatography was performed on
silica gel 60 0.063–0.200 mm/70-230 mesh Merck. Pyridine
was dried over KOH pellets. Anhydrous DMF was obtained
from commercial supplier (Sigma-Aldrich). Anhydrous
sodium sulfate was used as drying agent after work up when
extraction was applied.
1,3-Bis(4-cyanophenoxy)propan-2-ol (1c)
Using the general procedure above and the work up method
1, a white solid was obtained in 92% yield; mp:
163.9–165.6 °C. (lit. 120 °C). IR (ATR) vmax 3501, 3070,
2936, 2219, 1605, 1574, 1506, 1450, 1253, 1173, 1003,
1
837 cm−1; H NMR (DMSO-d6, 200 MHz): δ = 7.76 (4H,
d, J = 8.4 Hz, H-3’, H-5’), 7.13 (4H, d, J = 8.4 Hz, H-2’),
5.58 (1H, s, OH), 4.17 (5H, s, H-1, H-2); 13C NMR
(DMSO-d6, 50 MHz): δ = 162.0 (C, C-1′), 134.2 (CH, C-
3′), 119.2 (C, CN), 115.7 (CH, C-2′), 102.9 (C, C-4′), 69.5
(CH2, C-1), 67.1 (CH, C-2).
General procedure for synthesis of compounds 1a–1u
To a stirred solution of NaOH (38 mmol), appropriate
substituted phenol or naphthol (38 mmol) in water (30 mL)
at 60 °C was added dropwise epichlorohydrin (1 mL; 12.8
mmol). The reaction mixture was stirred at 60 °C for an
additional 14 h and then cooled to room temperature.
Compounds 1a–1u were obtained after work up by vaccum
filtration (method 1); by extraction with dichloromethane
and washing with 1 M aqueous NaOH (2 × 20 mL) and
water (5 × 50 mL), followed by organic phase separation,
1,3-Bis(2-nitrophenoxy)propan-2-ol (1d)
Using the general procedure above and the work up
method 1, a green solid was obtained in 64% yield; mp:
118.5–119 °C; IR (ATR) vmax 3551, 3111, 2905, 1606,
1583, 1481, 1455, 1513, 1344, 1248, 1048, 1090, 1026,
1
736 cm−1; H NMR (Acetone-d6, 200 MHz): δ = 7.84 (2H,
d, J = 7.6 Hz, H-3′), 7.66–7.62 (2H, m, H-5′), 7.42–7.38
(2H, m, H-4′), 7.15 (2H, d, J = 7.2 Hz, H-6′), 4.73 (1H, s,

Med Chem Res
H-2); 4.42 (5H, s, H-1, OH); 13C NMR (Acetone-d6, 50
MHz): δ = 152.8 (C, C-1′), 141.1 (C, C-2′), 135.2 (CH, C-
5′), 126.1 (CH, C-3′), 121.6 (CH, C-4′), 116.0 (CH, C-6′),
71.2 (CH2, C-1), 68.7 (CH, C-2).
(4H, m, H-2′, H-4′), 7.33–7.25 (2H, m, H-5′), 7.14–7.09
(2H, m, H-6′), 4.58 (1H, d, J = 5.0 Hz, OH), 4.27–4.04 (5H,
m, H-1, H-2), 3.74 (6H, s, COOCH3); 13C NMR (Acetone-
d6, 50 MHz): δ = 167.1 (C, COOCH3), 160.0 (C, C-1′),
132.5 (C, C-3′), 130.6 (CH, C-5′), 122.7 (CH, C-4′), 120.5
(CH, C-6′), 115.9 (CH, C-2′), 70.4 (CH2, C-1), 69.2 (CH,
C-2), 51.3 (CH3, COOCH3).
1,3-Bis(3-nitrophenoxy)propan-2-ol (1e)
Using the general procedure above and the work up method
1, a pale yellow solid was obtained in 89% yield; mp:
113.7–114.5 °C; IR (ATR) vmax 3341, 3095, 2926, 1616,
1582, 1532, 1483, 1518, 1341, 1243, 1125, 1141, 1025,
1,3-Bis(4-methoxycarbonylphenoxy)propan-2-ol (1i)
1
815, 734 cm−1; H NMR (Acetone-d6, 200 MHz): δ = 7.72
Using the general procedure above and the work up method
1, a white solid was obtained in 58% yield; mp: 106.7–108 °
C; IR (ATR) vmax 3486, 3081, 2997, 2951, 2877, 1709,
(4H, s, H-2′, H-4′), 7.61–7.53 (2H, m, H-5′), 7.45 (2H, s, H-
6′), 4.84 (1H, s, H-2), 4.42 (1H, s, OH), 4.37 (4H, s, H-1);
13C NMR (Acetone-d6, 50 MHz): δ = 160.4 (C, C-1′),
150.1 (C, C-3′), 131.2 (CH, C-5′), 122.4 (CH, C-4′), 116.4
(CH, C-6′), 109.8 (CH, C-2′), 70.8 (CH2, C-1), 68.9 (CH,
C-2).
1696, 1603, 1509, 1452, 1244, 1155, 1104, 845 cm−1; H
1
NMR (Acetone-d6, 200 MHz): δ = 7.96 (4H, d, J = 8.8 Hz,
H-3, H-5′), 7.07 (4H, d, J = 8.8 Hz, H-2′, H-6′), 4.72 (1H, s,
H-2), 4.39–4.28 (5H, m, H-1, OH), 3.84 (6H, s, COOCH3);
13C NMR (Acetone-d6, 50 MHz): δ = 167.0 (C, COOCH3),
163.7 (C, C-1′), 132.3 (CH, C-3′, C-5′), 123.7 (C, CH-4′),
115.3 (CH, C-2′, C-6′), 70.4 (CH2, C-1), 69.1 (CH, C-2),
52.1 (CH3, COOCH3).
1,3-Bis(4-nitrophenoxy)propan-2-ol (1f)
Using the general procedure above and the work up method
1,
a
yellow solid was obtained in 70% yield;
mp: 142.2–143.6 °C (lit. 145 °C); IR (ATR) vmax 3572,
3117, 2945, 1591, 1506, 1497, 1464, 1506, 1334, 1255,
1,3-Bis(2-methoxyphenoxy)propan-2-ol (1j)
1
1174, 1110, 847 cm−1; H NMR (Acetone-d6, 200 MHz):
δ = 8.21 (4H, d, J = 8.6 Hz, H-3′, H-5′), 7.19 (4H, d,
J = 8.6 Hz, H-2′, H-6′), 4.90 (1H, s, H-2), 4.44 (1H, s, OH),
4.38 (4H, s, H-1); 13C NMR (Acetone-d6, 50 MHz):
δ = 165.0 (C, C-1′), 142.5 (C, C-4′), 126.7 (CH, C-3′,
C-5′), 115.9 (CH, C-2′, C-6′), 71.0 (CH2, C-1), 68.9
(CH, C-2).
Using the general procedure above and the work up method
2, colorless oil was obtained in 87% yield; IR (ATR) vmax
3469, 3064, 2934, 2876, 2836, 1591, 1503, 1453, 1220,
1
1122, 1023, 738 cm−1; H NMR (CDCl3, 200 MHz): δ =
7.02–6.90 (8H, m, H-3′, H-4′, H-5′, H-6′), 4.45–4.40 (1H,
m, H-2), 4.24 (2H, dd, J = 9.8, 4.8 Hz, H-1a), 4.19 (2H, dd,
J = 9.8, 5.6 Hz, H-1b), 3.86 (6H, s, OCH3), 3.60 (1H, d, J
= 4.4 Hz, OH); 13C NMR (CDCl3, 50 MHz): δ = 150.0 (C,
C-1′), 148.4 (C, C-2′), 122.2 (CH, C-5′), 121.2 (CH, C-4′),
115.2 (CH, C-6′), 112.2 (CH, C-3′), 71.1 (CH, C-2), 68.3
(CH2, C-1), 56.0 (CH3, OCH3).
1,3-Bis(2-methoxycarbonylphenoxy)propan-2-ol (1g)
Using the general procedure above and the work up method
2, colorless oil was obtained in 47% yield. IR (ATR) vmax
3443, 2951, 1706, 1600, 1582, 1490, 1448, 1242, 1082,
752 cm-1; 1H NMR (CDCl3, 200 MHz): δ = 7.82 (2H, d, J
= 7.4 Hz, H-3‘), 7.47 (2H, t, J = 7.4 Hz, H-5‘), 7.07–6.97
(4H, m, H-4‘, H-6‘), 4.56 (1H, s, H-2), 4.38–4.35 (4H, m,
H-1), 3.88 (7H, s, COOCH3, OH); 13C NMR (CDCl3, 50
MHz): δ = 166.8 (C, COOCH3), 158.9 (C, C-1′), 134.1
(CH, C-5′), 131.9 (CH, C-3′), 121.1 (C, C-2′), 120.3 (CH,
C-4′), 114.8 (CH, C-6′), 70.4 (CH2, C-1), 68.4 (CH, C-2),
52.3 (CH3, COOCH3).
1,3-Bis(3-methoxyphenoxy)propan-2-ol (1k)
Using the general procedure above and the work up method
2, colorless oil was obtained in 93% yield; IR (ATR) vmax
3436, 3071, 2938, 2876, 2835, 1590, 1491, 1449, 1264,
1
1147, 1035, 759, 684 cm−1; H NMR (CDCl3, 200 MHz):
δ = 7.25–7.16 (2H, m, H-5′), 6.58–6.53 (6H, m, H-2′, H-4′,
H-6′), 4.40 (1H, asx, J = 5.2 Hz, H-2), 4.17 (2H, dd,
J = 9.6, 4.6 Hz, H-1a), 4.12 (2H, dd, J = 9.6, 6.0 Hz, H-1b),
3.80 (6H, s, OCH3), 2.70 (1H, d, J = 5.2 Hz, OH); 13C
NMR (CDCl3, 50 MHz): δ = 161.0 (C, C-3′), 159.8 (C, C-
1′), 130.2 (CH, C-5′), 107.1 (CH, C-2′), 106.8 (CH, C-4′),
101.3 (CH, C-6′), 68.9 (CH2, CH, C-1, C-2), 55.5
(CH3, OCH3).
1,3-Bis(3-methoxycarbonylphenoxy)propan-2-ol (1h)
Using the general procedure above and the work up method
2, colorless oil was obtained in 40% yield. IR (ATR) vmax
3485, 3077, 2951, 1716, 1585, 1488, 1274, 1099, 796, 731
cm−1 1H NMR (Acetone-d6, 200 MHz): δ = 7.48–7.44
;

Med Chem Res
1,3-Bis(4-methoxyphenoxy)propan-2-ol (1l)
50 MHz): δ = 156.5 (C, C-1′), 130.7 (C, C-4′), 130.2 (CH,
C-3′, C-5′), 114.6 (CH, C-2′, C-6′), 69.1 (CH, CH2, C-1, C-
2), 20.7 (CH3, CH3).
Using the general procedure above and the work up method
2, a white solid was obtained in 89% yield; mp: 91.1–92.7 °
C; IR (ATR) vmax 3492, 3105, 3069, 2954, 2939, 2880,
1,3-Bis(2-chlorophenoxy)propan-2-ol (1p)
2837, 1505, 1455, 1220, 1116, 1032, 826 cm−1; H NMR
1
(Acetone-d6, 200 MHz): δ = 6.89–6.86 (8H, m, H-2′, H-3′,
H-5′, H-6′), 4.42 (1H, d, J = 4.8 Hz, OH), 4.30–4.20 (1H,
m, H-2), 4.11 (2H, dd, J = 9.6, 4.0 Hz, H-1a), 4.04 (2H, dd,
J = 9.6, 5.6 Hz, H-1b), 3.73 (6H, s, OCH3); 13C NMR
(Acetone-d6, 50 MHz): δ = 155.1 (C, C-1′), 154.1 (C, C-4′),
116.4 (CH, C-6′), 115.5 (CH, C-5′), 71.0 (CH2, C-1), 69.5
(CH, C-2), 55.9 (CH3, OCH3).
Using the general procedure above and the work up method
3, a white solid was obtained in 45% yield; mp: 47.1–48.4 °
C. IR (ATR) vmax 3407, 3068, 2942, 2879, 1589, 1484,
1446, 1245, 1132, 1038, 743 cm−1; 1H NMR (CDCl3, 200
MHz): δ = 7.36–7.17 (4H, m, H-3′, H-5′), 6.99–6.91 (4H,
m, H-4′, H-6′), 4.46 (1H, s, H-2), 4.26 (4H, s, H-1), 2.90
(1H, s, OH); 13C NMR (CDCl3, 50 MHz): δ = 154.1 (C, C-
1′), 130.5 (CH, C-3′), 128.1 (CH, C-5′), 123.2 (C, C-2′),
122.3 (CH, C-4′), 114.1 (CH, C-6′), 69.8 (CH2, C-1), 68.7
(CH, C-2).
1,3-Bis(2-methylphenoxy)propan-2-ol (1m)
Using the general procedure above and the work up method
2, colorless oil was obtained in 77% yield; IR (ATR) vmax
3410, 3026, 2926, 2875, 1602, 1590, 1493, 1459, 1238,
1120, 1037, 745 cm−1; 1H NMR (Acetona-d6, 200 MHz): δ
= 7.14–7.10 (4H, m, H-3′, H-5′), 6.98–6.80 (4H, m, H-4′,
H-6′); 4.48–4.36 (2H, m, H-2, OH), 4.24 (2H, dd, J = 9.6,
4.6 Hz, H-1a), 4.17 (2H, dd, J = 9.6, 5.2 Hz, H-1b), 2.20
(6H, s, CH3); 13C NMR (Acetone-d6, 50 MHz): δ = 158.0
(C, C-1′), 131.4 (CH, C-3′), 127.8 (CH, C-5′), 127.3 (C, C-
2′), 121.3 (CH, C-4′), 112.1 (CH, C-6′), 70.3 (CH, C-2),
69.6 (CH2, C-1), 16.4 (CH3, CH3).
1,3-Bis(3-chlorophenoxy)propan-2-ol (1q)
Using the general procedure above and the work up method
3, colorless oil was obtained in 40% yield. IR (ATR) vmax
3399, 3070, 2937, 2879, 1593, 1579, 1477, 1228, 1093,
1
1040, 764, 678 cm−1; H NMR (CDCl3, 200 MHz): δ =
7.20 (2H, t, J = 8.0 Hz, H-5′), 6.97–6.93 (4H, m, H-2′, H-
4′), 6.83–6.79 (2H, m, H-6′), 4.37 (1H, s, H-2), 4.12 (4H, s,
H-1), 2.62 (1H, s, OH); 13C NMR (CDCl3, 50 MHz): δ =
159.2 (C, C-1′), 135.2 (C, C-3′), 130.5 (CH, C-5′), 121.7
(CH, C-4′), 115.2 (CH, C-2′), 113.2 (CH, C-6′), 69.0 (CH2,
C-1), 68.73 (CH, C-2).
1,3-Bis(3-methylphenoxy)propan-2-ol (1n)
Using the general procedure above and the work up method
2, colorless oil was obtained in 92% yield; IR (ATR) vmax
3404, 3037, 2923, 2874, 1601, 1584, 1488, 1454, 1254,
1,3-Bis(4-chlorophenoxy)propan-2-ol (1r)
Using the general procedure above and the work up method
3, a white solid was obtained in 45% yield; mp: 85.9–87.2 °
C (lit. 87–89 °C); IR (ATR) vmax 3525, 3068, 2928, 2872,
1
1157, 1044, 767, 688 cm−1; H NMR (CDCl3, 200 MHz):
δ = 7.20 (2H, t, J = 7.8 Hz, H-5‘), 6.84–6.75 (6H, m, H-2′,
H-4′, H-6′), 4.40 (1H, asx, J = 5.2 Hz, H-2), 4.16 (2H, d, J
= 4.6 Hz, H-1a), 4.16 (2H, d, J = 6.2 Hz, H-1b), 2.73 (1H,
d, J = 5.0 Hz, OH), 2.36 (6H, s, CH3); 13C NMR (CDCl3,
50 MHz): δ = 158.6 (C, C-1′), 139.8 (C, C-3′), 129.5 (CH,
C-5′), 122.3 (CH, C-4′), 115.6 (CH, C-2′), 111.6 (CH, C-6′),
69,0 (CH, C-2), 68.8 (CH2, C-1), 21.7 (CH3, CH3).
1594, 1580, 1488, 1448, 1232, 1120, 1008, 817 cm−1; H
1
NMR (CDCl3, 200 MHz): δ = 7.24 (4H, d, J = 9.0 Hz, H-
3′, H-5′), 6.86 (4H, d, J = 9.0 Hz, H-2′, H-6′), 4.41–4.31
(1H, m, H-2), 4.11 (4H, d, J = 4.6 Hz, H-1), 2.61 (1H, d, J
= 5.0 Hz, OH); 13C NMR (CDCl3, 50 MHz): δ = 157.2 (C,
C-1′), 126.7 (CH, C-3′, C-5′), 126.5 (C, C-4′), 116.0 (CH,
C-2′, C-6′), 69.2 (CH2, C-1), 68.9 (CH, C-2).
1,3-Bis(4-methylphenoxy)propan-2-ol (1o)
1,3-Bisphenoxypropan-2-ol (1s)
Using the general procedure above and the work up method
2, a pale yellow solid was obtained in 98% yield; mp:
79.6–81.1 °C (lit. 89–89.5 °C); IR (ATR) vmax 3514, 3068,
3027, 2983, 2947, 2923, 2860, 1609, 1585, 1509, 1230,
Using the general procedure above and the work up method
2, a pale yellow solid was obatined in 77% yield; mp:
77.8–79.0 °C (lit. 76–78 °C); IR (ATR) vmax 3514, 3065,
3040, 2944, 2873, 1597, 1586, 1495, 1228, 1116, 1034,
1
1118, 1013, 811 cm−1; H NMR (CDCl3, 200 MHz): δ =
7.08 (4H, d, J = 8.2 Hz, H-3′, H-5′), 6.82 (4H, d, J = 8.2
Hz, H-2′, H-6′), 4.36 (1H, aq, J = 5.2 Hz, H-2), 4.13 (2H,
dd, J = 9.8, 4.6 Hz, H-1a), 4.08 (2H, dd, J = 9.8, 6.0 Hz, H-
1b), 2.67 (1H, s, OH), 2.28 (6H, s, CH3); 13C NMR (CDCl3,
749, 690 cm−1 1H NMR (CDCl3, 200 MHz): δ =
;
7.36–7.27 (4H, m, H-3′, H-5′), 7.04–6.94 (6H, m, H-2′, H-
4′, H-6′), 4.43 (1H, asx, J = 5.2 Hz, H-2), 4.21 (2H, dd, J =
10.0, 4.4 Hz, H-1a), 4.15 (2H, dd, J = 10.0, 5.8 Hz, H-1b),

Med Chem Res
2.74 (1H, d, J = 5.2 Hz, OH); 13C NMR (CDCl3, 50 MHz):
δ = 158.6 (C, C-1′), 129.8 (CH, C-3′, C-5′), 121.5 (CH, C-
4′), 114.7 (CH, C-2′, C-6′), 69.0 (CH, C-2), 68.8 (CH2, C-
1).
9.0 Hz, H-6′), 7.17 (2H, t, J = 7.6 Hz, H-4′), 5.50–5.41 (1H,
m, H-2), 4.76–4.61 (4H, m, H-1), 3.36 (3H, s, OSO2CH3);
13C NMR (Acetone-d6, 50 MHz): δ = 160.7 (C, C-1′),
135.8 (CH, C-5′), 134.7 (CH, C-3′), 122.8 (CH, C-4′), 116.9
(C, CN), 113.9 (CH, C-6′), 102.8 (C, C-2′), 78.4 (CH, C-2),
68.9 (CH2, C-1), 38.6 (CH3, OSO2CH3).
1,3-bis(naphthalen-1-yloxy)propan-2-ol (1t)
Using the general procedure above and the work up method
3, a pale brown solid was obatined in 54% yield; mp:
63.4–64.7 °C (lit. 77–78 °C); IR (ATR) vmax 3450, 3053,
2998, 2927, 2876, 1595, 1578, 1508, 1461, 1238, 1098,
1,3-Bis(3-cyanophenoxy)propan-2-yl methanesulfonate (2b)
White solid, 75% yield; mp: 123.9–125.3 °C; IR (ATR)
vmax 3081, 3020, 2935, 2886, 2226, 1598, 1586, 1488,
1
1068 cm−1
;
1H NMR (CDCl3, 200 MHz): δ = 8.36–8.31
1456, 1343, 1329, 1170, 1257, 1049, 793, 678 cm−1; H
(2H, m, H-9′), 7.89–7.84 (2H, m, H-6′), 7.59–7.38 (8H, m,
H-3′, H-4′, H-7′, H-8′), 6.91 (2H, d, J = 7.4 Hz, H-2‘), 4.74
(1H, qn, J = 5.0 Hz, H-2), 4.46 (4H, d, J = 5.0 Hz, H-1),
2.73 (1H, s, OH); 13C NMR (CDCl3, 50 MHz): δ = 154.2
(C, C-1′), 134.7 (C, C-5′), 127.8 (CH, C-6′), 126.7 (CH, C-
7′), 126.0 (CH, C-8′), 125.6 (C, C-10′), 121.9 (CH, C-4′),
121.1 (CH, C-9′), 105.2 (CH, C-2′), 69.4 (CH2, C-1), 69.3
(CH, C-2).
NMR (CDCl3, 200 MHz): δ = 7.47–7.19 (8H, m, H-2′, H-
4′, H-5′, H-6′), 5.30–5.26 (1H, m, H-2), 4.38–4.36 (4H, m,
H-1), 3.16 (3H, s, OSO2CH3); 13C NMR (CDCl3, 50 MHz):
δ = 158.0 (C, C-1′), 130.9 (CH, C-5′), 125.9 (CH, C-4′),
119.7 (CH, C-6′), 118.5 (C, CN), 117.9 (CH, C-2′), 113.7
(C, C-3′), 76.9 (CH, C-2), 67.1 (CH2, C-1), 38.8 (CH3,
OSO2CH3).
1,3-Bis(4-cyanophenoxy)propan-2-yl methanesulfonate (2c)
1,3-Bis(naphthalen-2-yloxy)propan-2-ol (1u)
White solid, 88% yield; mp: 134.1–134.6 °C; IR (ATR)
vmax 3106, 3079, 3032, 2935, 2226, 1602, 1575, 1506,
Using the general procedure above and the work up method
3, a white solid was obtained in 65% yield; mp:
112.4–114.5 °C (lit. 91–92 °C); IR (ATR) vmax 3304, 3056,
2933, 1599, 1509, 1454, 1255, 1117, 1034 cm−1; 1H NMR
(CDCl3, 200 MHz): δ = 7.82–7.75 (6H, m, H-3′, H-5′, H-
8′), 7.53–7.37 (4H, m, H-6′, H-7′), 7.24 (4H, s, H-2′),
4.63–4.52 (1H, m, H-2), 4.42–4.29 (4H, m, H-1), 2.55 (1H,
s, OH); 13C NMR (CDCl3, 50 MHz): δ = 156.6 (C, C-1′),
134.7 (C, C-9′), 129.8 (CH, C-3′), 129.5 (C, C-4′), 127.9
(CH, C-5′), 127.0 (CH, C-8′), 126.7 (CH, C-7′), 124.1 (CH,
C-6′), 118.8 (CH, C-10′), 107.4 (CH, C-2′), 69.2 (CH2, C-
1), 69.1 (CH, C-2).
1459, 1345, 1171, 1249, 1040, 838 cm−1
;
1H NMR
(DMSO-d6, 200 MHz): δ = 7.80 (4H, d, J = 8.6 Hz, H-3′,
H-5′), 7.19 (4H, d, J = 8.6 Hz, H-2′, H-6′), 5.31 (1H, s, H-
2), 4.50 (2H, dd, J = 11.3, 3.8 Hz, H-1a), 4.42 (2H, dd, J =
11.3, 6.0 Hz, H-1b), 3.36 (3H, s, OSO2CH3); 13C NMR
(DMSO-d6, 50 MHz): δ = 161.2 (C, C-1′), 134.3 (CH, C-3′,
C-5′), 119.0 (C, CN), 115.8 (CH, C-2′, C-6′), 103.6 (C, C-
4′), 77.5 (CH, C-2), 66.9 (CH2, C-1), 38.1 (CH3,
OSO2CH3).
1,3-Bis(2-nitrophenoxy)propan-2-yl methanesulfonate (2d)
General procedure for synthesis of compounds 2a–2u
Green solid, 92% yield; mp: 105.9–107.2 °C; IR (ATR)
vmax 3112, 3021, 2941, 2885, 1605, 1585, 1488, 1451,
1
Methanesulfonyl chloride (4.8 mmol; 0.37 mL) was added
dropwise to a solution of an alcohol derivative (1.2 mmol)
in pyridine (3 mL), under stirring in ice-bath. After 4 h, at
room temperature, crushed ice was added to the flask and
then concentrated HCl was added until pH 1. The product
was extracted with dichloromethane (3 × 30 mL). The
organic layer was washed with water (5 × 50 mL), dried,
filtered and concentrated.
1517, 1351, 1351, 1178, 1252, 1033, 743 cm−1; H NMR
(DMSO-d6, 200 MHz): δ = 7.92 (2H, d, J = 7.2 Hz, H-3′),
7.70 (2H, t, J = 7.2 Hz, H-5′), 7.42 (2H, d, J = 8.2 Hz, H-
6′), 7.17 (2H, t, J = 7.4 Hz, H-4′), 5.36 (1H, s, H-2), 4.55
(4H, s, H-1), 3.28 (3H, s, OSO2CH3); 13C NMR (DMSO-
d6, 50 MHz): δ = 150.6 (C, C-1′), 139.4 (C, C-2′), 134.9
(CH, C-5′), 125.3 (CH, C-3′), 121.4 (CH, C-4′), 115.1 (CH,
C-6′), 76.9 (CH, C-2), 67.8 (CH2, C-1), 37.0 (CH3,
OSO2CH3).
1,3-Bis(2-cyanophenoxy)propan-2-yl methanesulfonate (2a)
1,3-Bis(3-nitrophenoxy)propan-2-yl methanesulfonate (2e)
White solid, 83% yield; mp: 126.6–127.6 °C; IR (ATR)
vmax 3019, 2934, 2231, 1597, 1580, 1493, 1446, 1355,
Pale yellow solid, 86% yield; mp: 147.5–148.6 °C; IR
(ATR) vmax 3102, 3032, 2937, 1582, 1481, 1454, 1520,
1
1176, 1239, 1031, 759 cm−1; H NMR (Acetone-d6, 200
1
MHz): δ = 7.71–7.68 (4H, m, H-3′, H-5′), 7.35 (2H, d, J =
1342, 1342, 1177, 1243, 1027, 735, 669 cm−1; H NMR

Med Chem Res
(DMSO-d6, 200 MHz): δ = 7.88–7.83 (4H, m, H-2′, H-4′),
7.65–7.49 (4H, m, H-5′, H-6′), 5.34 (1H, s, H-2), 4.53
(4H, s, H-1), 3.34 (3H, s, OSO2CH3); 13C NMR (DMSO-
d6, 50 MHz): δ = 158.4 (C, C-1′), 148.7 (C, C-3′), 130.9
(CH, C-5′), 122.1 (CH, C-4′), 116.2 (CH, C-6′), 109.2 (CH,
C-2′), 77.6 (CH, C-2), 67.3 (CH2, C-1), 38.1 (CH3,
OSO2CH3).
1,3-Bis(4-methoxycarbonylphenoxy)propan-2-yl
methanesulfonate (2i)
White solid, 90% yield; mp: 148.9–150.1 °C; IR (ATR)
vmax 3013, 2955, 1716, 1604, 1581, 1509, 1341, 1165,
1284, 1165, 1245, 1018, 843 cm−1; 1H NMR (CDCl3, 200
MHz): δ = 7.98 (4H, d, J = 8.0 Hz, H-3‘, H-5‘), 7.13 (4H, d,
J = 8.0 Hz, H-2′, H-6′), 5.37 (1H, s, H-2), 4.56 (4H, s, H-1),
3.84 (6H, s, COOCH3), 3.28 (3H, s, OSO2CH3); 13C NMR
(CDCl3, 50 MHz): δ = 166.9 (C, COOCH3), 163.0 (C, C-
1′), 132.4 (CH, C-3′, C-5′), 124.3 (C, C-4′), 115.4 (CH, C-
2′, C-6′), 78.9 (CH, C-2), 68.0 (CH2, C-1), 52.2 (CH3,
COOCH3), 38.7 (CH3, OSO2CH3).
1,3-Bis(4-nitrophenoxy)propan-2-yl methanesulfonate (2f)
Pale yellow solid, 99% yield; mp: 153.4–155.0 °C; IR
(ATR) vmax 1608, 1592, 1497, 1455, 1508, 1341, 1341,
1
1176, 1263, 1046, 846 cm−1; H NMR (Acetone-d6, 200
MHz): δ = 8.25 (4H, d, J = 8.6 Hz, H-3′, H-5′), 7.26 (4H, d,
J = 8.6 Hz, H-2′, H-6′), 5.44 (1H, s, H-2), 4.67 (4H, s, H-1),
3.31 (3H, s, OSO2CH3); 13C NMR (Acetone-d6, 50 MHz):
δ = 164.2 (C, C-1′), 143.0 (C, C-4′), 126.7 (CH, C-3′, C-5′),
116.0 (CH, C-2′, C-6′), 78.5 (CH, C-2), 68.5 (CH2, C-1),
38.7 (CH3, OSO2CH3).
1,3-Bis(2-methoxyphenoxy)propan-2-yl methanosulfonate
(2j)
Colorless oil, 87% yield; IR (ATR) vmax 3065, 3032, 2937,
2837, 1591, 1504, 1454, 1351, 1171, 1252, 1024, 739
cm−1 1H NMR (Acetone-d6, 200 MHz): δ = 7.07–6.86
;
(8H, m, H-3′, H-4′, H-5′, H-6′), 5.26 (1H, qn, J = 5.0 Hz, H-
2), 4.39 (4H, d, J = 5.0 Hz, H-1), 3.82 (6H, s, OCH3), 3.33
(3H, s, OSO2CH3); 13C NMR (Acetone-d6, 50 MHz): δ =
150.9 (C, C-1‘), 149.0 (C, C-2′), 123.1 (CH, C-5′), 121.8
(CH, C-4′), 115.4 (CH, C-6′), 113.37 (CH, C-3′), 80.1 (CH,
C-2), 69.4 (CH2, C-1), 56.2 (CH3, OCH3), 38.6 (CH3,
OSO2CH3).
1,3-Bis(2-methoxycarbonylphenoxy)propan-2-yl
methanesulfonate (2g)
Colorless oil, 86% yield; IR (ATR) vmax 3029, 2951,
1720, 1600, 1583, 1491, 1448, 1356, 1173, 1243, 1173,
1243, 1032, 753 cm−1 1H NMR (CDCl3, 200 MHz):
;
δ = 7.81 (2H, d, J = 7.8 Hz, H-3′), 7.53–7.45 (2H, m,
H-5′), 7.07–7.00 (6H, m, H-4′, H-6′), 5.36–5.31 (1H, m,
H-2), 4.48 (4H, d, J = 4.8 Hz, H-1), 3.84 (6H, s,
COOCH3), 3.21 (3H, s, OSO2CH3); 13C NMR (CDCl3,
50 MHz): δ = 166.3 (C, COOCH3), 157.4 (C, C-1′),
133.8 (CH, C-3′), 132.0 (CH, C-5′), 121.6 (CH, C-4′),
121.0 (C, C-2′), 114.1 (CH, C-6′), 78.1 (CH, C-2),
68.4 (CH2, C-1), 52.1 (CH3, COOCH3); 38.5 (CH3,
OSO2CH3).
1,3-Bis(3-methoxyphenoxy)propan-2-yl methanosulfonate
(2k)
Colorless oil, 98% yield; IR (ATR) vmax 3033, 2939, 2837,
1590, 1492, 1450, 1355, 1336, 1171, 1150, 1265, 1034,
1
760, 685 cm−1; H NMR (Acetone-d6, 200 MHz): δ = 7.21
(2H, t, J = 8.2 Hz, H-5′), 6.61–6.55 (6H, m, H-2′, H-4′, H-
6′), 5.26 (1H, qn, J = 5.0 Hz, H-2), 4.40 (4H, d, J = 5.0 Hz,
H-1), 3.78 (6H, s, OCH3), 3.25 (3H, s, OSO2CH3); 13C
NMR (Acetone-d6, 50 MHz): δ = 162.1 (C, C-3′), 160.5 (C,
C-1′), 131.0 (CH, C-5′), 108.1 (CH, C-6′), 107.6 (CH, C-4′),
101.9 (CH, C-2′), 79.4 (CH, C-2), 67.9 (CH2, C-1), 55.7
(CH3, OCH3), 38.7 (CH3, OSO2CH3).
1,3-Bis(3-methoxycarbonylphenoxy)propan-2-yl
methanesulfonate (2h)
Colorless oil, 90% yield; IR (ATR) vmax 3023, 2952, 1716,
1,3-Bis(4-methoxyphenoxy)propan-2-yl methanosulfonate
1586, 1488, 1357, 1173, 1274, 1173, 1221, 1037, 793, 731
(2l)
1
cm−1; H NMR (CDCl3, 200 MHz): δ = 7.69 (2H, d, J =
7.4 Hz, H-4′), 7.59 (2H, s, H-2′), 7.38 (2H, t, J = 7.8 Hz, H-
5′), 7.14 (2H, d, J = 7.8 Hz, H-6′), 5.31–5.26 (1H, m, H-2),
4.39 (4H, d, J = 4.6 Hz, H-1), 3.92 (6H, s, COOCH3), 3.18
(3H, s, OSO2CH3); 13C NMR (CDCl3, 50 MHz): δ = 166.8
(C, COOCH3), 158.1 (C, C-1′), 132.0 (C, C-3′), 129.9 (CH,
C-5′), 123.3 (CH, C-4′), 119.9 (CH, C-6′), 115.2 (CH, C-2′),
77.8 (CH, C-2), 67.3 (CH2, C-1), 52.4 (CH3, COOCH3),
38.8 (CH3, OSO2CH3).
Colorless oil, 96% yield; IR (ATR) vmax 3045, 2937, 2835,
1
1505, 1458, 1354, 1171, 1221, 1030, 822 cm−1; H NMR
(CDCl3, 200 MHz): δ = 6.86 (8H, s, H-2‘, H-3‘, H-5‘, H-6‘),
5.21 (1H, qn, J = 5.2 Hz, H-2), 4.28 (4H, d, J = 5.2 Hz, H-
1), 3.78 (6H, s, OCH3), 3.16 (3H, s, OSO2CH3); 13C NMR
(CDCl3, 50 MHz): δ = 154.6 (C, C-4′), 152.2 (C, C-1′),
115.8 (CH, C-2′), 115.0 (CH, C-5′), 78.8 (CH, C-2), 68.0
(CH2, C-1), 55.9 (CH3, OCH3), 38.7 (CH3, OSO2CH3).

Med Chem Res
1,3-Bis(2-methylphenoxy)propan-2-yl methanesulfonate
(C, C-2′), 122.8 (CH, C-4′), 114.0 (CH, C-6′), 78.0 (CH,
(2m)
C-2), 68.2 (CH2, C-1), 38.7 (CH3, OSO2CH3).
Yellow solid, 85% yield; mp: 53.1–57.2 °C; IR (ATR) vmax
3032, 2985, 2936, 2888, 1601, 1589, 1495, 1455, 1349,
1171, 1240, 1023, 748 cm−1; 1H NMR (CDCl3, 200 MHz):
δ = 7.27–7.17 (4H, m, H-3′, H-5′), 6.98–6.86 (4H, m, H-4′,
H-6′), 5.37–5.32 (1H, m, H-2), 4.39 (2H, d, J = 5.0 Hz, H-
1a), 4.38 (2H, d, J = 3.0 Hz, H-1b), 3.15 (3H, s, OSO2CH3),
2.27 (6H, s, CH3); 13C NMR (CDCl3, 50 MHz): δ = 156.3
(C, C-1′), 131.2 (CH, C-3′), 127.2 (CH, C-5′), 127.0 (C, C-
2′), 121.7 (CH, C-4′), 111.5 (CH, C-6′), 78.5 (CH, C-2),
67.3 (CH2, C-1), 38.7 (CH3, OSO2CH3), 16.4 (CH3, CH3).
1,3-Bis(3-chlorophenoxy)propan-2-yl methanesulfonate
(2q)
White solid, 86% yield; mp: 62.4–64.0 °C; IR (ATR) vmax
3073, 3032, 2939, 2880, 1592, 1582, 1478, 1456, 1355,
1
1173, 1228, 1036, 766, 677 cm−1; H NMR (CDCl3, 200
MHz): δ = 7.24 (2H, t, J = 8.0 Hz, H-5′), 7.02–6.93 (4H, m,
H-2′, H-4′), 6.85–6.80 (2H, m, H-6′), 5.24 (1H, qn, J = 5.2
Hz, H-2), 4.32 (4H, d, J = 5.2 Hz, H-1), 3.16 (3H, s,
OSO2CH3); 13C NMR (CDCl3, 50 MHz): δ = 158.7 (C, C-
1′), 135.4 (C, C-3′), 130.7 (CH, C-5′), 122.3 (CH, C-4′),
115.4 (CH, C-2′), 113.1 (CH, C-6′), 77.6 (CH, C-2), 67.2
(CH2, C-1), 38.73 (CH3, OSO2CH3).
1,3-Bis(3-methylphenoxy)propan-2-yl methanesulfonate
(2n)
1,3-Bis(4-chlorophenoxy)propan-2-yl methanesulfonate
(2r)
Colorless oil, 73% yield; IR (ATR) vmax 3032, 2936, 1602,
1584, 1489, 1454, 1356, 1171, 1158, 1255, 1039, 771, 688
1
cm−1; H NMR (CDCl3, 200 MHz): δ = 7.21 (2H, t, J =
White solid, 91% yield; mp: 89.6–91.5 °C; IR (ATR) vmax
7.4 Hz, H-5′), 6.86–6.73 (6H, m, H-2′, H-4′, H-6′),
5.28–5.20 (1H, m, H-2), 4.33 (4H, d, J = 5.0 Hz, H-1), 3.17
(3H, s, OSO2CH3), 2.36 (6H, s, CH3); 13C NMR (CDCl3,
50 MHz): δ = 158.2 (C, C-1′), 140.0 (C, C-3′), 129.6 (CH,
C-5′), 122.8 (CH, C-4′), 115.7 (CH, C-2′), 111.7 (CH, C-6′),
78.6 (CH, C-2), 67.2 (CH2, C-1), 38.7 (CH3, OSO2CH3),
21.7 (CH3, CH3).
3043, 2939, 1594, 1583, 1489, 1454, 1346, 1173, 1235,
1052, 816 cm−1 1H NMR (CDCl3, 200 MHz): δ = 7.26
;
(4H, s, H-3′, H-5′), 6.88 (4H, d, J = 6.8 Hz, H-2′, H-6′),
5.24 (1H, s, H-2), 4.32 (4H, d, J = 4.6 Hz, H-1), 3.16 (3H,
s, OSO2CH3); 13C NMR (CDCl3, 50 MHz): δ = 156.6 (C,
C-1′), 129.8 (CH, C-3′, C-5′), 127.0 (C, C-4′), 116.1 (CH,
C-2′, C-6′), 77.8 (CH, C-2), 67.4 (CH2, C-1), 38.7 (CH3,
OSO2CH3).
1,3-Bis(4-methylphenoxy)propan-2-yl methanesulfonate
(2o)
1,3-Bisphenoxypropan-2-yl methanesulfonate (2s)
White solid, 96% yield; mp: 48.1–49.7 °C; IR (ATR) vmax
Colorless oil, 77% yield; IR (ATR) vmax 3032, 2937, 2882,
1598, 1588, 1493, 1456, 1354, 1171, 1232, 1036, 750, 689
cm−1; 1H NMR (CDCl3, 200 MHz): δ = 7.36–7.28 (4H, m,
H-3′, H-5′), 7.05–6.95 (6H, m, H-2′, H-4′, H-6′), 5.29 (1H,
qn, J = 5.2 Hz, H-2), 4.45 (2H, dd, J = 11.0, 4.4 Hz, H-1a),
4.40 (2H, dd, J = 11.0, 5.4 Hz, H-1b), 3.25 (3H, s,
OSO2CH3); 13C NMR (CDCl3, 50 MHz): δ = 159.3 (C,
C-1′), 130.5 (CH, C-3′, C-5′), 122.3 (CH, C-4′), 115.5 (CH,
C-2′, C-6′), 79.5 (CH, C-2), 67.8 (CH2, C-1), 38.7 (CH3,
OSO2CH3).
3031, 2925, 2876, 1586, 1508, 1456, 1355, 1172, 1231,
1035, 804 cm−1 1H NMR (CDCl3, 200 MHz): δ = 7.13
;
(4H, d, J = 8.0 Hz, H-3′, H-5′), 6.84 (4H, d, J = 8.0 Hz, H-
2′, H-6′), 5.27–5.19 (1H, m, H-2), 4.31 (4H, d, J = 5.0 Hz,
H-1), 3.16 (3H, s, OSO2CH3), 2.32 (6H, s, CH3); 13C NMR
(CDCl3, 50 MHz): δ = 156.1 (C, C-1′), 131.2 (C, C-4′),
130.3 (CH, C-3′, C-5′), 114.7 (CH, C-2′, C-6′), 78.7 (CH,
C-2), 67.4 (CH2, C-1), 38.7 (CH3, OSO2CH3), 20.6
(CH3, CH3).
1,3-Bis(2-chlorophenoxy)propan-2-yl methanesulfonate
1,3-Bis(naphthalen-1-yloxy)propan-2-yl methanesulfonate
(2p)
(2t)
White solid, 90% yield; mp: 74.8–75.2 °C; IR (ATR) vmax
Rosaceous solid, 50% yield; mp: 94.3–95.8 °C; IR (ATR)
vmax 3054, 2944, 2880, 1597, 1579, 1508, 1450, 1344,
3031, 2957, 1589, 1578, 1486, 1448, 1362, 1176, 1169,
1
1
1247, 1037, 750 cm−1; H NMR (CDCl3, 200 MHz): δ =
1170, 1239, 1066 cm−1; H NMR (CDCl3, 200 MHz): δ =
7.41–7.23 (4H, m, H-3‘, H-5‘), 7.03–6.94 (4H, m, H-4′, H-
6′), 5.34–5.29 (1H, m, H-2), 4.45 (4H, d, J = 5.2 Hz, H-1),
3.29 (1H, s, OSO2CH3); 13C NMR (CDCl3, 50 MHz): δ =
153.7 (C, C-1′), 130.8 (CH, C-3′), 128.2 (CH, C-5′), 123.2
8.34 (2H, d, J = 5.0 Hz, H-9′), 7.85 (2H, d, J = 5.2 Hz, H-
6′), 7.56–7.38 (8H, m, H-3′, H-4′, H-7′, H-8′), 6.89 (2H, d,
J = 7.2 Hz, H-2′), 5.67–5.65 (1H, m, H-2), 4.61 (4H, d, J =
4.6 Hz, H-1), 3.16 (3H, s, OSO2CH3); 13C NMR (CDCl3,

Med Chem Res
50 MHz): δ = 153.8 (C, C-1′), 134.8 (C, C-5′), 127.8 (CH,
C-6′), 126.8 (CH, C-7′), 125.9 (CH, C-8′), 125.7 (C, C-10′),
121.8 (CH, C-4′), 121.7 (CH, C-9′), 105.5 (CH, C-2′), 78.0
(CH, C-2), 67.6 (CH2, C-1), 38.9 (CH3, OSO2CH3).
1,3-Bis(4-cyanophenoxy)propan-2-yl azide (3c)
White solid, 60% yield after recrystalization from iso-
propanol; mp: 111.8–112.7 °C; IR (ATR) vmax 3098, 2941,
2883, 2221, 2136, 2077, 1604, 1577, 1505, 1461, 1249,
1015, 834 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ = 7.80
(4H, d, J = 8.6 Hz, H-3‘, H-5‘), 7.17 (4H, d, J = 8.6 Hz, H-
2′, H-6′), 4.42–4.24 (5H, m, H-1, H-2); 13C NMR (DMSO-
d6, 50 MHz): δ = 161.3 (C, C-1′), 134.3 (CH, C-3′, C-5′),
119.0 (C, CN), 115.7 (CH, C-2′, C-6′), 103.5 (C, C-4′), 67.5
(CH2, C-1), 58.8 (CH, C-2).
1,3-Bis(naphthalen-2-yloxy)propan-2-yl methanesulfonate
(2u)
White solid, 93% yield; mp: 88.1–90.5 °C; IR (ATR) vmax
3057, 2936, 2878, 1599, 1509, 1468, 1455, 1352, 1171,
1254, 1035 cm−1
;
1H NMR (CDCl3, 200 MHz): δ =
7.82–7.75 (6H, m, H-3′, H-5′, H-8′), 7.53–7.36 (4H, m, H-
6′, H-7′), 7.27–7.16 (4H, m, H-2′, H-10′), 5.41 (1H, qn, J =
5.2 Hz, H-2), 4.51 (4H, d, J = 5.2 Hz, H-1), 3.22 (3H, s,
OSO2CH3); 13C NMR (CDCl3, 50 MHz): δ = 156.0 (C, C-
1′), 134.6 (C, C-9′), 130.0 (C, C-4′), 129.7 (CH, C-3′),
127.9 (CH, C-5′), 127.1 (CH, C-8′), 126.9 (CH, C-7′), 124.4
(CH, C-6′), 118.5 (CH, C-2′), 107.6 (CH, C-10′), 78.3 (CH,
C-2), 67.3 (CH2, C-1), 38.8 (CH3, OSO2CH3).
1,3-Bis(2-nitrophenoxy)propan-2-yl azide (3d)
Green solid, 74% yield after recrystalization from iso-
propanol; mp: 96.1–96.6 °C; IR (ATR) vmax 3081, 2932,
2140, 2081, 1605, 1582, 1488, 1448, 1516, 1344, 1251,
1010, 742 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ = 7.91
(2H, dd, J = 8.0, 1.4 Hz, H-3′), 7.69 (2H, m, H-5′), 7.41
(2H, d, J = 8.4 Hz, H-6′), 7.17 (2H, t, J = 8.0 Hz, H-4′),
4.51–4.37 (5H, m, H-1, H-2); 13C NMR (DMSO-d6, 50
MHz): δ = 150.7 (C, C-1′), 139.4 (C, C-2′), 134.7 (CH, C-
5′), 125.2 (CH, C-3′), 121.3 (CH, C-4′), 115.1 (CH, C-6′),
68.3 (CH2, C-1), 58.7 (CH, C-2).
General procedure for synthesis of compounds 3a–3u
To a stirred solution of methanesulfonate (0.8 mmol) in
DMF (3 mL) at 80 °C was added sodium azide (8 mmol).
After 24 h, crushed ice was added to the flask. The product
was extracted with dichloromethane (3 × 30 mL). The
organic layer was washed with water (5 × 50 mL), dried,
filtered, and concentrated.
1,3-Bis(3-nitrophenoxy)propan-2-yl azide (3e)
Pale brown solid, 96% yield; mp: 119.4–120.6 °C; IR
(ATR) vmax 3101, 2942, 2148, 2089, 1621, 1582, 1485,
1467, 1513, 1357, 1347, 1239, 1018, 791, 734 cm−1; H
1
1,3-Bis(2-cyanophenoxy)propan-2-yl azide (3a)
NMR (DMSO-d6, 200 MHz): δ = 7.87–7.78 (4H, m, H-2′,
H-4′), 7.61 (2H, t, J = 8.0 Hz, H-5′), 7.48 (2H, d, J = 8.0
Hz, H-6′), 4.48–4.33 (5H, m, H-1, H-2); 13C NMR (DMSO-
d6, 50 MHz): δ = 158.5 (C, C-1′), 148.7 (C, C-3′), 130.9
(CH, C-5′), 122.1 (CH, C-4′), 116.2 (CH, C-6′), 108.9 (CH,
C-2′), 67.9 (CH2, C-1), 59.0 (CH, C-2).
White solid, 84% yield; mp: 83.8–84.6 °C; IR (ATR) vmax
3079, 2939, 2884, 2227, 2104, 1598, 1580, 1491, 1449,
1
1253, 1045, 1022, 750 cm−1; H NMR (Acetone-d6, 200
MHz): δ = 7.71–7.66 (4H, m, H-3′, H-5′), 7.36–7.12 (4H,
m, H-4′, H-6′), 4.62–4.51 (5H, m, H-1, H-2); 13C NMR
(Acetone-d6, 50 MHz): δ = 160.8 (C, C-1′), 135.7 (CH, C-
5′), 134.7 (CH, C-3′), 122.7 (CH, C-4′), 116.6 (C, CN),
113.9 (CH, C-6′), 102.9 (C, C-2′), 69.0 (CH2, C-1), 60.3
(CH, C-2).
1,3-Bis(4-nitrophenoxy)propan-2-yl azide (3f)
White solid, 84% yield; mp: 116.7–117.9 °C; IR (ATR)
vmax 3112, 3085, 2933, 2109, 1608, 1590, 1496, 1455,
1507, 1338, 1248, 1033, 854, 842 cm−1; 1H NMR (DMSO-
d6, 200 MHz): δ = 8.23 (4H, d, J = 9.2 Hz, H-3′, H-5′), 7.21
(4H, d, J = 9.2 Hz, H-2′, H-6′), 4.49–4.35 (5H, m, H-1, H-
2); 13C NMR (DMSO-d6, 50 MHz): δ = 163.1 (C, C-1′),
141.3 (C, C-4′), 126.0 (CH, C-3′, C-5′), 115.2 (CH, C-2′, C-
6′), 68.0 (CH2, C-1), 58.9 (CH, C-2).
1,3-Bis(3-cyanophenoxy)propan-2-yl azide (3b)
White solid, 82% yield after recrystalization from iso-
propanol; mp: 84.1–84.5 °C; IR (ATR) vmax 3076, 2942,
2883, 2232, 2151, 2089, 1595, 1492, 1464, 1255, 1024,
789, 677 cm−1 1H NMR (Acetone-d6, 200 MHz): δ =
;
7.58–7.35 (8H, m, H-2′, H-4′, H-5′, H-6′), 4.51–4.39 (5H,
m, H-1, H-2); 13C NMR (Acetone-d6, 50 MHz): δ = 159.6
(C, C-1′), 131.8 (CH, C-5′), 126.0 (CH, C-4′), 121.1 (CH,
C-6′), 119.1 (C, CN), 118.4 (CH, C-2′), 114.2 (C, C-3′),
68.8 (CH2, C-1), 60.5 (CH, C-2).
1,3-Bis(2-methoxycarbonylphenoxy)propan-2-yl azide (3g)
Colorless oil, 82% yield; IR (ATR) vmax 3028, 2951, 2104,
1720, 1600, 1583, 1491, 1448, 1243, 1174, 1243, 1049,
1032, 753 cm−1 1H NMR (CDCl3, 200 MHz): δ = 7.82
;

Med Chem Res
(2H, dd, J = 8.0, 1.8 Hz, H-3′), 7.51–7.43 (2H, m, H-5′),
7.06–7.01 (4H, m, H-4′, H-6′), 4.39–4.21 (5H, m, H-1, H-
2), 3.86 (6H, s, COOCH3); 13C NMR (CDCl3, 50 MHz): δ
= 166.7 (C, COOCH3), 157.8 (C, C-1′), 133.7 (CH, C-5′),
132.1 (CH, C-3′), 121.3 (CH, C-4′), 120.9 (C, C-2′), 113.7
(CH, C-6′), 68.3 (CH2, C-1), 58.6 (CH, C-2), 52.2 (CH3,
COOCH3).
4.27 (5H, s, H-1, H-2), 3.77 (6H, s, OCH3); 13C NMR
(CDCl3, 50 MHz): δ = 162.1 (C, C-3′), 160.7 (C, C-1′),
131.0 (CH, C-5′), 107.9 (CH, C-6′), 107.6 (CH, C-4′), 101.9
(CH, C-2′), 68.4 (CH2, C-1), 60.8 (CH, C-2), 55.7 (CH3,
OCH3).
1,3-Bis(4-methoxyphenoxy)propan-2-yl azide (3l)
1,3-Bis(3-methoxycarbonylphenoxy)propan-2-yl azide (3h)
White solid, 83% yield; mp: 43.7–45.1 °C; IR (ATR) vmax
3064, 2936, 2836, 2152, 2108, 1592, 1504, 1468, 1455,
1221, 1208, 1036, 1024, 825 cm−1; 1H NMR (CDCl3, 200
MHz): δ = 6.87 (8H, s, H-2′, H-3′, H-5′, H-6′), 4.20–4.11
(5H, m, H-1, H-2), 3.79 (6H, s, OCH3); 13C NMR (CDCl3,
50 MHz): δ = 154.6 (C, C-1′), 152.5 (C, C-4′), 115.9 (CH,
C-6′), 114.9 (CH, C-5′), 68.5 (CH2, C-1), 59.8 (CH, C-2),
55.9 (CH3, OCH3).
Colorless oil, 77% yield; IR (ATR) vmax 3075, 2951, 2879,
2098, 1716, 1586, 1488, 1273, 1099, 1218, 1030, 752, 680
1
cm−1; H NMR (CDCl3, 200 MHz): δ = 7.69 (4H, d, J =
7.6 Hz, H-4′), 7.59 (2H, s, H-2′), 7.38 (2H, t, J = 8.0 Hz, H-
5′), 7.18–7.13 (2H, m, H-6′), 4.32–4.18 (5H, m, H-1, H-2);
3.93 (6H, s, COOCH3); 13C NMR (CDCl3, 50 MHz): δ =
166.9 (C, COOCH3), 158.2 (C, C-1′), 131.8 (C, C-3′), 129.8
(CH, C-5′), 123.1 (CH, C-4′), 120.2 (CH, C-6′), 114.8 (CH,
C-2′), 67.7 (CH2, C-1), 59.5 (CH, C-2), 52.5 (CH3,
COOCH3).
1,3-Bis(2-methylphenoxy)propan-2-yl azide (3m)
Colorless oil, 46% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99.5:0.5); IR
(ATR) vmax 3027, 2928, 2874, 2100, 1602, 1590, 1493,
1,3-Bis(4-methoxycarbonylphenoxy)propan-2-yl azide (3i)
1
1459, 1236, 1050, 1024, 746 cm−1; H NMR (Acetone-d6,
White solid, 88% yield; mp: 98.3–100.5 °C; IR (ATR) vmax
3008, 2956, 2146, 2093, 1716, 1705, 1605, 1510, 1470,
1284, 1167, 1244, 1016, 844 cm−1; 1H NMR (CDCl3, 200
MHz): δ = 8.01 (4H, d, J = 8.8 Hz, H-3′, H-5′), 6.96 (4H, d,
J = 8.8 Hz, H-2′, H-6′), 4.27–4.22 (5H, m, H-1, H-2), 3.89
(6H, s, COOCH3); 13C NMR (CDCl3, 50 MHz): δ = 166.8
(C, COOCH3), 161.8 (C, C-1′), 131.9 (CH, C-3′, C-5′),
123.7 (C, C-4′), 114.3 (CH, C-2′, C-6′), 67.6 (CH2, C-1),
59.4 (CH, C-2), 52.2 (CH3, COOCH3).
200 MHz): δ = 7.20–7.14 (4H, m, H-3′, H-5′), 7.00–6.84
(4H, m, H-4′, H-6′), 4.40–4.26 (5H, m, H-1, H-2), 2.24 (6H,
s, CH3); 13C NMR (Acetone-d6, 50 MHz): δ = 157.5 (C, C-
1′), 131.6 (CH, C-3′), 127.9 (CH, C-5′), 127.4 (C, C-2′),
121.9 (CH, C-4′), 112.1 (CH, C-6′), 68.5 (CH2, C-1), 61.3
(CH, C-2), 16.4 (CH3, CH3).
1,3-Bis(3-methylphenoxy)propan-2-yl azide (3n)
Colorless oil, 62% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99:1); IR (ATR)
vmax 3037, 2924, 2874, 2095, 1602, 1584, 1488, 1456,
1,3-Bis(2-methoxyphenoxy)propan-2-yl azide (3j)
Colorless oil, 85% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 95:5); IR (ATR)
vmax 3066, 3002, 2935, 2836, 2101, 1592, 1500, 1454,
1
1288, 1254, 1035, 768, 687 cm−1; H NMR (Acetone-d6,
200 MHz): δ = 7.18 (2H, t, J = 7.6 Hz, H-5′), 6.82–6.78
(6H, m, H-2′, H-4′, H-6′), 4.33–4.25 (5H, m, H-1, H-2),
2.30 (6H, s, CH3); 13C NMR (Acetone-d6, 50 MHz): δ =
159.5 (C, C-1′), 140.4 (C, C-3′), 130.2 (CH, C-5′), 122.9
(CH, C-4′), 116.3 (CH, C-2′), 112.5 (CH, C-6′), 68.3 (CH2,
C-1), 60.9 (CH, C-2), 21.5 (CH3, CH3).
1
1250, 1220, 1024, 739 cm−1; H NMR (Acetone-d6, 200
MHz): δ = 7.05–6.90 (8H, m, H-3′, H-4′, H-5′, H-6′),
4.32–4.22 (5H, m, H-1, H-2), 3.82 (6H, s, OCH3); 13C
NMR (Acetone-d6, 50 MHz): δ = 151.3 (C, C-1′), 149.2 (C,
C-2′), 123.2 (CH, C-4′), 121.8 (CH, C-5′), 116.2 (CH, C-6′),
113.7 (CH, C-3′), 69.9 (CH2, C-1), 61.3 (CH, C-2), 56.3
(CH3, OCH3).
1,3-Bis(4-methylphenoxy)propan-2-yl azide (3o)
1,3-Bis(3-methoxyphenoxy)propan-2-yl azide (3k)
White solid, 85% yield; mp: 46.3–48.7 °C; IR (ATR) vmax
3027, 2935, 2920, 2885, 2862, 2140, 2088, 1609, 1585,
1
Colorless oil, 57% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 95:5); IR (ATR)
vmax 3070, 2939, 2876, 2836, 2095, 1590, 1491, 1450,
1508, 1450, 1230, 1024, 804 cm−1; H NMR (Acetone-d6,
200 MHz): δ = 7.11 (4H, d, J = 7.8 Hz, H-3′, H-5′), 6.89
(4H, dd, J = 7.8, 1.4 Hz, H-2′, H-6′), 4.29–4.24 (5H, m, H-
1, H-2), 2.25 (6H, s, CH3); 13C NMR (Acetone-d6, 50
MHz): δ = 157.4 (C, C-1′), 131.2 (C, C-4′), 130.9 (CH,
1
1283, 1263, 1036, 759, 684 cm−1; H NMR (CDCl3, 200
MHz): δ = 7.20 (2H, s, H-5′), 6.57 (6H, s, H-2′, H-4′, H-6′),

Med Chem Res
C-3′, C-5′), 115.4 (CH, C-2′, C-6′), 68.5 (CH2, C-1), 60.9
1,3-Bis(naphthalen-1-yloxy)propan-2-yl azide (3t)
(CH, C-2), 20.6 (CH3, CH3).
Colorless oil, 78% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99.5:0.5); IR
(ATR) vmax 3053, 2929, 2873, 2092, 1594, 1577, 1507,
1,3-Bis(2-chlorophenoxy)propan-2-yl azide (3p)
1457, 1264, 1237, 1018 cm−1 1H NMR (CDCl3, 200
;
Colorless oil, 85% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99.5:0.5); IR
(ATR) vmax 3067, 2939, 2879, 2104, 1587, 1483, 1446,
MHz): δ = 8.41 (2H, s, H-9′), 7.93 (2H, s, H-6′), 7.61–7.52
(8H, m, H-3′, H-4′, H-7′, H-8′), 6.97 (2H, d, J = 7.0 Hz, H-
2′), 4.57 (5H, s, H-1, H-2), 13C NMR (CDCl3, 50 MHz): δ
= 154.0 (C, C-1′), 134.7 (C, C-5′), 127.8 (CH, C-6′), 126.8
(CH, C-7′), 125.8 (C, C-10′), 122.1 (CH, C-4′), 121.5 (CH,
C-9′), 105.1 (CH, C-2′), 68.1 (CH2, C-1), 60.2 (CH, C-2).
1
1243, 1039, 742 cm−1; H NMR (CDCl3, 200 MHz): δ =
7.42 (2H, dd, J = 8.4, 2.4 Hz, H-3′), 7.36–7.28 (2H, m, H-
5′), 7.20 (2H, dd, J = 8.4, 1.4 Hz, H-6′), 7.00 (2H, dt, J =
7.8, 1.4 Hz, H-4‘), 4.50–4.38 (5H, m, H-1, H-2); 13C NMR
(CDCl3, 50 MHz): δ = 154.9 (C, C-1‘), 131.1 (C-3′), 129.2
(CH, C-5′), 123.4 (C, C-2′), 123.1 (CH, C-4′), 114.9 (CH,
C-6′), 69.2 (CH2, C-1), 60.8 (CH, C-2).
1,3-Bis(naphthalen-2-yloxy)propan-2-yl azide (3u)
White solid, 74% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99.5:0.5); mp:
58.4–59.1 °C; IR (ATR) vmax 3056, 2931, 2875, 2093,
1599, 1509, 1457, 1253, 1016; 1H NMR (CDCl3, 200
MHz): δ = 7.81–7.23 (14H, m, H-2′, H-3′, H-5′, H-6′, H-7′,
H-8′, H-10′), 4.39–4.37 (5H, m, H-1, H-2); 13C NMR
(CDCl3, 50 MHz): δ = 156.3 (C, C-1′), 134.6 (C, C-9′),
129.9 (CH, C-3′), 129.5 (C, C-4′), 127.9 (CH, C-5′), 127.0
(CH, C-8′), 126.8 (CH, C-7′), 124.2 (CH, C-6′), 118.8 (CH,
C-2′), 107.2 (CH, C-10′), 67.8 (CH2, C-1), 59.7 (CH, C-2).
1,3-Bis(3-chlorophenoxy)propan-2-yl azide (3q)
Colorless oil, 73% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99.5:0.5); IR
(ATR) vmax 3070, 2937, 2879, 2094, 1592, 1580, 1478,
1
1242, 1227, 1025, 764, 677 cm−1; H NMR (CDCl3, 200
MHz): δ = 7.22 (2H, t, J = 8.0 Hz, H-5′), 7.00–6.94 (4H, m,
H-2′, H-4′), 6.82 (2H, d, J = 8.0 Hz, H-6′), 4.17–4.13 (5H,
m, H-1, H-2); 13C NMR (CDCl3, 50 MHz): δ = 159.0 (C,
C-1′), 135.4 (C, C-3′), 130.6 (CH, C-5′), 122.1 (CH, C-4′),
115.4 (CH, C-2′), 113.3 (CH, C-6′), 67.9 (CH2, C-1), 59.5
(CH, C-2).
General procedure for synthesis of compounds 4a–4c
and 4g–4u
To a solution of azide (0.4 mmol) in THF or MeOH (10 mL)
was added 10% palladium on activated carbon. The reaction
was stirred under hydrogen atmosphere for 4 h. The catalyst
was filtrated off and the solvent was removed under reduced
pressure. The residue was reconstituted in MeOH and HCl
concentrated was added. The solvent was evaporated to give
pure amine salt.
1,3-Bis(4-chlorophenoxy)propan-2-yl azide (3r)
White solid, 78% yield; mp: 59.8–61.1 °C; IR (ATR) vmax
3075, 3058, 2948, 2928, 2877, 2147, 2095, 1594, 1581,
1487, 1451, 1239, 1022, 814 cm−1; 1H NMR (CDCl3, 200
MHz): δ = 7.26 (4H, d, J = 8.2 Hz, H-3′, H-5′), 6.87 (4H, d,
J = 8.2 Hz, H-2′, H-6′), 4.16 (5H, s, H-1, H-2); 13C NMR
(CDCl3, 50 MHz): δ = 156.9 (C, C-1′), 129.7 (CH, C-3′, C-
5′), 126.9 (C, C-4′), 116.2 (CH, C-2′, C-6′), 68.0 (CH2, C-
1), 59.6 (CH, C-2).
1,3-Bis(2-cyanophenoxy)propan-2-aminium chloride (4a)
White solid, 92% yield; mp: 181.3–184.1 °C; IR (ATR)
vmax 2881, 2225, 1598, 1579, 1488, 1448, 1260, 1246,
1026, 753 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ = 8.94
(3H, s, NH3+Cl−), 7.79–7.67 (4H, m, H-3′, H-5′),
7.36–7.13 (4H, m, H-4′, H-6′), 4.64–4.49 (4H, m, H-1),
4.05–4.00 (1H, m, H-2); 13C NMR (DMSO-d6, 50 MHz): δ
= 159.1 (C, C-1′), 135.3 (CH, C-5′), 133.9 (CH, C-3′),
122.1 (CH, C-4′), 116.2 (C, CN), 113.3 (CH, C-6′), 101.2
(C, C-2′), 66.0 (CH2, C-1); 48.6 (CH, C-2).
1,3-Bisphenoxypropan-2-yl azide (3s)
Colorless oil, 77% yield after purification with silica gel
column chromatography (Hexanes/EtOAc 99:1); IR (ATR)
vmax 3063, 3041, 2933, 2877, 2101, 1598, 1587, 1493,
1
1457, 1233, 1032, 749, 688 cm−1; H NMR (Acetone-d6,
200 MHz): δ = 7.36–7.27 (4H, m, H-3′, H-5′), 7.03–6.94
(6H, m, H-2′, H-4′, H-6′), 4.37–4.22 (5H, m, H-1, H-2); 13
C
1,3-Bis(3-cyanophenoxy)propan-2-aminium chloride (4b)
NMR (Acetone-d6, 50 MHz): δ = 159.5 (C, C-1‘), 130.5
(CH, C-3′, C-5′), 122.2 (CH, C-4′), 115.5 (CH, C-2′, C-6′),
68.4 (CH2, C-1), 60.9 (CH, C-2).
White solid, 86% yield; mp: 199.6–201.7 °C; IR (ATR)
vmax 2746, 2231, 1600, 1578, 1507, 1481, 1262, 1247,

Med Chem Res
1041, 783, 680 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ =
8.87 (3H, s, NH3+Cl−), 7.58–7.37 (8H, m, H-2′, H-4′, H-5′,
H-6′), 4.44 (2H, dd, J = 10.4, 3.6 Hz, H-1a), 4.37 (2H, dd,
J = 10.4, 5.0 Hz, H-1b), 3.96–3.94 (1H, m, H-2); 13C NMR
(DMSO-d6, 50 MHz): δ = 157.9 (C, C-1′), 131.0 (CH, C-
5′), 125.4 (CH, C-4′), 120.7 (CH, C-6′), 118.5 (C, CN),
117.8 (CH, C-2′), 112.3 (C, C-3′), 65.6 (CH2, C-1), 49.0
(CH, C-2).
= 8.85 (3H, s, NH3+Cl−), 7.94 (4H, d, J = 8.6 Hz, H-3′, H-
5′), 7.13 (4H, d, J = 8.6 Hz, H-2′, H-6′), 4.43–4.35 (4H, m,
H-1), 3.98 (1H, s, H-2), 3.81 (6H, s, COOCH3); 13C NMR
(DMSO-d6, 50 MHz): δ = 165.9 (C, COOCH3), 161.6 (C,
C-1′), 131.3 (CH, C-3′, C-5′), 122.6 (C, C-4′), 114.8 (CH,
C-2′, C-6′), 65.3 (CH2, C-1), 52.0 (CH3, COOCH3), 49.1
(CH, C-2).
1,3-Bis(2-methoxyphenoxy)propan-2-aminium chloride (4j)
1,3-Bis(4-cyanophenoxy)propan-2-aminium chloride (4c)
White solid, 85% yield; mp: 71.9–74.8 °C; IR (ATR) vmax
White solid, 88% yield; mp: 181.1–183.9 °C; IR (ATR)
vmax 3056, 2226, 1603, 1578, 1505, 1463, 1253, 1027, 831
2954, 1593, 1504, 1456, 1253, 1219, 1055, 1034, 747
1
cm−1; H NMR (DMSO-d6, 200 MHz): δ = 8.68 (3H, s,
cm−1; H NMR (DMSO-d6, 200 MHz): δ = 8.86 (3H, s,
NH3+Cl−), 7.10–6.85 (8H, m, H-3′, H-4′, H-5′, H-6′), 4.30
(4H, d, J = 5.2 Hz, H-1), 3.76 (7H, s, H-2, OCH3); 13C
NMR (DMSO-d6, 50 MHz): δ = 149.7 (C, C-1′), 147.2 (C,
C-2′), 122.7 (CH, C-4′), 120.8 (CH, C-5′), 115.8 (CH, C-6′),
112.7 (CH, C-3′), 66.8 (CH2, C-1), 55.7 (CH3, OCH3), 49.6
(CH, C-2).
1
NH3+Cl−), 7.81 (4H, d, J = 7.0 Hz, H-3′, H-5′), 7.18 (4H,
d, J = 7.0 Hz, H-2′, H-6′), 4.42 (4H, s, H-1), 3.99 (1H, s, H-
2); 13C NMR (DMSO-d6, 50 MHz): δ = 161.2 (C, C-1′),
134.3 (CH, C-3′, C-5′), 119.1 (C, CN), 115.9 (CH, C-2′, C-
6′), 103.7 (C, C-4′), 65.5 (CH2, C-1), 48.9 (CH, C-2).
1,3-Bis(2-(methoxycarbonyl)phenoxy)propan-2-aminium
1,3-Bis(3-methoxyphenoxy)propan-2-aminium chloride (4k)
chloride (4g)
White solid, 79% yield; mp: 135.8–138.8 °C; IR (ATR)
vmax 3049, 2938, 2834, 1603, 1587, 1490, 1453, 1284,
Colorless oil, 86% yield; IR (ATR) vmax 2950, 1699, 1600,
1
1582, 1490, 1449, 1244, 1133, 1244, 1046, 1029, 753
1263, 1051, 1040, 764, 751, 686 cm−1; H NMR (DMSO-
cm−1; H NMR (DMSO-d6, 200 MHz): δ = 8.80 (3H, s,
d6, 200 MHz): δ = 8.79 (3H, s, NH3+Cl-), 7.21 (2H, t, J =
8.8 Hz, H-5′), 6.61–6.58 (6H, m, H-2′, H-4′, H-6′), 4.31
(4H, s, H-1), 3.87–3.33 (1H, m, H-2), 3.73 (6H, s, OCH3);
13C NMR (DMSO-d6, 50 MHz): δ = 160.5 (C, C-3′), 159.0
(C, C-1′), 130.1 (CH, C-5′), 107.2 (CH, C-6′), 106.8 (CH,
C-4′), 101.1 (CH, C-2′), 65.0 (CH2, C-1), 55.2 (CH3,
OCH3), 49.3 (CH, C-2).
1
NH3+Cl−), 7.72–7.54 (4H, m, H-3′, H-5′), 7.25–7.06 (4H,
m, H-4′, H-6′), 4.52–4.38 (4H, m, H-1), 3.94–3.90 (1H, m,
H-2), 3.76 (6H, s, COOCH3); 13C NMR (DMSO-d6, 50
MHz): δ = 166.1 (C, COOCH3), 158.9 (C, C-1′), 133.9
(CH, C-5′), 131.1 (CH, C-3′), 121.4 (CH, C-4′), 120.5 (C,
C-2′), 114.5 (CH, C-6′), 65.8 (CH2, C-1), 52.0 (CH3,
COOCH3), 49.2 (CH, C-2).
1,3-Bis(4-methoxyphenoxy)propan-2-aminium chloride (4l)
1,3-Bis(3-(methoxycarbonyl)phenoxy)propan-2-aminium
chloride (4h)
White solid, 78% yield; mp: 115.3–116.9 °C; IR (ATR)
vmax 3044, 2909, 2877, 2830, 1616, 1587, 1505, 1469,
1
White solid, 88% yield; mp: 154.7–157.2 °C; IR (ATR)
vmax 2953, 1702, 1584, 1490, 1441, 1280, 1189, 1242,
1218, 1034, 822 cm−1; H NMR (CDCl3, 200 MHz): δ =
8.88 (3H, s, NH3+Cl−), 6.87 (4H, d, J = 8.2 Hz, H-3′, H-5′),
6.71 (4H, d, J = 8.2 Hz, H-2′, H-6′), 4.22 (4H, s, H-1), 3.78
(1H, s, H-2), 3.70 (6H, s, OCH3); 13C NMR (CDCl3, 50
MHz): δ = 154.6 (C, C-4′), 151.9 (C, C-1′), 116.1 (CH, C-
2′, C-6′), 114.8 (CH, C-3′, C-5′), 65.2 (CH2, C-1), 55.8
(CH3, OCH3), 50.8 (CH, C-2).
1221, 1052, 752, 679 cm−1 1H NMR (DMSO-d6, 200
;
MHz): δ = 8.82 (3H, s, NH3+Cl-), 7.54–7.33 (8H, m, H-2‘,
H-4‘, H-5‘, H-6‘), 4.40 (4H, s, H-1), 3.84 (7H, s, H-2,
COOCH3); 13C NMR (DMSO-d6, 50 MHz): δ = 166.0 (C,
COOCH3), 157.9 (C, C-1′), 131.0 (C, C-3′), 130.2 (CH, C-
5′), 122.2 (CH, C-4′), 119.9 (CH, C-6′), 115.0 (CH, C-2′),
65.4 (CH2, C-1), 52.4 (CH3, COOCH3), 49.3 (CH, C-2).
1,3-Bis(2-tolyloxy)propan-2-aminium chloride (4m)
1,3-Bis(4-(methoxycarbonyl)phenoxy)propan-2-aminium
chloride (4i)
Brown solid, 77% yield; mp: 139.0–142.7 °C; IR (ATR)
1
vmax 2874, 1590, 1494, 1459, 1238, 1050, 744 cm−1; H
NMR (CDCl3, 200 MHz): δ = 7.11–7.08 (4H, m, H-3′, H-
White solid, 85% yield; mp: 182.1–184.4 °C; IR (ATR)
vmax 2952, 1703, 1605, 1581, 1511, 1455, 1299, 1173,
5′), 6.90–6.79 (4H, m, H-4′, H-6′), 5.26 (3H, s, NH3+Cl−),
4.21 (4H, s, H-1), 3.74 (1H, s, H-2), 2.22 (6H, s, CH3); 13
C
1
1254, 1027, 848 cm−1; H NMR (DMSO-d6, 200 MHz): δ
NMR (CDCl3, 50 MHz): δ = 156.3 (C, C-1′), 131.0 (CH,

Med Chem Res
C-3′), 127.1 (C, CH, C-2′, C-5′), 121.3 (CH, C-4′), 111.2
(CH, C-6′), 67.2 (CH2, C-1), 50.8 (CH, C-2), 16.58 (CH3,
CH3).
1,3-Bis(4-chlorophenoxy)propan-2-aminium chloride (4r)
Brown solid, 67% yield; mp: 169.3–171.1 °C; IR (ATR)
vmax 2878, 1595, 1585, 1514, 1488, 1465, 1233, 1045, 821
1
cm−1; H NMR (DMSO-d6, 200 MHz): δ = 8.81 (3H, s,
1,3-Bis(3-tolyloxy)propan-2-aminium chloride (4n)
NH3+Cl−), 7.36 (4H, d, J = 8.8 Hz, H-3′, H-5′), 7.04 (4H,
d, J = 8.8 Hz, H-2′, H-6′), 4.35 (2H, dd, J = 10.0, 3.8 Hz,
H-1a), 4.27 (2H, dd, J = 10.0, 5.0 Hz, H-1b), 3.91–3.89
(1H, m, H-2); 13C NMR (DMSO-d6, 50 MHz): δ = 156.6
(C, C-1′), 129.3 (CH, C-3′, C-5′), 125.1 (C, C-4′), 116.6
(CH, C-2′, C-6′), 65.4 (CH2, C-1), 49.2 (CH, C-2).
White solid, 71% yield; mp: 131.6–133.1 °C; IR (ATR)
vmax 2881, 1605, 1583, 1522, 1487, 1464, 1255, 1062,
1
1051, 764, 690 cm−1; H NMR (CDCl3, 200 MHz): δ =
7.11–7.04 (5H, m, NH3+Cl−, H-5′), 6.77–6.73 (6H, m, H-
2′, H-4′, H-6′), 4.25 (4H, d, J = 5.0 Hz, H-1), 3.77–3.74
(1H, m, H-2), 2.26 (6H, s, CH3); 13C NMR (CDCl3, 50
MHz): δ = 157.9 (C, C-1′), 139.8 (C, C-3′), 129.4 (CH, C-
5′), 122.6 (CH, C-4′), 115.6 (CH, C-2′), 111.9 (CH, C-6′),
64.5 (CH2, C-1), 50.6 (CH, C-2), 21.6 (CH3, CH3).
1,3-Diphenoxypropan-2-aminium chloride (4s)
White solid, 84% yield; mp: 125.6–129.1 °C; IR (ATR)
vmax 2881, 1597, 1586, 1494, 1463, 1240, 1039, 748, 689
cm−1 1H NMR (CDCl3, 200 MHz): δ = 8.86 (3H, s,
;
1,3-Bis(4-tolyloxy)propan-2-aminium chloride (4o)
NH3+Cl−), 7.21–6.90 (10H, m, H-2′, H-3′, H-4′, H-5, H-6′),
4.24 (4H, d, J = 4.8 Hz, H-1), 3.75 (1H, s, H-2); 13C NMR
(CDCl3, 50 MHz, CDCl3): δ = 157.7 (C, C-1′), 129.7 (CH,
C-3′, C-5′), 121.8 (CH, C-4′), 115.0 (CH, C-2′, C-6′), 64.3
(CH2, C-1), 50.6 (CH, C-2).
White solid, 73% yield; mp: 132.0–133.6 °C; IR (ATR)
vmax 2859, 1610, 1587, 1506, 1466, 1232, 1046, 801 cm−1
;
1H NMR (CDCl3, 200 MHz): δ = 8.89 (3H, s, NH3+Cl-),
6.97 (4H, d, J = 8.2 Hz, H-3′, H-5′), 6.82 (4H, d, J = 8.2
Hz, H-2′, H-6′), 4.23 (4H, 4d, J = 4.4 Hz, H-1), 3.76 (1H, s,
H-2), 2.24 (6H, s, CH3); 13C NMR (CDCl3, 50 MHz): δ =
155.7 (C, C-1′), 131.0 (C, C-4′), 130.1 (CH, C-3′, C-5′),
114.9 (CH, C-2′, C-6′), 64.5 (CH2, C-1), 50.7 (CH, C-2),
20.7 (CH3, CH3).
1,3-Bis(naphthalen-1-yloxy)propan-2-aminium chloride
(4t)
Rosaceous solid, 42% yield; mp: 213.2–215.2 °C; IR (ATR)
vmax 2884, 1596, 1578, 1508, 1459, 1267, 1238, 1072
1
cm−1; H NMR (DMSO-d6, 200 MHz): δ = 9.02 (3H, s,
1,3-Bis(2-chlorophenoxy)propan-2-aminium chloride (4p)
NH3+Cl−), 8.54 (2H, d, J = 7.4 Hz, H-9′), 7.88 (2H, d, J =
7.2 Hz, H-6′), 7.54–7.40 (8H, m, H-3′, H-4′, H-7′, H-8′),
7.05 (2H, d, J = 7.2 Hz, H-2′), 4.64 (4H, s, H-1), 4.27 (1H,
s, H-2); 13C NMR (DMSO-d6, 50 MHz): δ = 153.4 (C, C-
1′), 134.0 (C, C-5′), 127.3 (CH, C-6′), 126.6 (CH, C-7′),
126.1 (CH, C-8′), 125.3 (CH, C-3′), 124.8 (CH, C-10′),
122.5 (CH, C-4′), 120.7 (CH, C-9′), 105.3 (CH, C-2′), 65.6
(CH2, C-1), 49.3 (CH, C-2).
Brown solid, 71% yield; mp: 158.3–160.7 °C; IR (ATR)
vmax 2752, 1590, 1486, 1463, 1447, 1244, 1062, 1039, 745
1
cm−1; H NMR (DMSO-d6, 200 MHz): δ = 8.80 (3H, s,
NH3+Cl−), 7.47–7.22 (6H, m, H-3′, H-5′, H-6′), 7.03 (2H, t,
J = 7.4 Hz, H-4′), 4.45–4.43 (4H, m, H-1), 3.99 (1H, s, H-
2); 13C NMR (DMSO-d6, 50 MHz): δ = 153.2 (C, C-1′),
130.2 (CH, C-3′), 128.6 (CH, C-5′), 122.73 (C, C-2′), 122.0
(CH, C-4′), 114.8 (CH, C-6′), 66.2 (CH2, C-1), 49.0 (CH,
C-2).
1,3-Bis(naphthalen-2-yloxy)propan-2-aminium chloride
(4u)
1,3-Bis(3-chlorophenoxy)propan-2-aminium chloride (4q)
Pale yellow solid, 65% yield; mp: 181.0–184.5 °C; IR
(ATR) vmax 2880, 1594, 1506, 1458, 1277, 1243, 1083,
1052 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ = 8.88 (3H,
s, NH3+Cl−), 7.90–7.83 (6H, m, H-3′, H-5′, H-8′),
7.51–7.26 (8H, m, H-2′, H-6′, H-7′, H-10′), 4.52 (4H, s, H-
1), 4.08 (1H, s, H-2); 13C NMR (DMSO-d6, 50 MHz): δ =
155.7 (C, C-1′), 134.1 (C, C-9′), 129.5 (CH, C-3′), 128.8 (C,
C-4′), 127.6 (CH, C-5′), 126.9 (CH, C-8′), 126.6 (CH, C-7′),
124.0 (CH, C-6′), 118.7 (CH, C-2′), 107.2 (CH, C-10′), 65.2
(CH2, C-1), 49.4 (CH, C-2).
White solid, 63% yield; mp: 145.9–149.5 °C; IR (ATR)
vmax 2831, 1593, 1580, 1519, 1508, 1475, 1464, 1229,
1041, 758, 676 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ =
8.78 (3H, s, NH3+Cl−), 7.34–7.31 (2H, m, H-5′), 7.09–7.03
(6H, m, H-2′, H-4′, H-6′), 4.35 (4H, s, H-1), 3.91 (1H, s, H-
2); 13C NMR (DMSO-d6, 50 MHz): δ = 158.7 (C, C-1′),
133.7 (C, C-3′), 131.0 (CH, C-5′), 121.4 (CH, C-4′), 115.0
(CH, C-2′), 113.8 (CH, C-6′), 65.4 (CH2, C-1), 49.1
(CH, C-2).

Med Chem Res
General procedure for synthesis of compounds 4d–4f
fetal bovine serum (FBS, Sigma), 20 mM L-glutamine, 200
U/mL penicillin, and 100 μg/mL streptomycin, at pH 7.4.
Stationary-phase promastigotes were prepared as described
(Coelho et al. 2003). Murine peritoneal macrophages were
obtained from female BALB/c mice (8 weeks old), which
were purchased from the Institute of Biological Sciences of
UFMG. The Animal Use Committee from UFMG approved
the experimental protocol (code 136/2012).
To a stirred solution of azide derivative (100 mg; 0.27
mmol) in dry acetonitrile (5 mL) at room temperature was
added triethylamine (0.14 mL; 1.08 mmol) and dithiotreitol
(164 mg; 1.06 mmol). After 4 h, acetonitrile was evapo-
rated, the residue was reconstituted in CHCl3 (30 mL) and
washed with water (3 × 50 mL). The organic layer was
dried, filtered, and concentrated.
Antileishmanial activity
1,3-Bis(2-nitrophenoxy)propan-2-aminium chloride (4d)
The inhibition of Leishmania growth was assessed in vitro
by cultivating stationary-phase promastigotes of L. amazo-
nensis (1 × 106 cells) in the presence of each individual
compound (0–100 µM), in 96-well culture plates (Nunc,
Nunclon®, Roskilde, Denmark), for 48 h at 24 °C. A pre-
vious titration curve was performed to determine the best
time of inhibition of L. amazonensis growth incubating with
the evaluated products (data not shown). Cell viability was
assessed by measuring the cleavage of 2 mg/mL of MTT [3-
(4.5-dimethylthiazol-2-yl)-2.5-diphenyl tetrazolium bro-
mide] (Sigma). Absorbances were measured by using a
multi-well scanning spectrophotometer (Molecular Devices,
Spectra Max Plus, Canada), at a wavelength of 570 nm.
Amphotericin B (1 μM) was used as a positive control. The
concentration of the compounds needed to inhibit 50% of
the Leishmania viability (IC50) was determined by applying
the sigmoidal regression of the concentration-response
curves, using different concentrations of the compounds.
Data shown are representative of three independent
experiments, performed in triplicate, which presented
similar results.
Yellow solid, 80% yield; mp: 127.0–130.1 °C; IR (ATR)
vmax 2855, 1606, 1584, 1488, 1462, 1518, 1343, 1251,
1029, 737 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ = 8.81
(3H, s, NH3+Cl−), 7.92 (2H, s, H-3′), 7.70 (2H, s, H-5′),
7.43 (2H, s, H-6′), 7.20 (2H, s, H-4′), 4.54 (4H, s, H-1),
3.98 (1H, s, H-2); 13C NMR (DMSO-d6, 50 MHz): δ =
150.6 (C, C-1′), 139.5 (C, C-2′), 134.9 (CH, C-5′), 125.4
(CH, C-3′), 121.5 (CH, C-4′), 115.3 (CH, C-6′), 66.2 (CH2,
C-1), 48.6 (CH, C-2).
1,3-Bis(3-nitrophenoxy)propan-2-aminium chloride (4e)
Pale yellow solid, 71% yield; mp: 246.0–247.9 °C; IR
(ATR) vmax 2802, 3066, 3007, 2922, 1614, 1584, 1503,
1
1482, 1455, 1529, 1348, 1241, 1036, 814, 734 cm−1; H
NMR (DMSO-d6, 200 MHz): δ = 8.87 (3H, s, NH3+Cl–),
7.88–7.81 (4H, m, H-2′, H-4′), 7.66–7.49 (4H, m, H-5′, H-
6′), 4.48 (4H, s, H-1), 4.02 (1H, s, H-2); 13C NMR (DMSO-
d6, 50 MHz): δ = 158.3 (C, C-1′), 148.7 (C, C-3′), 131.0
(CH, C-5′), 122.0 (CH, C-4′), 116.3 (CH, C-6′), 109.5 (CH,
C-2′), 65.9 (CH2, C-1), 49.1 (CH, C-2).
Cytotoxicity assay
1,3-Bis(4-nitrophenoxy)propan-2-aminium chloride (4f)
The inhibition of 50% of the macrophage viability (CC50)
was calculated by cultivating macrophages (5 × 105 cells)
in the presence of each individual compound (0–200 µM) in
96-well plates for 48 h, at 37 °C. A previous titration curve
was performed to determine the best time of inhibition of
macrophages viability incubating with the evaluated pro-
ducts (data not shown). Cell viability was assessed by the
MTT assay, and amphotericin B (1 μM) was used as a
control. The SI of the compounds was calculated by
determining the ratio between CC50 and IC50. Data shown
are representative of three independent experiments, per-
formed in triplicate, which presented similar results.
White solid, 54% yield; mp: 211.4–213.6 °C; IR (ATR)
vmax 2882, 1608, 1592, 1505, 1463, 1505, 1347, 1253,
1040, 848 cm−1; 1H NMR (DMSO-d6, 200 MHz): δ = 8.95
(3H, s, NH3+Cl−), 8.24 (4H, d, J = 9.2 Hz, H-3′, H-5′), 7.23
(4H, d, J = 9.2 Hz, H-2′, H-6′), 4.55 (2H, dd, J = 10.4, 4.2
Hz, H-1a), 4.47 (4H, dd, J = 10.4, 5.4 Hz, H-1b), 4.06–4.04
(1H, m, H-2); 13C NMR (DMSO-d6, 50 MHz): δ = 162.9
(C, C-1′), 141.4 (C, C-4′), 125.9 (CH, C-3′, C-5′), 115.4
(CH, C-2′, C-6′), 65.9 (CH2, C-1), 48.9 (CH, C-2).
Biological assays
Parasites and mice
Treatment of infected macrophages
L. amazonensis (IFLA/BR/1967/PH-8) was used. Parasites
were grown at 24 °C in Schneider’s medium (Sigma, St.
Louis, MO, USA), supplemented with 20% heat-inactivated
Murine macrophages (5 × 105 cells) were plated on round
glass coverslips inside the wells of a 24-well culture plate
(Nunc) in an RPMI 1640 medium supplemented with 20%

Med Chem Res
proteus lipopolysaccharides. European
119–131
J
Org Chem 2012:
FBS, 2 mM L-glutamine, 200 U/mL penicillin, and 100 µg/
mL streptomycin, at pH 7.4. After 24 h of incubation at 37 °
C in 5% CO2, stationary-phase promastigotes of L. ama-
zonensis were added to the wells (5 × 106 cells), and the
cultures were incubated for 24 h at 37 °C, 5% CO2. A
previous titration curve was performed to determine the
minimum time incubation of parasites with the macro-
phages, in order to obtain the maximum of infection into the
host cells (data not shown). Next, free parasites were
removed by extensive washing with an RPMI 1640 med-
ium, and infected macrophages were quantified and treated
for 48 h with in the presence of each selected compound
(15, 10, 5, and 2.5 µg/mL), at 24 °C in 5% CO2. Cells were
washed in RPMI 1640 and incubated with 4% paraf-
ormaldehyde for 15 min, at which time they were treated
with 70% ethanol in an ice-bath for 4 h and again washed
three times with sterile PBS. Amphotericin B (1 μM) was
used as a control. The percentage of the inhibition of
Leishmania intra-macrophage viability was determined by
counting 200 cells in triplicate. Data shown are repre-
sentative of three independent experiments, performed in
triplicate, which presented similar results.
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Acknowledgements Authors would like to thank the CNPq,
CAPES, FAPEMIG, INCT-if and INCT-Nanobiofar for their financial
support. E.A.F. Coelho and R.J. Alves are recipients of productivity
grants of CNPq.
Jorda R, Sacerdoti-Sierra N, Voller J, Havlíček L, Kráčalíková K,
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MD, Jaffe CL (2011) Anti-leishmanial activity of disubstituted
purines and related pyrazolo[4,3-d]pyrimidines. Bioorg Med
Chem Lett 14:4233–4237
Compliance with ethical Standards
Conflict of interest The authors declared that they have no com-
peting interests.
Lagorce D, Maupetit J, Baell J, Sperandio O, Tufféry P, Miteva MA,
Galons H, Villoutreix BO (2011) The FAF-Drugs2 server: a
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