Design, synthesis and biological evaluation of novel ring-opened cromakalim analogues with relaxant effects on vascular and respiratory smooth muscles and as stimulators of elastin synthesis

Article abstract of DOI:10.1016/j.ejmech.2017.12.071

Two new series of ring-opened analogues of cromakalim bearing sulfonylurea moieties (series A: with N-unmethylated sulfonylureas, series B: with N-methylated sulfonylureas) were synthesized and tested as relaxants of vascular and respiratory smooth muscle

Full text of DOI:10.1016/j.ejmech.2017.12.071

Accepted Manuscript
Design, synthesis and biological evaluation of novel ring-opened cromakalim
analogues with relaxant effects on vascular and respiratory smooth muscles and as
stimulators of elastin synthesis
Mourad Bouhedja, Basile Peres, Wassim Fhayli, Zeinab Ghandour, Ahcène
Boumendjel, Gilles Faury, Smail Khelili
PII:
S0223-5234(17)31102-9
10.1016/j.ejmech.2017.12.071
EJMECH 10049
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 5 May 2017
Revised Date: 17 December 2017
Accepted Date: 18 December 2017
Please cite this article as: M. Bouhedja, B. Peres, W. Fhayli, Z. Ghandour, Ahcè. Boumendjel, G. Faury,
S. Khelili, Design, synthesis and biological evaluation of novel ring-opened cromakalim analogues with
relaxant effects on vascular and respiratory smooth muscles and as stimulators of elastin synthesis,
European Journal of Medicinal Chemistry (2018), doi: 10.1016/j.ejmech.2017.12.071.
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ACCEPTED MANUSCRIPT
Design, Synthesis and Biological Evaluation of Novel Ring-Opened Cromakalim
Analogues with Relaxant Effects on Vascular and Respiratory Smooth Muscles and as
Stimulators of Elastin Synthesis
Mourad BOUHEDJA, Basile PERES, Wassim FHAYLI, Zeinab GHANDOUR, Ahcène
*
BOUMENDJEL, Gilles FAURY and Smail KHELILI

ACCEPTED MANUSCRIPT
Design, Synthesis and Biological Evaluation of Novel Ring-Opened Cromakalim
Analogues with Relaxant Effects on Vascular and Respiratory Smooth Muscles and as
Stimulators of Elastin Synthesis
a,b
b
c
c
Mourad BOUHEDJA , Basile PERES , Wassim FHAYLI , Zeinab GHANDOUR ,
b
c
a
Ahcène BOUMENDJEL , Gilles FAURY and Smail KHELILI *
a
Laboratoire de Phytochimie et de Pharmacologie, Département de Chimie, Faculté des Sciences
Exactes et Informatique, Université Mohamed Seddik Ben Yahia Jijel, B.P. 98 Ouled Aissa, 18000
Jijel, Algeria
b
Université Grenoble-Alpes/CNRS, Département de Pharmacochimie Moléculaire
UMR 5063, F-38041 Grenoble, France
c
Laboratoire "Hypoxie : Physiopathologie Cardiovasculaire et Respiratoire" (HP2),
INSERM U1042-Université Grenoble Alpes, F-38042 La Tronche, France
Abstract
Two new series of ring-opened analogues of cromakalim bearing sulfonylurea moieties
(series A: with N-unmethylated sulfonylureas, series B: with N-methylated sulfonylureas)
were synthesized and tested as relaxants of vascular and respiratory smooth muscles (rat aorta
and trachea, respectively). Ex vivo biological evaluations indicated that the most active
compounds, belonging to series B, displayed a marked vasorelaxant activity on endothelium-
intact aortic rings and the trachea. A majority of series B compounds exhibited a higher
vasorelaxant activity (EC < 22 µM) than that of the reference compound diazoxide (EC =
50
50
2
4 µM). Interestingly, several tested compounds of series B also presented stronger relaxant
effects on the trachea than the reference compound cromakalim (EC50 = 124 µM), in
particular compounds B4, B7 and B16 (EC < 10 µM). By contrast, series A derivatives were
5
0
poorly active on aortic rings (EC > 57 µM for all, and EC > 200 µM for a majority of
5
0
50
them), but some of them showed an interesting relaxing effect on trachea (i.e. A15 and A33,
EC = 30 µM). The most potent compounds of both series, i.e. A15, A33 and B16, tested on
50
aortic rings in the presence of glibenclamide or 80 mM KCl, suggested that they acted as
2
+
voltage-gated Ca channel blockers, like verapamil, instead of being ATP-potassium
channel activators, as is cromakalim, the parent molecule. Further investigations on cultured
vascular smooth muscle cells showed a strong stimulating effect on elastin synthesis,
especially compound B16, which was more active at 20 µM than diazoxide, a reference ATP-

ACCEPTED MANUSCRIPT
sensitive potassium channel activator. Taken together, our results show that the N-methylation
of the sulfonylurea moieties of ring-opened cromakalim analogues led to new compounds
blocking calcium-gated channels, which had a major impact on the arterial and tracheal
activities as well as selectivity.
2
+
Keywords: ring-opened cromakalim analogues, Ca -gated channels, Ritter reaction, relaxant
activity, aortic rings, trachea, elastin synthesis.
1
. Introduction
Hypertension is one of most common cardiovascular diseases, which represents the
major risk factor for endothelial dysfunction, metabolic syndrome, renal dysfunction,
congestive heart failure, coronary artery disease, stroke and sudden death [1-3]. Several
antihypertensive drugs used in the treatment of this disease are available, including diuretics,
sympatholytics, vasodilators, and calcium channel and angiotensin inhibitors, which control
arterial blood pressure at four effector sites: resistance and capacitance vessels, heart, and
kidney [4].
The use of drugs relaxing vascular smooth muscle cells (VSMCs) has been one of the
major choices in the treatment of hypertension but, unfortunately, they are all associated with
undesirable side effects: fatigue, mood change, and sleep disturbances [5]. Therefore, there is
an insistent need for developing new vasorelaxant agents with minimal side effects [6]. ATP-
sensitive potassium channel (KATP channel) openers constitute an important class of
compounds relaxing VSMCs, including different types of chemical structures such as racemic
cromakalim (1), diazoxide (2), pinacidil (3), nicorandil (4), and minoxidil (5) (Figure 1) [7-
1
0]. Cromakalim (1), the first benzopyran-type potassium channel activator, is known to be a
potent antihypertensive agent [11-22]. The cromakalim skeleton has been used as a model in a
new pharmacological investigation, which led to some potassium channel openers (PCOs)
having potential interesting therapeutic applications in various diseases, especially in
hypertension, asthma, and urinary incontinence [23]. In our efforts to develop new derivatives
of the cromakalim-related PCO family, we previously developed a large number of
compounds, with some of which having shown very interesting pharmacological profiles as
activators of KATP channels (compounds 6-13, Figure 2) [11,14,16]. Indeed, we were the first
to report the development of simplified analogues of cromakalim by opening its heterocyclic
side (giving more flexible molecules) and introducing amide, urea and sulfonylurea moieties
(compounds 10-13, Figure 2) [16]. More recently, other derivatives of cromakalim showed

ACCEPTED MANUSCRIPT
interesting antitumor activity, especially an inhibitory activity of the growth of human glioma
cell lines [19].
Further derivatives of compounds 10 and 11 (Figure 2) were also prepared. Those bearing
urea moieties (compound 12, Figure 2), whose development is underway, were more active
than those with sulfonylurea and amide ones (compound 13, Figure 2) as vasodilators or
inhibitors of insulin secretion by pancreatic β-cells [16]. The urea derivatives were less acidic
than sulfonylureas due to the presence, in the latter, of a NH group linked to both a CO and a
SO group, which suggests the existence of both neutral and negative ionic forms at
2
physiological pH.
Based on these previous data, we proposed in the present work the synthesis of new
sulfonylurea derivatives by alkylation of the NH group, as cited above, in order to reduce the
acidity and permit the existence of a neutral form only. Furthermore, we created a chiral
center on the benzylic atom, located in the ortho position to the alkoxy groups, similar to the
situation in cromakalim itself. The activity and potential tissue-selectivity of these new
derivatives (Figure 3) were pharmacologically evaluated in vascular (aortic rings) and
respiratory (trachea) smooth muscles of rat precontracted by 30 mM KCl. The most active
compounds were tested again in the aortic ring model, in the presence of glibenclamide, a
KATP channel blocker, or 80 mM KCl, in order to determine the mechanism(s) of action of
these compounds.
Also, it has already been demonstrated that minoxidil and diazoxide, two KATP channel
openers and vasodilators, increased the expression of the elastin gene, in vitro, in skin
fibroblasts and vascular smooth muscle cells [24,25] and in vivo in young or adult rats, as well
as in old mice [26-29]. This led to an increase in the arterial content in elastin, the
extracellular matrix protein which mainly provides the extensible tissues (including skin,
lungs and arteries) with elasticity [26-29]. This is of particular importance since the elastin
gene expression is interrupted after childhood and therefore not replaced when degraded
during adulthood and ageing, leading to arteries that are more rigid and provoking several
cardiovascular dysfunctions [30-32]. New compounds capable of re-inducing elastin synthesis
by VSMCs would be highly useful for the treatment of the pathological stiffening of arteries
related to ageing. We therefore also evaluated the efficiency of our target compounds for
stimulating elastin synthesis by VSMCs.
2
2
. Results and discussion
.1. Synthesis

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The synthetic routes of simplified cromakalim derivatives bearing sulfonylurea moieties,
series A and series B, are summarized in Scheme 1.
N-(2,5-dimethoxybenzyl)sulfonylureas A1-3 were prepared by condensation of 2,5-
dimethoxbenzylamine 1a with an appropriate sulfonyl isocyanate. The N-methylated
sulfonylureas B1-3 were obtained by methylation of A1-3 using methyl iodide, in the
presence of sodium carbonate, by refluxing in acetonitrile.
The two series of compounds A4-33 and B4-33 were obtained from ortho-
hydroxyacetophenones according to five or six steps (Scheme 1).
The access to the target compounds required the synthesis of key intermediates, the primary
amines R/S-1-(2-alkoxy-5-halogenophenyl)ethanamine 6a-j.
Firstly, hydroxyacetophenones 2a-e were alkylated using halogenoalkanes under alkaline
conditions. The expected compound was easily separated from the starting material using the
extraction of their ethyl acetate solution by a saturated solution of sodium hydrogen
carbonate.
The resulting ortho-alkoxyketones 3a-j were reduced to secondary alcohols 4a-j with
sodium borohydride in methanol. The acetylamino derivatives 5a-j were prepared by the
Ritter reaction from alcohols 4a-j. This reaction occurred in acetonitrile supplemented with
concentrated sulfuric acid. Access to the corresponding benzylamine derivatives 6a-j was
achieved, in excellent yields, by the hydrolysis of 5 with hydro-methanolic solution of sodium
hydroxide. Amines 6a-j were converted into the desired compounds A4-33 by condensation
with an appropriate sulfonyl isocyanate (series A) in methylene chloride at room temperature.
Finally, the N-(1-(2-alkoxy-5-halophenyl)ethyl)-N’-methyl-N’-arylsulfonylureas B4-33
were obtained by N-alkylation of the corresponding sulfonylureas A4-33, with methyl iodide
in acetonitrile, in the presence of sodium carbonate under reflux (series B, Scheme 1).
1
All these derivatives were crystallized in appropriate solvents and characterized by MS, H
13
NMR and C NMR. The purity of final compounds was assessed by elemental analysis prior
to pharmacological evaluations.
2
2
.2. Biological activity
.2.1. Myorelaxant effect on rat aortic rings
The vasorelaxant activities of compounds (series A and B) were evaluated ex vivo on
endothelium-intact rat aortic rings pre-contracted with a hyperpotassic 30 mM KCl solution.
The results obtained from compounds of the series A and B –in the concentration range of 1-
3
00 µM, reference drugs (diazoxide, pinacidil, cromakalim), and previously described

ACCEPTED MANUSCRIPT
molecules (6-11), were expressed as EC and E values and summarized in Tables 1 and 2,
5
0
max
respectively. In vascular smooth muscles, (±)-cromakalim displayed a marked myorelaxant
activity. As reported, the previously synthesized ring-closed benzopyran-type
arylsulfonylureas (8-9) also produced a marked vasorelaxant effect but such compounds were
less potent than (±)-cromakalim [14].
The biological data reported in Tables 1 and 2 indicate that most of the unmethalyted
sulfonylurea derivatives (series A) were poorly active on rat aortic rings, except for the o-
isopropoxy or o-benzyloxy compounds A11, A15 and A33, which were the most potent in
this series [EC = 61.8 ± 9.9 (E = 93.2 ± 3.1 ), EC = 57.5 ± 11.7 (E = 95.1 ± 4.1) and
50
max
50
max
6
5.3 ± 5.4 (Emax = 125.5 ± 17.8), respectively], although they were much less active than the
reference compounds. It can be observed that the preferred R group for the myorelaxant
activity was a benzyl or an iPr, while Z should be a methyl or an electron-withdrawing group
such as Cl. In most cases, compounds of series B (N-methalyted sulfonylureas) exerted a
more pronounced myorelaxant activity than their analogues in series A (p < 0.05), except
when R corresponded to the benzyl group (compare A15, A32 and A33 with B15, B32 and
B33, Table 1). Indeed, the preferred R groups for series B were ethyl and methyl. The
creation of chiral centers (R’ = CH ) was very favorable for the relaxant activity, which led to
3
the most potent vasorelaxant compounds, B16 and B26 [EC = 7.2 ± 0.8 (E = 102.7 ± 1.8)
5
0
max
and EC = 7.8 ± 1.1 (E = 104.4 ± 1.3)], respectively. These compounds have chlorine and
5
0
max
fluorine atoms as the X-substituent and a hydrogen atom or methyl group as the Z-substituent,
respectively.
Taken as a whole, in series B, the rank order of preference for the X-substituent was found
to be Cl~F > Br > OCH > H > CH , while that of the Z-substituent was H > CH > Cl.
3
3
3
The introduction of a methyl group on the nitrogen atom located between the two
withdrawing groups (a sulfonyl and a carbonyl group) of series A, leading to series B,
dramatically increased their biological effects on rat aortic smooth muscles. It could be due to
the weak acidity of compound A15 (pK = 5.31). Thus, the non-N-methylated compounds of
a
series A are able to be deprotonated at physiological pH 7.40 and present in solution as a
mixture of ionic and neutral forms. By contrast, the N-methylated analogues of series B are
not ionized and present in solution as neutral species. This feature indicates that the presence
of a neutral nitrogen atom linked to the sulfonyl function in the B series is good for the
biological activity, allowing for a favorable interaction with the receptor protein site. This
confirms the results obtained with opened analogues of cromakalim bearing urea moieties,
which exist in physiological media only under neutral form [16]. Such a phenomenon has also

ACCEPTED MANUSCRIPT
been observed in a recent work describing the development of new sulfonylureas and
carbonylureas as ATP-dependent potassium openers with vasodilatory activity [33]. The latter
are weakly acidic (exist uniquely under neutral form at physiological pH) and have a very
powerful vasorelaxant effect, whereas sulfonylureas have a weak acid character (exist in two
forms, neutral and ionized negatively charged, at physiological pH) and are poor vasodilators
[
33]. It could be very interesting to develop other analogues of series B, by methylating the
other nitrogen atom of the sulfonylurea group or both of its nitrogen atoms. This hypothetic
structural modulation could have an interesting impact on the biological activity.
2
.2.2. Myorelaxant mechanisms of action on rat aorta rings
Three of the most active products in each series were selected (A15, A33 and B16) for
further pharmacological investigations in order to identify their mechanisms of action.
+
First, the compounds were tested in 30 mM K -depolarized rat aortic rings incubated in
the continuous presence of 1 or 10 µM glibenclamide, a specific blocker of KATP channels
[34,35]. If the drugs acted as a potassium channel opener, then a drastic reduction in
myorelaxant activity should be observed in the presence of glibenclamide [12]. As shown in
Table 3 and Figure 4 left panel, no dose-dependent decrease in the vasorelaxant effect of
drugs was observed when increasing the glibenclamide concentration in the bathing
medium (p > 0.05). By contrast, under the same experimental conditions, the EC values of
5
0
the reference compound cromakalim were markedly increased by 33- and 671-fold in the
presence of 1 µM and 10 µM glibenclamide, respectively (p < 0.05, Table 3).
Furthermore, the myorelaxant activities of the tested drugs, cromakalim and verapamil
were examined in rat aortic rings precontracted by 80 mM KC1, which strongly inhibits or
blocks KATP channels (Table 3 and Figure 4 right panel). In this condition, the vasodilatory
+
potency of K channel openers should be reduced compared to their activity on 30 mM KCl
2+
induced contractions [12,35,36], while drugs directly interfering with Ca channels, such as
2
+
Ca entry blockers (e.g. verapamil), are expected to express the same myorelaxant efficacy
on 30 and 80 mM KCl precontracted aortic rings [37]. Indeed, pure potassium channel
+
openers are able to suppress smooth muscle contractions induced by low K concentrations
+
(
30 mM or less), but not high depolarizing K concentrations (80 mM). At high depolarizing
+
K concentrations (80 mM), potassium equilibrium potential and cell membrane potential are
+
so close that the hyperpolarization induced by K channel opening is too weak to close
2
+
voltage-operated Ca channels [8,38,39]. As indicated in Table 3 and Figure 4 (right panel),
the vasorelaxant properties of the selected compounds remained unchanged under 80 mM

ACCEPTED MANUSCRIPT
KCl-induced precontraction (p > 0.05), whereas the myorelaxant effect of (±)-cromakalim
was extremely reduced (p < 0.05). The myorelaxant effects of verapamil were also unaltered
by the presence of 1 µM or 10 µM glibenclamide in the bathing medium and persisted in the
8
0 mM KCl media [36].
Altogether, in vascular smooth muscle cells, the pharmacological profiles of the selected
compounds A15, A33 and B16 are different from those of KATP channel openers and similar
2
+
to that of the Ca entry blocker verapamil. Interestingly, a certain structural similarity exists
between verapamil and series B compounds (Figure 5), which could explain the similarity of
their pharmacological profile. Indeed, both molecules have two substituted aromatic rings
spaced by a chiral benzylic carbon and an N-methyl group.
2
.2.3. Myorelaxant effect on rat trachea rings
Potassium channel openers, such as cromakalim, are also known to be active as
bronchorelaxants [40,41]. This effect is partially antagonized by glibenclamide, suggesting
that the bronchodilator activity of the drugs reflects, at least in part, their KATP channel
2
+
opening properties [42]. In previous reports, Ca entry blockers such as verapamil and
nifedipine have also been described as active relaxants on KCl-contracted guinea pig trachea
[
43,44].
To evaluate the tracheorelaxant activity of the newly synthesized compounds, eight
derivatives, A15, A33, B1, B4, B5, B6, B7 and B16 were selected and their relaxant activities
were measured in rat trachea contracted by 30 mM KCl. (±)-Cromakalim and verapamil were
used as reference compounds. The drug concentration that caused a 50% relaxation (EC )
5
0
was calculated from concentration-response curves (Table 4). The results clearly showed that
the reference compound (±)-cromakalim (EC = 124.4 µM) was weakly active, whereas all
5
0
selected products induced marked tracheorelaxant effects (1.7 < EC < 39.3 µM, 4.7 < E <
max
5
0
6
5.4, p < 0.05). The N-methylated compound B16 (X = Cl, Z = H) was the most potent (EC50
1.7 µM) in this series and had an activity similar to that of verapamil. Moreover, the aorta
=
selectivity ratio (tracheal vs vascular tissue) was also calculated using the formula [EC50
trachea (µM)/EC aorta (µM)]. Regarding the selectivity profile, and compared to the parent
5
0
compound (±)-cromakalim, these new drugs, in particular B16, exhibited a relative preference
for the tracheal tissue with the exception of B1, which showed almost the same potency on the
two tissues (p > 0.05), and B6, which displayed a relative preference (p < 0.05) for the
vascular smooth muscle (Table 4).

ACCEPTED MANUSCRIPT
2
.2.4. Stimulation of elastin synthesis in cultured vascular smooth muscle cells
Four of the most efficient tested vasodilators, A15, A33, B16, and B19, were evaluated for
their abilities to enhance elastin synthesis in cultured vascular smooth muscle cells (VSMCs).
In this test, cultured VSMCs from the rat aorta were incubated with selected compounds
dissolved in DMSO at different concentrations: 0 (DMSO alone added to cells), 20 and 50
µM (Figure 6). After 48 hours, the extracellular elastin quantities were determined
spectrophotometrically at 450 nm by ELISA technique (Figure 6). Diazoxide was used as a
positive reference regarding elastin production by vascular smooth muscle cells [26].
Compared to control conditions (DMSO alone), diazoxide induced a significant activation of
elastin production at 50 µM (+92%, 1-way ANOVA, p < 0.05), but not at 20 µM.
As shown in Figure 6, at 20 µM, compound B16, the most active relaxant compound of both
vascular and tracheal smooth muscles, stimulated elastin production compared to the effect of
vehicle alone (DMSO) and was therefore more active than diazoxide at this concentration.
The other analogues (A15, A33 and B19), as well as diazoxide, tested at the same
concentration, failed to stimulate elastin synthesis.
At 50 µM, compounds A15 and B19 were as potent as or slightly less potent than
diazoxide, respectively (p > 0.05). At 50 µM, compound B16 expressed the same potency as
at 20 µM, reflecting a ‟ceiling effect”, while compound A33 was completely unable to
enhance elastin production (p > 0.05).
Keeping in mind that diazoxide is a potassium channel opener, while A15, B16 and B19 have
been shown to be calcium channel blockers, it is legitimate to question the mechanism(s)
allowing all of these compounds to stimulate elastin synthesis. We can consider that the
activation of potassium channels should not be considered as the sole mechanism for
stimulating the synthesis of elastin, but it is is possibly the relaxation of the smooth muscle,
2
+
which happens by different mechanisms (blocking of Ca gated channels in the case of our
molecules) that is the triggering event. This hypothesis is strongly supported by a recent study
2
+
showing that Ca influx inhibits elastin synthesis by rat aortic smooth muscle cells [45]. The
results of our study confirm this mechanism, since we obtained vasodilatory molecules
blocking calcium gated channels and stimulating the synthesis of elastin.
3
. Conclusion
Starting from the KATP channel opener cromakalim, structural modulations by ring opening
led to two series of compounds (series A and B) bearing sulfonylurea moieties. Series A
molecules (N-unmethylated sulfonylureas) were found to have poor relaxant activity on

ACCEPTED MANUSCRIPT
vascular smooth muscles in contrast to series B compounds (N-methylated sulfonylureas),
with some of the latter drugs being even more active than the reference compound diazoxide,
but less active than cromakalim. These results strongly suggest that the lack of activity of
series A molecules was dependent on their ionization at physiological pH, because of the
acidic character linked to their unmethylated sulfonylurea function. In aortic rings
precontracted with 80 mM KCl or 30 mM KCl in the presence of glibenclamide, the
2
+
vasodilatory activities of compounds A15, A33, B16 and verapamil (a voltage-gated Ca
channel blocker) were preserved, while that of cromakalim (a KATP channel activator) was
lost. Such data suggested the involvement of voltage-gated calcium channels, instead of KATP
channels, in the vasorelaxant activity of our new compounds, which would mean that these
compounds are verapamil-like.
Interestingly, in the trachea, some selected compounds (A15, A33, B1, B4-B7 and
B16) showed a potent relaxant activity, stronger than on aortic rings (exept B6), in particular
compounds B16, which was the most active and the most tissue-selective compound, while
cromakalim had little activity in this organ.
In addition, compounds A15, B16 and B19 exhibited a marked stimulating effect on elastin
synthesis by cultured vascular smooth muscle cells, close to that of diazoxide regarding A15
and B19 (50 µM). Interestingly, 20 µM B16 markedly stimulated elastin expression while the
reference compound diazoxide was inactive at this low dose.
Molecules of series B such as B16 could represent a class of vasorelaxant drugs, relatively
selective of tracheal tissue and endowed with interesting stimulating activity of elastin
production by vascular smooth muscle cells, which, in a long term, could improve arterial
elasticity and hemodynamics. Further in vivo tests need to be performed to ascertain such a
hypothesis. Additional perspectives are needed to clarify the mechanism(s) involved in the
stimulation of elastin production.
4
. Experimental section
.1. Chemistry
4
Reagents and solvents were purchased from usual commercial suppliers and were used
without further purification. Yields reported refer to purified products. All reactions were
routinely checked by thin-layer chromatography (TLC) on Merck Silica Gel 60 F254
(0.25mmthick) and visualization was performed with UV light (254 nm, 360 nm). Melting
1
13
points were obtained on a Büchi melting point B540 capillary apparatus. H and C NMR
1
spectra were recorded on a Brüker Advance-400 instrument (400 MHz for H and 100 MHz

ACCEPTED MANUSCRIPT
1
3
13
for C) in DMSO-d (except compound B14 which was recorded in CDCl ), while C NMR
6
3
spectra of compounds A28-A32 were recorded on a Brüker Avance DPX 250 spectrometer
62.9 MHz) in in DMSO-d . Chemical shifts (δ) are reported in ppm relative to TMS as an
(
6
internal standard, or to the solvent in which the spectrum was recorded. The abbreviations s =
singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets, q = quartet, sept =
septuplet, br s = broad singlet, CHar = aromatic CH are used throughout. Coupling constants J
are given in Hertz. Electrospray ionization ESI mass spectra were acquired by the Institut de
Chimie Moléculaire de Grenoble (ICMG), on an Esquire 300 plus Brüker Daltonis instrument
with a nanospray inlet. Elemental analyses (C, H, N) were performed at the Institut de Chimie
Moléculaire de Grenoble (ICMG).
4
.1.1. General procedure for the synthesis of o-alkoxyacetophenones (3a-j)
4
.1.1.1. 5-Bromo-2-methoxyacetophenone (3a) [46,47]
A mixture of 5-Bromo-2-hydroxyacetophenone 2a (10 g, 46.5 mmol, 1 eq), potassium
carbonate (9.62 g, 69.75 mmol, 1.5 eq) and iodomethane (5.8 mL, 93 mmol, 2 eq) in DMF
(120 mL) were stirred overnight in a sealed round bottom flask at room temperature. DMF
was removed under reduced pression and the residue was partitioned between water and
EtOAc. The combined EtOAc extracts were washed with brine, 0.5 M NaOH and then three
times with water. The organic layer was dried over MgSO and the solvent evaporated. The
4
product was obtained as an off-white solid (9.5 g, 89%). m.p. 31-32°C. SM (ESI): m/z 251-
+
1
2
8
1
53 [M+Na] . H NMR (δ ppm): 2.54 (s, 3H, COCH ), 3.90 (s, 3H, OCH ), 7.18 (d, J
=
3
3
ortho
.9 Hz, 1H, CHar), 7.66 (d, Jmeta = 2.6 Hz, 1H, CHar), 7.72 (dd, Jortho = 8.9 Hz, Jmeta = 2.6 Hz,
H, CHar).
4
.1.1.2. 5-Bromo-2-ethoxyacetophenone (3b)
The title compound was obtained as described for 3a, starting from 2a (10 g, 46.5 mmol) and
bromoethane (7 mL, 93 mmol). White powder (10 g, 88%). m.p. 69-70°C. SM (ESI): m/z
+
1
2
65-267 [M+Na] . H NMR (δ ppm): 1.40 (t, J = 6.9 Hz, 3H, OCH CH ), 2.56 (s, 3H,
2 3
COCH ), 4.17 (q, J = 6.9 Hz, 2H, OCH CH ), 7.16 (d, J = 8.9 Hz, 1H, CHar), 7.66 (d,
ortho
3
2
3
Jmeta = 2.6 Hz, 1H, CHar), 7.69 (dd, Jortho = 8.9 Hz, Jmeta = 2.6 Hz, 1H, CHar).
4
.1.1.3. 5-Bromo-2-isopropoxyacetophenone (3c)
The title compound was obtained as described for 3a, starting from 2a (10 g, 46.5 mmol) and
-bromopropane (8.7 mL, 93 mmol). White powder (10.25 g, 85%). m.p. 40-41°C. SM
2

ACCEPTED MANUSCRIPT
+
1
(
ESI): m/z 279-281 [M+Na] . H NMR (δ ppm): 1.34 (d, J = 6.0 Hz, 6H, OCH(CH ) ), 2.54
3
2
(
s, 3H, COCH ), 4.79 (sept, J = 6.0 Hz, 1H, OCH(CH ) ), 7.18 (d, 1H, J
= 8.9 Hz, CHar),
3
3 2
ortho
7
.63 (d, 1H, Jmeta = 2.6 Hz, CHar), 7.67 (dd, Jortho = 8.9 Hz, Jmeta = 2.6 Hz, 1H, CHar).
4
.1.1.4. 2-Benzyloxy-5-bromoacetophenone (3d)
The title compound was obtained as described for 3a, starting from 2a (10 g, 46.5 mmol) and
benzylbromide (11 mL, 93 mmol). The crude product was washed with petroleum ether 40/60
to eliminate excess of benzylbromide and recrystallized from cyclohexane to afford 3d as
+
1
pure white crystals (9.42 g, 63%). m.p. 77-78°C. SM (ESI): m/z 327-329 [M+Na] . H NMR
(
δ ppm): 2.52 (s, 3H, COCH ), 5.26 (s, 2H, OCH ), 7.27 (d, J
= 8.7 Hz, 1H, CHar), 7.37
3
2
ortho
(m, 1H, CHar), 7.43 (m, 2H, CHar), 7.51 (m, 2H, CHar), 7.70 (m, 2H, CHar).
4
.1.1.5. 5-Chloro-2-methoxyacetophenone (3e)
The title compound was obtained as described for 3a, starting from 5-chloro-2-
hydroxyacetophenone 2b (10 g, 58.62 mmol) and iodomethane (7.24 mL, 117.24 mmol).
+
1
White powder (9.38 g, 86%). m.p. 34-35°C. SM (ESI): m/z 185-187 [M+H] . H NMR (δ
ppm): 2.54 (s, 3H, COCH ), 3.90 (s, 3H, OCH ), 7.23 (d, J = 8.9 Hz, 1H, CHar), 7.54 (d,
3
3
ortho
Jmeta = 2.7 Hz, 1H, CHar), 7.60 (dd, Jortho = 8.9 Hz, Jmeta = 2.7 Hz, 1H, CHar).
4
.1.1.6. 5-Chloro-2-ethoxyacetophenone (3f)
The title compound was obtained as described for 3a, starting from 5-chloro-2-
hydroxyacetophenone 2b (10 g, 58.62 mmol) and bromoethane (8.75 mL, 117.24 mmol).
+
1
White powder (10.6 g, 91%). m.p. 80-81°C. SM (ESI): m/z 199-201 [M+H] . H NMR (δ
ppm): 1.40 (t, J = 6.9 Hz, 3H, OCH CH ), 2.56 (s, 3H, COCH ), 4.17 (q, J = 6.9 Hz, 2H,
2
3
3
OCH CH ), 7.20 (d, J = 8.9 Hz, 1H, CHar), 7.54 (d, Jmeta = 2.7 Hz, 1H, CHar), 7.57 (dd,
ortho
2
3
Jortho = 8.9 Hz, Jmeta = 2.7 Hz, 1H, CHar).
4
.1.1.7. 5-Fluoro-2-methoxyacetophenone (3g)
The title compound was obtained as described for 3a, starting from 5-fluoro-2-
hydroxyacetophenone 2c (10 g, 64.88 mmol) and iodomethane (8 mL, 129.76 mmol).
+
1
Yellowish oil (10.18 g, 93%). SM (ESI): m/z 169 [M+H] . H NMR (δ ppm): 2.54 (s, 3H,
COCH ), 3.89 (s, 3H, OCH ), 7.20 (m, 1H, CHar), 7.34 (m, 1H, CHar), 7.39 (m, 1H, CHar).
3
3
4
.1.1.8. 5-Fluoro-2-ethoxyacetophenone (3h)

ACCEPTED MANUSCRIPT
The title compound was obtained as described for 3a, starting from 5-fluoro-2-
hydroxyacetophenone 2c (10 g, 64.88 mmol) and bromoethane (9.7 mL, 129.76 mmol). White
+
1
powder (11.11 g, 94%). m.p. 78-79°C. SM (ESI): m/z 183 [M+H] . H NMR (δ ppm): 1.40
(
t, J = 6.9 Hz, 3H, OCH CH ), 2.57 (s, 3H, COCH ), 4.15 (q, J = 6.9 Hz, 2H, OCH CH ),
2 3 3 2 3
7
.19 (m, 1H, CHar), 7.34 (m, 1H, CHar), 7.39 (m, 1H, CHar).
4
.1.1.9. 2-Benzyloxyacetophenone (3i)
The title compound was obtained as described for 3a, starting from 2-hydroxyacetophenone
d (10 g, 73.45 mmol) and benzylbromide (17.45 mL, 146.9 mmol). The crude product was
washed with petroleum ether 40/60 to eliminate excess of benzylbromide and afforded 3i as
2
+
1
white powder (14.17 g, 85%). m.p. 40-41°C. SM (ESI): m/z 249 [M+Na] . H NMR (δ
ppm): 2.53 (s, 3H, COCH ), 5.26 (s, 2H, OCH ), 7.05 (m, 1H, CHar), 7.27 (m, 1H, CHar),
3
2
7
1
.36 (m, 1H, CHar), 7.43 (m, 2H, CHar), 7.54 (m, 3H, CHar), 7.61 (dd, Jortho = 7.7 Hz, Jmeta
.7 Hz, 1H, CHar).
=
4
.1.1.10. 2-Benzyloxy-5-methylacetophenone (3j)
The title compound was obtained as described for 3a, starting from 2-hydroxy-5-
methylacetophenone 2e (10 g, 66.6 mmol) and benzylbromide (15.82 mL, 133.2 mmol). The
crude product was purified by chromatography (petroleum ether) to eliminate excess of
+
benzylbromide and afforded 3j as yellowish oil (12.5 g, 78%). SM (ESI): m/z 263 [M+Na] .
1
H NMR (δ ppm): 2.27 (s, 3H, PhCH ), 2.51 (s, 3H, COCH ), 5.21 (s, 2H, OCH ), 7.16 (d,
3
3
2
Jortho = 8.4 Hz, 1H, CHar), 7.35 (m, 2H, CHar), 7.42 (m, 3H, CHar), 7.51 (m, 2H, CHar).
4
.1.2. General procedure for the synthesis of o-alkoxyalcools (4a-j)
4
.1.2.1. R/S-1-(5-bromo-2-methoxyphenyl)-1-ethanol (4a)
Sodium borohydride (2.35 g, 62.21 mmol, 1.5 eq) was added portionvise to a stirred
suspension of 3a (9.5 g, 41.47 mmol, 1 eq) in methanol (140 mL) at 0 °C, and the mixture
was kept at this temperature for a further 30 min. The mixture was stirred for an
additional 30 min at ambient temperature, and the solvent was evaporated under vacuum
.
After addition of water the suspension was acidified with 6N hydrochloric acid (80 ml) and
the product was extracted with ethyl acetate. The organic layer was dried over magnesium
sulfate, filtered, and evaporated under reduced pressure. The resulting yellowish oil was
+
1
dried under vacuum to afford 4a (9 g, 93%). SM (ESI): m/z 253-255 [M+Na] . H NMR (δ
ppm): 1.26 (d, J = 6.4 Hz, 3H, CHCH ), 3.79 (s, 3H, OCH ), 4.95 (m, 1H, OHCHCH ), 5.19
3
3
3

ACCEPTED MANUSCRIPT
(d, J = 4.5 Hz, 1H, OHCH), 6.92 (d, Jortho = 8.8 Hz, 1H, CHar), 7.37 (dd, Jortho = 8.8 Hz, Jmeta
=
2.6 Hz, 1H, CHar), 7.54 (dd, Jmeta = 2.6 Hz, Jpara = 0.6 Hz, 1H, CHar).
4
.1.2.2. R/S-1-(5-bromo-2-ethoxyphenyl)-1-ethanol (4b)
The title compound was obtained as described for 4a, starting from 5-bromo-2-
ethoxyacetophenone 3b (10 g, 41.13 mmol) and sodium borohydride (2.33 g, 61.7 mmol)
.
+
1
Yellowish oil (9.35 g, 92%). SM (ESI): m/z 267-269 [M+Na] . H NMR (δ ppm): 1.27 (d, J
6.3 Hz, 3H, CHCH ), 1.33 (m, 3H, OCH CH ), 4.02 (m, 2H, OCH CH ), 4.96 (m, 1H,
=
3
2
3
2
3
OHCHCH ), 5.18 (d, 1H, J = 4.5 Hz, OHCH), 6.89 (d, J
= 8.6 Hz, 1H, CHar), 7.33 (dd,
3
ortho
Jortho = 8.6 Hz, Jmeta = 2.6 Hz, 1H, CHar), 7.54 (d, Jmeta = 2.6 Hz, 1H, CHar).
4
.1.2.3. R/S-1-(5-bromo-2-isopropoxyphenyl)-1-ethanol (4c)
The title compound was obtained as described for 4a, starting from 5-bromo-2-
isopropoxyacetophenone 3c (10 g, 38.9 mmol) and sodium borohydride (2.21 g, 58.35
+
1
mmol)
. Yellowish oil (9.76 g, 96%). SM (ESI): m/z 281-283 [M+Na] . H NMR (δ ppm):
1
.25 (d, J = 6.0 Hz, 6H, OCH(CH ) ), 1.26 (d, J = 7.2 Hz, 3H, CHCH ), 4.60 (sept, J = 6.0
3
2
3
Hz, 1H, OCH(CH ) ), 4.93 (m, 1H, OHCHCH ), 5.13 (d, J = 4.7 Hz, 1H, OHCH), 6.91 (d,
3
2
3
Jortho = 8.7 Hz, 1H, CHar), 7.31 (dd, Jortho = 8.7 Hz, Jmeta = 2.7 Hz, 1H, CHar), 7.52 (d, Jmeta
=
2
.7 Hz, 1H, CHar).
4
.1.2.4. R/S-1-(2-(benzyloxy)-5-bromophenyl)-1-ethanol (4d)
The title compound was obtained as described for 4a, starting from 2-benzyloxy-5-
bromoacetophenone 3d (9.4 g, 30.8 mmol) and sodium borohydride (1.75 g, 46.2 mmol)
.
+
1
Yellowish oil (8.52 g, 90%). SM (ESI): m/z 289-291 [M+H-H O] . H NMR (δ ppm): 1.28
2
(
d, J = 6.1 Hz, 3H, CHCH ), 5.00 (m, 1H, OHCHCH ), 5.13 (m, 2H, OCH ), 5.18 (d, J = 4.1
3 3 2
Hz, 1H, OHCH), 6.99 (d, Jortho = 8.7 Hz, 1H, CHar), 7.34 (m, 2H, CHar), 7.40 (m, 4H,
CHar), 7.55 (d, Jmeta = 2.7 Hz, 1H, CHar).
4
.1.2.5. R/S-1-(5-chloro-2-methoxyphenyl)-1-ethanol (4e)
The title compound was obtained as described for 4a, starting from 5-chloro-2-
methoxyacetophenone 3e (9.3 g, 50.37 mmol) and sodium borohydride (2.86 g, 75.55
+
1
mmol)
. Yellowish oil (7.71 g, 82%). SM (ESI): m/z 169-171 [M+H-H O] . H NMR (δ
2
ppm): 1.27 (d, J = 6.5 Hz, 3H, CHCH ), 3.79 (s, 3H, OCH ), 4.96 (m, 1H, OHCHCH ), 5.19
3
3
3

ACCEPTED MANUSCRIPT
(d, J = 4.4 Hz, 1H, OHCH), 6.96 (d, Jortho = 8.7 Hz, 1H, CHar), 7.24 (dd, Jortho = 8.7 Hz, Jmeta
=
2.7 Hz, 1H, CHar), 7.42 (d, Jmeta = 2.7 Hz, 1H, CHar).
4
.1.2.6. R/S-1-(5-chloro-2-ethoxyphenyl)-1-ethanol (4f)
The title compound was obtained as described for 4a, starting from 5-chloro-2-
ethoxyacetophenone 3f (10 g, 50.34 mmol) and sodium borohydride (2.86 g, 75.51 mmol)
.
+
1
Yellowish oil (9.7 g, 96%). SM (ESI): m/z 183-185 [M+H-H O] . H NMR (δ ppm): 1.28
2
(
d, J = 6.3 Hz, 3H, CHCH ), 1.33 (m, 3H, OCH CH ), 4.02 (m, 2H, OCH CH ), 4.98 (m, 1H,
3 2 3 2 3
OHCHCH ), 5.17 (d, J = 4.4 Hz, 1H, OHCH), 6.93 (d, J
= 8.7 Hz, 1H, CHar), 7.20 (dd,
3
ortho
Jortho = 8.7 Hz, Jmeta = 2.7 Hz, 1H, CHar), 7.43 (d, Jmeta = 2.7 Hz, 1H, CHar).
4
.1.2.7. R/S-1-(5-fluoro-2-methoxyphenyl)-1-ethanol (4g)
The title compound was obtained as described for 4a, starting from 5-fluoro-2-
methoxyacetophenone 3g (10 g, 59.47 mmol) and sodium borohydride (3.37 g, 89.2 mmol)
.
+
1
Yellowish oil (9.9 g, 97%). SM (ESI): m/z 153 [M+H-H O] . H NMR (δ ppm): 1.27 (d, J
2
=
6.3 Hz, 3H, CHCH ), 3.78 (s, 3H, OCH ), 4.97 (m, 1H, OHCHCH ), 5.14 (d, J = 4.4 Hz,
3 3 3
1
H, OHCH), 6.94 (m, 1H, CHar), 7.00 (m, 1H, CHar), 7.20 (m, 1H, CHar).
4
.1.2.8. R/S-1-(2-ethoxy-5-fluorophenyl)-1-ethanol (4h)
The title compound was obtained as described for 4a, starting from 2-ethoxy-5-
fluoroacetophenone 3h (11 g, 60.38 mmol) and sodium borohydride (3.43 g, 90.57 mmol)
.
+
+ 1
Yellowish oil (10.75 g, 96%). SM (ESI): 167 [M+H-H O] ,184 [M] . H NMR (δ ppm):
2
1
.28 (d, J = 6.3 Hz, 3H, CHCH ), 1.33 (m, 3H, OCH CH ), 4.02 (m, 2H, OCH CH ), 4.97
3 2 3 2 3
(
m, 1H, OHCHCH ), 5.12 (d, J = 4.4 Hz, 1H, OHCH), 6.92 (m, 1H, CHar), 6.97 (m, 1H,
3
CHar), 7.19 (m, 1H, CHar).
4
.1.2.9. R/S-1-(2-benzyloxyphenyl)-1-ethanol (4i)
The title compound was obtained as described for 4a, starting from 2-benzyloxyacetophenone
3
i (14 g, 61.87 mmol) and sodium borohydride (3.51 g, 92.8 mmol)
.
Yellowish oil (13 g,
+
+ 1
9
2%). SM (ESI): m/z 211 [M+H-H O] , 251 [M+Na] . H NMR (δ ppm): 1.31 (d, J = 6.3
2
Hz, 3H, CHCH ), 5.00 (d, J = 4.4 Hz, 1H, OHCH), 5.10 (m, 1H, OHCHCH ), 5.14 (m, 2H,
3
3
OCH ), 6.96 (m, 1H, CHar), 7.02 (m, 1H, CHar), 7.19 (m, 1H, CHar), 7.35 (m, 1H, CHar),
2
7
.42 (m, 2H, CHar), 7.49 (m, 3H, CHar).

ACCEPTED MANUSCRIPT
4
.1.2.10. R/S-1-(2-(benzyloxy)-5-methylphenyl)-1-ethanol (4j)
The title compound was obtained as described for 4a, starting from 2-benzyloxy-5-
methylacetophenone 3j (12 g, 49.94 mmol) and sodium borohydride (2.83 g, 74.91 mmol)
.
+
+ 1
Yellowish oil (11.61 g, 96%). SM (ESI): m/z 255 [M+H-H O] , 265 [M+Na] . H NMR (δ
2
ppm): 1.29 (d, J = 6.3 Hz, 3H, CHCH ), 2.25 (s, 3H, PhCH ), 4.95 (d, J = 4.4 Hz, 1H,
3
3
OHCH), 5.05 (m, 1H, OHCHCH ), 5.09 (m, 2H, OCH ), 6.90 (d, J = 8.2 Hz, 1H, CHar),
ortho
3
2
6
.97 (dd, Jortho = 8.2 Hz, Jmeta = 2.2 Hz, 1H, CHar), 7.28 (d, Jmeta = 2.2 Hz, 1H, CHar), 7.33
(m, 1H, CHar), 7.41 (m, 2H, CHar), 7.46 (m, 2H, CHar).
4
.1.3. General procedure for the synthesis of acetamides (5a-j) by Ritter reaction
4
.1.3.1. R/S-N-(1-(5-bromo-2-methoxyphenyl)ethyl)acetamide (5a)
A suspension of 4a (9 g, 38.95 mmol) in acetonitrile (112.5 mL) was added dropwise to
a stirred solution of acetonitrile (22 mL) in 98% sulfuric acid (5.63 mL) kept
between10°C and 0°C. Stirring was pursued for 1 h at room temperature. The solution
was poured into cold water, and the precipitate was collected by filtration, washed with
water, and purified by recrystallization from ethyl acetate to afford compound 5a as a white
-
1
solid (9.5 g, 89%). m.p. 165-166°C
.
SM (ESI ): m/z 270-272 [M-H] . H NMR (δ ppm):
1
.23 (d, J = 6.9 Hz, 3H, CHCH ), 1.87 (s, 3H, COCH ), 3.81 (s, 3H, OCH ), 5.18 (m, 1H,
3
3
3
NHCHCH ), 6.95 (d, J
= 8.9 Hz, 1H, CHar), 7.39 (m, 2H, CHar), 8.30 (d, J = 8.2 Hz, 1H,
3
ortho
NHCH).
4
.1.3.2. R/S-N-(1-(5-bromo-2-ethoxyphenyl)ethyl)acetamide (5b)
The title compound was obtained as described for 5a, starting from R/S-1-(5-bromo-2-
ethoxyphenyl)-1-ethanol 4b (9 g, 36.72 mmol). White solid (8.77 g, 83%). m.p. 113-114°C
.
-
1
SM (ESI): m/z 284-286 [M-H] . H NMR (δ ppm): 1.25 (d, J = 7.0 Hz, 3H, CHCH ), 1.35 (t,
3
J = 6.9 Hz, 3H, OCH CH ), 1.87 (s, 3H, COCH ), 4.06 (q, J = 6.9 Hz, 2H, OCH CH ), 5.16
2
3
3
2
3
(
m, 1H, NHCHCH ), 6.93 (m, 1H, CHar), 7.35 (m, 2H, CHar), 8.28 (d, J = 8.2 Hz, 1H,
3
NHCH).
4
.1.3.3. R/S-N-(1-(5-bromo-2-isopropoxyphenyl)ethyl)acetamide (5c)
The title compound was obtained as described for 5a, starting from R/S-1-(5-bromo-2-
isopropoxyphenyl)-1-ethanol 4c (9 g, 34.73 mmol). White solid (9.36 g, 89%). m.p. 138 °C
.
-
1
SM (ESI): m/z 298-300 [M-H] . H NMR (δ ppm): 1.23 (d, J = 6.9 Hz, 3H, CHCH ), 1.27
3
(
d, J = 6.0 Hz, 3H, OCH(CH ) ), 1.28 (d, J = 6.0 Hz, 3H, OCH(CH ) ), 1.85 (s, 3H, COCH ),
3 2 3 2 3

ACCEPTED MANUSCRIPT
4
.62 (sept, J = 6.0 Hz, 1H, OCH(CH ) ), 5.13 (m, 1H, NHCHCH ), 6.95 (d, J
= 8.7 Hz,
3
2
3
ortho
1
H, CHar), 7.32 (dd, Jortho = 8.7 Hz, Jmeta = 2.6 Hz, 1H, CHar), 7.35 (d, Jmeta = 2.6 Hz, 1H,
CHar), 8.23 (d, J = 8.2 Hz, 1H, NHCH).
4
.1.3.4. R/S-N-(1-(2-(benzyloxy)-5-bromophenyl)ethyl)acetamide (5d)
The title compound was obtained as described for 5a, starting from R/S-1-(2-(benzyloxy)-5-
bromophenyl)-1-ethanol 4d (8 g, 26.04 mmol). White solid (7.53 g, 83%). m.p. 176-177 °C
.
-
1
SM (ESI): m/z 346-348 [M-H] . H NMR (δ ppm): 1.28 (d, J = 7.0 Hz, 3H, CHCH ), 1.85
3
(
s, 3H, COCH ), 5.17 (m, 2H, OCH ), 5.26 (m, 1H, NHCHCH ), 7.03 (d, J
= 8.7 Hz, 1H,
3
2
3
ortho
CHar), 7.36 (m, 2H, CHar), 7.42 (m, 3H, CHar), 7.49 (m, 2H, CHar), 8.33 (d, J = 8.2 Hz, 1H,
NHCH).
4
.1.3.5. R/S-N-(1-(5-chloro-2-methoxyphenyl)ethyl)acetamide (5e)
The title compound was obtained as described for 5a, starting from R/S-1-(5-chloro-2-
methoxyphenyl)-1-ethanol 4e (7 g, 37.5 mmol). White solid (7.32 g, 85%). m.p. 151-152°C
.
+
+ 1
SM (ESI): 228-230 [M+H] , 250-252 [M+Na] . H NMR (δ ppm): 1.23 (d, J = 6.9 Hz, 3H,
CHCH ), 1.87 (s, 3H, COCH ), 3.82 (s, 3H, OCH ), 5.15 (m, 1H, NHCHCH ), 7.00 (m, 1H,
3
3
3
3
CHar), 7.26 (m, 2H, CHar), 8.30 (d, J = 8.0 Hz, 1H, NHCH).
4
.1.3.6. R/S-N-(1-(5-chloro-2-ethoxyphenyl)ethyl)acetamide (5f)
The title compound was obtained as described for 5a, starting from R/S-1-(5-fluoro-2-
methoxyphenyl)-1-ethanol 4f (9 g, 44.85 mmol). White solid (9.45 g, 87%). m.p. 129-130°C
.
+
+ 1
SM (ESI): m/z 242-244 [M+H] , 264-266 [M+Na] . H NMR (δ ppm): 1.25 (d, J = 7.0 Hz,
3
H, CHCH ), 1.35 (t, J = 7.0 Hz, 3H, OCH CH ), 1.87 (s, 3H, COCH ), 4.05 (q, J = 7.0 Hz,
3
2
3
3
2
H, OCH CH ), 5.17 (m, 1H, NHCHCH ), 6.97 (d, J = 8.7 Hz, 1H, CHar), 7.23 (m, 2H,
ortho
2
3
3
CHar), 8.28 (d, J = 8.2 Hz, 1H, NHCH).
4
.1.3.7. R/S-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)acetamide (5g)
The title compound was obtained as described for 5a, starting from R/S-1-(5-fluoro-2-
ethoxyphenyl)-1-ethanol 4g (9 g, 52.88 mmol). White solid (10.1 g, 90%). m.p. 147-148°C
.
+
+
+ 1
SM (ESI): m/z 212 [M+H] , 234 [M+Na] , 445 [2M+Na] . H NMR (δ ppm): 1.25 (d, J =
7
.0 Hz, 3H, CHCH ), 1.87 (s, 3H, COCH ), 3.81 (s, 3H, OCH ), 5.17 (m, 1H, NHCHCH ),
3 3 3 3
6
.97 (m, 1H, CHar), 7.02 (m, 1H, CHar), 7.07 (m, 1H, CHar), 8.22 (d, J = 8.0 Hz, 1H,
NHCH).

ACCEPTED MANUSCRIPT
4
.1.3.8. R/S-N-[1-(2-ethoxy-5-fluorophenyl)ethyl]acetamide (5h)
The title compound was obtained as described for 5a, starting from R/S-1-(2-ethoxy-5-
fluorophenyl)-1-ethanol 4h (10 g, 54.28 mmol). White solid (11.19 g, 91%). m.p. 140-141°C
.
+
+ 1
SM (ESI): m/z 226 [M+H] , 248 [M+Na] . H NMR (δ ppm): 1.26 (d, J = 7.0 Hz, 3H,
CHCH ), 1.35 (t, J = 7.0 Hz, 3H, OCH CH ), 1.87 (s, 3H, COCH ), 4.04 (q, J = 7.0 Hz, 2H,
3
2
3
3
OCH CH ), 5.19 (m, 1H, NHCHCH ), 6.95 (m, 1H, CHar), 7.00 (m, 1H, CHar), 7.06 (m, 1H,
2
3
3
CHar), 8.20 (d, J = 8.0 Hz, 1H, NHCH).
4
.1.3.9. R/S-N-(1-(2-(benzyloxy)phenyl)ethyl)acetamide (5i)
The title compound was obtained as described for 5a, starting from R/S-1-(2-
benzyloxyphenyl)-1-ethanol 4i (12 g, 52.56 mmol). White solid (12.88 g, 91%). m.p. 148-
+
+ 1
1
3
1
49°C
. SM (ESI): m/z 270 [M+H] , 292 [M+Na] . H NMR (δ ppm): 1.29 (d, J = 7.0 Hz,
H, CHCH ), 1.86 (s, 3H, COCH ), 5.17 (m, 2H, OCH ), 5.30 (m, 1H, NHCHCH ), 6.94 (m,
3
3
2
3
H, CHar), 7.04 (dd, Jortho = 8.2 Hz, Jpara = 0.7 Hz, 1H, CHar), 7.19 (dd, Jortho = 8.2 Hz, Jmeta
1.7 Hz, 1H, CHar), 7.29 (m, 1H, CHar), 7.34 (m, 1H, CHar), 7.42 (m, 2H, CHar), 7.51 (m,
=
2
H, CHar), 8.24 (d, J = 8.0 Hz, 1H, NHCH).
4
.1.3.10. R/S-N-(1-(2-(benzyloxy)-5-methylphenyl)ethyl)acetamide (5j)
The title compound was obtained as described for 5a, starting from R/S-1-(2-(benzyloxy)-5-
methylphenyl)-1-ethanol 4j (11 g, 45.4 mmol). White solid (11.5 g, 89%). m.p. 131-132°C
.
+
+ 1
SM (ESI): m/z 284 [M+H] , 306 [M+Na] . H NMR (δ ppm): 1.28 (d, J = 7.0 Hz, 3H,
CHCH ), 1.86 (s, 3H, COCH ), 2.24 (s, 3H, PhCH ), 5.12 (m, 2H, OCH ), 5.28 (m, 1H,
3
3
3
2
NHCHCH ), 6.92 (d, J
= 8.4 Hz, 1H, CHar), 6.98 (dd, Jortho = 8.4 Hz, Jmeta = 1.9 Hz, 1H,
3
ortho
CHar), 7.10 (d, Jmeta = 1.9 Hz, 1H, CHar), 7.34 (m, 1H, CHar), 7.41 (m, 2H, CHar), 7.49 (m,
2
H, CHar), 8.20 (d, J = 8.2 Hz, 1H, NHCH).
4
.1.4. General procedure for the synthesis of amines (6a-j)
4
.1.4.1. R/S-1-(5-bromo-2-methoxyphenyl)ethanamine hydrochloride (6a)
R/S-(1-(5-bromo-2-methoxyphenyl)ethyl)acetamide 5a (9.5 g, 34.91 mmol, 1 eq) was
dissolved in methanol (300 mL). A solution of sodium hydroxide (140 g, 3500 mmol,
1
00 eq) in water (100 mL) was added carefully. The mixture was heated under Argon,
for 60 h at 250°C, and then methanol was removed under vacuum. The mixture was
poured into ice and extracted with diethyl ether (3×150 mL). The combined organic layers
were washed with water, dried over anhydrous MgSO , filtered, and the filtrate was
4

ACCEPTED MANUSCRIPT
decolorized with charcoal. After concentration under reduced pressure to half of the
volume and treatment with ether saturated with gaseous hydrochloric acid, the solvent
was evaporated. The oily residue was precipitated from diethyl ether after stirring
overnight, and the precipitate formed was collected by filtration, washed with diethyl
ether and then recrystallized in methanol/acetonitrile (1:9). The amine hydrochloride was
obtained as a white crystals (7.83 g, 84%). m.p. 176-177°C. SM (ESI): m/z 213-215 [M+H-
+
+
+ 1
NH Cl] , 230-232 [M+H-HCl] , 252-254 [M+Na-HCl] . H NMR (δ ppm): 1.47 (d, J = 6.7
4
Hz, 3H, CHCH ), 3.85 (s, 3H, OCH ), 4.56 (m, 1H, CHCH ), 7.07 (d, J = 8.9 Hz, 1H,
ortho
3
3
3
CHar), 7.55 (dd, Jortho = 8.9 Hz, Jmeta = 2.4 Hz, 1H, CHar), 7.69 (d, Jmeta = 2.4 Hz, 1H, CHar),
+
8
.53 (br s, 3H, NH ).
3
4
.1.4.2. R/S-1-(5-bromo-2-ethoxyphenyl)ethanamine hydrochloride (6b)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(5-bromo-2-
ethoxyphenyl)ethyl)acetamide 5b (8.5 g, 29.7 mmol) and sodium hydroxide (119 g, 2.97
mol). White crystals (6.67 g, 80%). m.p. 237-238°C. SM (ESI): m/z 227-229 [M+H-
+
+
+ 1
NH Cl] , 244-246 [M+H-HCl] , 266-268 [M+Na-HCl] . H NMR (δ ppm): 1.37 (m, 3H,
4
OCH CH ), 1.47 (d, J = 6.7 Hz, 3H, CHCH ), 4.11 (m, 2H, OCH CH ), 4.58 (m, 1H,
2
3
3
2
3
CHCH ), 7.06 (d, J
= 8.9 Hz, 1H, CHar), 7.52 (dd, Jortho = 8.9 Hz, Jmeta = 2.5 Hz, 1H,
3
ortho
+
CHar), 7.68 (d, Jmeta = 2.5 Hz, 1H, CHar), 8.50 (br s, 3H, NH ).
3
4
.1.4.3. R/S-1-(5-bromo-2-isopropoxyphenyl)ethanamine hydrochloride (6c)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(5-bromo-2-
isopropoxyphenyl)ethyl)acetamide 5c (9 g, 29.98 mmol) and sodium hydroxide (120 g,
mol). White crystals (6.22 g, 70%). m.p. 214-215°C SM (ESI): m/z 241-243 [M+H-
3
.
+
+
+ 1
NH Cl] , 258-260 [M+H-HCl] , 280-282 [M+Na-HCl] . H NMR (δ ppm): 1.29 (d, J = 6.0
4
Hz, 3H, OCH(CH ) ), 1.32 (d, J = 6.0 Hz, 3H, OCH(CH ) ), 1.46 (d, J = 6.8 Hz, 3H,
3
2
3 2
CHCH ), 4.54 (m, 1H, CHCH ), 4.69 (sept, J = 6,0 Hz, 1H, OCH(CH ) ), 7.08 (d, J = 8.9
ortho
3
3
3 2
Hz, 1H, CHar), 7.49 (dd, Jortho = 8.9 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.73 (d, Jmeta = 2.5 Hz,
+
1
H, CHar), 8.65 (br s, 3H, NH ).
3
4
.1.4.4. R/S-1-(2-(benzyloxy)-5-bromophenyl)ethanamine hydrochloride (6d)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(2-(benzyloxy)-
-bromophenyl)ethyl)acetamide 5d (7.5 g, 21.54 mmol) and sodium hydroxide (86 g, 2.154
mol). White crystals (5.51 g, 74%). m.p. 159-160°C SM (ESI): m/z 289-291 [M+H-
5
.

ACCEPTED MANUSCRIPT
+
+
+ 1
NH Cl] , 306-308 [M+H-HCl] , 328-330 [M+Na-HCl] . H NMR (δ ppm): 1.48 (d, J = 6.7
4
Hz, 3H, CHCH ), 4.64 (m, 1H, CHCH ), 5.21 (m, 2H, OCH ), 7.14 (d, J = 8.9 Hz, 1H,
ortho
3
3
2
CHar), 7.36 (m, 1H, CHar), 7.43 (m, 2H, CHar), 7.50 (m, 2H, CHar), 7.53 (dd, Jortho= 8.9 Hz,
+
Jmeta = 2.5 Hz, 1H, CHar), 7.74 (d, Jmeta = 2.5 Hz, 1H, CHar), 8.58 (br s, 3H, NH ).
3
4
.1.4.5. R/S-1-(5-chloro-2-methoxyphenyl)ethanamine hydrochloride (6e)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(5-chloro-2-
methoxyphenyl)ethyl)acetamide 5e (7 g, 30.74 mmol) and sodium hydroxide (123 g, 3.074
mol). White crystals (5.33 g, 78%). m.p. 190-191°C. SM (ESI): m/z 169-171 [M+H-
+
+
+ 1
NH Cl] , 186-188 [M+H-HCl] , 208-210 [M+Na-HCl] . H NMR (δ ppm): 1.48 (d, J = 6.8
4
Hz, 3H, CHCH ), 3.85 (s, 3H, OCH ), 4.56 (m, 1H, CHCH ), 7.12 (d, J = 8.9 Hz, 1H,
ortho
3
3
3
CHar), 7.42 (dd, Jortho = 8.9 Hz, Jmeta = 2.6 Hz, 1H, CHar), 7.59 (d, Jmeta = 2.6 Hz, 1H, CHar),
+
8
.56 (br s, 3H, NH ).
3
4
.1.4.6. R/S-1-(5-chloro-2-ethoxyphenyl)ethanamine hydrochloride (6f)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(5-chloro-2-
ethoxyphenyl)ethyl)acetamide 5f (9 g, 37.23 mmol) and sodium hydroxide (149 g, 3.723
+
mol). White crystals (7.3 g, 83%). m.p. 226-227°C
.
SM (ESI): m/z 183-185 [M+H-NH Cl] ,
4
+
+ 1
2
1
00-202 [M+H-HCl] , 222-224 [M+Na-HCl] . H NMR (δ ppm): 1.37 (m, 3H, OCH CH ),
2 3
.48 (d, J = 6.7 Hz, 3H, CHCH ), 4.10 (m, 2H, OCH CH ), 4.57 (m, 1H, CHCH ), 7.10 (d,
3
2
3
3
Jortho = 8.9 Hz, 1H, CHar), 7.39 (dd, Jortho = 8.9 Hz, Jmeta = 2.3 Hz, 1H, CHar), 7.60 (d, Jmeta
=
+
2
.3 Hz, 1H, CHar), 8.61 (br s, 3H, NH ).
3
4
.1.4.7. R/S-1-(5-fluoro-2-methoxyphenyl)ethanamine hydrochloride (6g)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(5-fluoro-2-
methoxyphenyl)ethyl)acetamide 5g (10 g, 47.34 mmol) and sodium hydroxide (189 g, 4.734
+
mol). white crystals (6.7 g, 68%). m.p. 201-202°C
.
SM (ESI): m/z 153 [M+H-NH Cl] , 170
4
+
+ 1
[
(
M+H-HCl] , 192 [M+Na-HCl] . H NMR (δ ppm): 1.48 (d, J = 6.8 Hz, 3H, CHCH ), 3.83
3
s, 3H, OCH ), 4.57 (m, 1H, CHCH ), 7.09 (m, 1H, CHar), 7.20 (m, 1H, CHar), 7.47 (m, 1H,
3
3
+
CHar), 8.66 (br s, 3H, NH ).
3
4
.1.4.8. R/S-1-(2-ethoxy-5-fluorophenyl)ethanamine hydrochloride (6h)
The title compound was obtained as described for 6a, starting from R/S-N-[1-(2-ethoxy-5-
fluorophenyl)ethyl]acetamide 5h (11 g, 48.83 mmol) and sodium hydroxide (195 g, 4.883

ACCEPTED MANUSCRIPT
+
mol). White crystals (7.6 g, 70%). m.p. 184-185°C. SM (ESI): m/z 167 [M+H-NH Cl] , 184
4
+
+ 1
[
M+H-HCl] , 206 [M+Na-HCl] . H NMR (δ ppm): 1.36 (m, 3H, OCH CH ), 1.49 (d, J =
2 3
6
7
.8 Hz, 3H, CHCH ), 4.08 (m, 2H, OCH CH ), 4.59 (m, 1H, CHCH ), 7.08 (m, 1H, CHar),
3 2 3 3
+
.17 (m, 1H, CHar), 7.47 (m, 1H, CHar), 8.66 (br s, 3H, NH ).
3
4
.1.4.9. R/S-1-(2-benzyloxyphenyl)ethanamine hydrochloride (6i)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(2-
benzyloxy)phenyl)ethyl)acetamide 5i (12 g, 44.55 mmol) and sodium hydroxide (178 g,
.455 mol). White crystals (10.42 g, 88%). m.p. 138-139°C SM (ESI): m/z 211 [M+H-
(
4
.
+
+ 1
NH Cl] , 228 [M+H-HCl] . H NMR (δ ppm): 1.50 (d, J = 6.8 Hz, 3H, CHCH ), 4.67 (m,
4
3
1
H, CHCH ), 5.21 (m, 2H, OCH ), 7.05 (d, J = 7.5 Hz, 1H, CHar), 7.16 (d, Jortho = 8.2
ortho
3
2
Hz, 1H, CHar), 7.36 (m, 2H, CHar), 7.43 (m, 2H, CHar), 7.51 (m, 2H, CHar), 7.56 (d, Jortho
=
+
7
.5 Hz, 1H, CHar), 8.56 (br s, 3H, NH ).
3
4
.1.4.10. R/S-1-(2-(benzyloxy)-5-methylphenyl)ethanamine hydrochloride (6j)
The title compound was obtained as described for 6a, starting from R/S-N-(1-(2-(benzyloxy)-
5
-methylphenyl)ethyl)acetamide 5j (11 g, 38.82 mmol) and sodium hydroxide (155 g, 3.882
+
mol). White crystals (9.74 g, 90%). m.p. 156-157°C
.
SM (ESI): m/z 225 [M+H-NH Cl] ,
4
+
1
2
4
42 [M+H-HCl] . H NMR (δ ppm): 1.49 (d, J = 6.7 Hz, 3H, CHCH ), 2.27 (s, 3H, PhCH ),
3 3
.63 (m, 1H, CHCH ), 5.16 (m, 2H, OCH ), 7.03 (d, J = 8.4 Hz, 1H, CHar), 7.14 (dd,
ortho
3
2
Jortho = 8.4 Hz, Jmeta = 1.5 Hz, 1H, CHar), 7.35 (m, 1H, CHar), 7.42 (m, 3H, CHar), 7.49 (m,
+
2
H, CHar), 8.59 (br s, 3H, NH ).
3
4
.1.5. General procedure for the synthesis of sulfonylureas (A1-33)
4
.1.5.1. 1-(2,5-dimethoxybenzyl)-3-phenylsulfonylurea (A1)
Benzenesulfonyl isocyanate (0.96 mL, 7.18 mmol, 1.2 eq) was added to a solution of amine
(1 g, 5.98 mmol, 1 eq) in anhydrous methylene chloride (10 mL). After 30 min, the
resulting white precipitate was collected by filtration, washed with diethyl ether, and dried.
The product was recrystallized in ethyl acetate White solid (1.5 g, 71%). m.p. 144-145°C
SM (ESI ): m/z 351 [M+H] , 373 [M+Na] . H NMR (δ ppm): 3.64 (s, 3H, OCH ), 3.73 (s,
1a
.
.
+
+ 1
3
3
H, OCH ), 4.11 (d, J = 5.8 Hz, 2H, CH NH), 6.64 (d, J
= 3.0 Hz, 1H, CHar), 6.79 (dd,
3
2
meta
Jortho = 8.8 Hz, Jmeta = 3.0 Hz, 1H, CHar), 6.87 (t, J = 5.8 Hz, 1H, CH NH), 6.89 (d, Jortho
=
2
8
.8 Hz, 1H, CHar), 7.61 (m, 2H, CHar), 7.70 (m, 1H, CHar), 7.91 (m, 2H, CHar), 10.77 (s,
13
1
H, SO NH). C NMR (δ ppm): 38.4, 55.3, 55.7, 111.4, 112.1, 114.2, 127.1, 127.4, 129.0,
2

ACCEPTED MANUSCRIPT
1
33.2, 140.1, 150.7, 151.2, 152.9. Anal. Calcd for C H N O S: C, 54.85, H, 5.18, N, 7.99,
1
6
18
2
5
found: C, 55.18, H, 5.26, N, 8.11.
4
.1.5.2. 1-(2,5-dimethoxybenzyl)-3-(4-methylphenyl)sulfonylurea (A2)
The title compound was obtained as described for A1, starting from 1a (1 g, 5.98 mmol) and
4
1
-methylbenzenesulfonyl isocyanate (1.1 mL, 7.18 mmol). White solid (1.5 g, 68%). m.p.
+
+ 1
47-148°C. SM (ESI): m/z 365 [M+H] , 387 [M+Na] . H NMR (δ ppm): 2.40 (s, 3H,
PhCH ), 3.64 (s, 3H, OCH ), 3.73 (s, 3H, OCH ), 4.10 (d, J = 6.1 Hz, 2H, CH NH), 6.62 (d,
3
3
3
2
Jmeta = 3.0 Hz, 1H, CHar), 6.78 (dd, Jortho = 8.8 Hz, Jmeta = 3.0 Hz, 1H, CHar), 6.83 (t, J = 6.1
Hz, 1H, CH NH), 6.89 (d, J = 8.8 Hz, 1H, CHar), 7.40 (d, Jortho = 8.1 Hz, 2H, CHar), 7.79
2
ortho
13
(
d, Jortho = 8.1 Hz, 2H, CHar), 10.68 (s, 1H, SO NH). C NMR (δ ppm): 21.0, 38.3, 55.2,
2
5
5.7, 111.4, 112.0, 114.2, 127.2, 127.5, 129.4, 137.3, 143.6, 150.7, 151.3, 152.9. Anal. Calcd
for C H N O S: C, 56.03, H, 5.53, N, 7.69, found: C, 56.40, H, 5.52, N, 7.68.
1
7
20
2
5
4
.1.5.3. 1-(2,5-dimethoxybenzyl)-3-(4-chlorophenyl)sulfonylurea (A3)
The title compound was obtained as described for A1, starting from 1a (1 g, 5.98 mmol) and
4
1
3
1
-chlorobenzenesulfonyl isocyanate (1.07 mL, 7.18 mmol). White solid (1.95 g, 85%). m.p.
+
+ 1
86-187°C
H, OCH ), 3.73 (s, 3H, OCH ), 4.11 (d, J = 6.0 Hz, 2H, CH NH), 6.61 (d, J
meta
.
SM (ESI): m/z 385-387 [M+H] , 407-409 [M+Na] . H NMR (δ ppm): 3.65 (s,
= 3.1 Hz,
3
3
2
H, CHar), 6.78 (dd, Jortho = 8.9 Hz, Jmeta = 3.1 Hz, 1H, CHar), 6.89 (m, 2H, CH NH +
2
13
CHar), 7.69 (m, 2H, CHar), 7.92 (m, 2H, CHar), 10.84 (s, 1H, SO NH). C NMR (δ ppm):
2
3
8.3, 55.3, 55.7, 111.4, 112.0, 114.2, 127.4, 129.1, 129.2, 138.1, 139.0, 150.7, 151.3, 152.9.
Anal. Calcd for C H ClN O S: C, 49.94, H, 4.45, N, 7.28, found: C, 50.08, H, 4.32, N, 7.50.
1
6
17
2
5
4
.1.5.4. R/S-1-[1-(5-bromo-2-methoxyphenyl)ethyl]-3-phenylsulfonylurea (A4)
The title compound was obtained as described for A1, starting from amine 6a (1 g, 4.35
mmol) and benzenesulfonyl isocyanate (0.7 mL, 5.22 mmol). White solid (1.4 g, 77%). m.p.
+
+ 1
1
71-172°C
J = 6.8 Hz, 3H, CHCH ), 3.79 (s, 3H, OCH ), 4.86 (m, 1H, NHCHCH ), 6.95 (d, J
ortho
.
SM (ESI): m/z 413-415 [M+H] , 435-437 [M+Na] . H NMR (δ ppm): 1.24 (d,
= 8.7
3
3
3
Hz, 1H, CHar), 7.10 (d, J = 8.4 Hz, 1H, CHNH), 7.33 (d, Jmeta = 2.6 Hz, 1H, CHar), 7.39 (dd,
Jortho = 8.7 Hz, Jmeta = 2.6 Hz, 1H, CHar), 7.60 (m, 2H, CHar), 7.68 (m, 1H, CHar), 7.89 (m,
1
3
2
1
4
H, CHar), 10.68 (s, 1H, SO NH). C NMR (δ ppm): 21.2, 44.6, 55.7, 112.0, 113.3, 127.1,
2
28.7, 129.0, 130.5, 133.2, 134.2, 140.1, 150.4, 155.2. Anal. Calcd for C H BrN O S: C,
16
17
2
4
6.50, H, 4.15, N, 6.78, found: C, 46.82, H, 4.34, N, 6.63.

ACCEPTED MANUSCRIPT
4
.1.5.5. R/S-1-[1-(5-bromo-2-methoxyphenyl)ethyl]-3-(4-methylphenyl)sulfonylurea (A5)
The title compound was obtained as described for A1, starting from amine 6a (1 g, 4.35
mmol) and 4-methylbenzenesulfonyl isocyanate (0.8 mL, 5.22 mmol). White solid (1.43 g,
+
+ 1
77%). m.p. 165-166°C
. SM (ESI): m/z 427-429 [M+H] , 449-451 [M+Na] . H NMR (δ
ppm): 1.24 (d, J = 7.0 Hz, 3H, CHCH ), 2.39 (s, 3H, PhCH ), 3.79 (s, 3H, OCH ), 4.85 (m,
3
3
3
1
H, NHCHCH ), 6.95 (d, J
= 8.7 Hz, 1H, CHar), 7.05 (d, J = 8.4 Hz, 1H, NHCH), 7.31
3
ortho
(d, Jmeta = 2.4 Hz, 1H, CHar), 7.39 (m, 3H, CHar), 7.77 (m, 2H, CHar), 10.59 (s, 1H,
13
SO NH). C NMR (δ ppm): 21.0, 21.2, 44.6, 55.7, 111.9, 113.3, 127.1, 128.7, 129.4, 130.5,
2
1
34.3, 137.3, 143.6, 150.4, 155.2. Anal. Calcd for C H BrN O S: C, 47.78, H, 4.48, N, 6.56,
17 19 2 4
found: C, 48.01, H, 4.54, N, 6.67.
4
.1.5.6. R/S-1-[1-(5-bromo-2-methoxyphenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea (A6)
The title compound was obtained as described for A1, starting from amine 6a (1 g, 4.35
mmol) and 4-chlorobenzenesulfonyl isocyanate (0.78 mL, 5.22 mmol). White solid (1.5 g,
-
1
7
6
1
7
%). m.p. 173-174°C
.
SM (ESI): m/z 445-447-449 [M-H] . H NMR (δ ppm):
1
.24 (d, J =
.8 Hz, 3H, CHCH ), 3.79 (s, 3H, OCH ), 4.86 (m, 1H, NHCHCH ), 6.95 (d, J
= 8.6 Hz,
3
3
3
ortho
H, CHar), 7.14 (d, J = 8.3 Hz, 1H, NHCH), 7.31 (d, Jmeta = 2.5 Hz, 1H, CHar), 7.38 (dd,
Jortho = 8.6 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.68 (d, Jortho = 8.8 Hz, 2H, CHar), 7.90 (d, Jortho
=
1
3
8
1
4
.8 Hz, 2H, CHar), 10.77 (s, 1H, SO NH). C NMR (δ ppm): 21.1, 44.5, 55.7, 111.9, 113.3,
2
28.6, 129.2, 130.5, 134.2, 138.1, 138.9, 150.4, 155.2. Anal. Calcd for C H BrClN O S: C,
1
6
16
2
4
2.92, H, 3.60, N, 6.26, found: C, 43.13, H, 3.66, N, 6.34.
4
.1.5.7. R/S-1-[1-(5-bromo-2-ethoxyphenyl)ethyl]-3-phenylsulfonylurea (A7)
The title compound was obtained as described for A1, starting from amine 6b (1 g, 4.1 mmol)
and benzenesulfonyl isocyanate (0.66 mL, 4.92 mmol). White solid (1.38 g, 78%). m.p.
+
+ 1
1
79-180°C. SM (ESI): m/z 427-429 [M+H] , 449-451 [M+Na] . H NMR (δ ppm): 1.27 (d,
J = 6.8 Hz, 3H, CHCH ), 1.32 (m, 3H, OCH CH ), 4.03 (m, 2H, OCH CH ), 4.86 (m, 1H,
3
2
3
2
3
NHCHCH ), 6.93 (d, J
= 8.6 Hz, 1H, CHar), 7.04 (d, J = 8.3 Hz, 1H, NHCH), 7.31 (d,
3
ortho
Jmeta = 2.5 Hz, 1H, CHar), 7.36 (dd, Jortho = 8.6 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.60 (m, 2H,
13
CHar), 7.68 (m, 1H, CHar), 7.89 (m, 2H, CHar), 10.77 (s, 1H, SO NH). C NMR (δ ppm):
2
1
4.4, 21.0, 44.8, 63.8, 111.8, 114.1, 127.0, 128.8, 129.0, 130.5, 133.2, 134.2, 140.1, 150.4,
54.6. Anal. Calcd for C H BrN O S: C, 47.78, H, 4.48, N, 6.56, found: C, 47.57, H, 4.45,
1
1
7
19
2
4
N, 6.49.

ACCEPTED MANUSCRIPT
4
.1.5.8. R/S-1-[1-(5-bromo-2-ethoxyphenyl)ethyl]-3-(4-methylphenyl)sulfonylurea (A8)
The title compound was obtained as described for A1, starting from amine 6b (1 g, 4.1 mmol)
and 4-methylbenzenesulfonyl isocyanate (0.75 mL, 4.92 mmol). White solid (1.41 g, 78%).
+
+ 1
m.p. 184-185°C. SM (ESI): m/z 441-443 [M+H] , 463-465 [M+Na] . H NMR (δ ppm):
1
2
8
.24 (d, J = 6.8 Hz, 3H, CHCH ), 1.32 (m, 3H, OCH CH ), 2.38 (s, 3H, PhCH ), 4.03 (m,
3
2
3
3
H, OCH CH ), 4.86 (m, 1H, NHCHCH ), 6.93 (d, J
= 8.6 Hz, 1H, CHar), 6.99 (d, J =
2
3
3
ortho
.3 Hz, 1H, NHCH), 7.29 (d, Jmeta = 2.5 Hz, 1H, CHar), 7.36 (dd, Jortho = 8.6 Hz, Jmeta = 2.5
Hz, 1H, CHar), 7.39 (d, Jortho = 8.3 Hz, 2H, CHar), 7.77 (d, Jortho = 8.3 Hz, 2H, CHar), 10.61
13
(
br s, 1H, SO NH). C NMR (δ ppm): 14.4, 21.0, 44.8, 63.7, 111.8, 114.1, 127.1, 128.8,
2
1
4
4
29.4, 130.5, 134.3, 137.3, 143.6, 150.4, 154.6. Anal. Calcd for C H BrN O S: C, 48.99, H,
18 21 2 4
.80, N, 6.35, found: C, 49.08, H, 4.85, N, 6.50.
.1.5.9. R/S-1-[1-(5-bromo-2-ethoxyphenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea (A9)
The title compound was obtained as described for A1, starting from amine 6b (1 g, 4.1 mmol)
and 4-chlorobenzenesulfonyl isocyanate (0.73 mL, 4.92 mmol). White solid (1.33 g, 70%).
+
+ 1
m.p. 190-191°C. SM (ESI): m/z 461-463-465 [M+H] , 483-485-487 [M+Na] . H NMR (δ
ppm): 1.27 (d, J = 6.8 Hz, 3H, CHCH ), 1.32 (m, 3H, OCH CH ), 4.03 (m, 2H, OCH CH ),
3
2
3
2
3
4
.86 (m, 1H, NHCHCH ), 6.92 (d, J
= 8.6 Hz, 1H, CHar), 7.07 (d, J = 8.1 Hz, 1H,
3
ortho
NHCH), 7.29 (d, Jmeta = 2.5 Hz, 1H, CHar), 7.36 (dd, Jortho = 8.6 Hz, Jmeta = 2.5 Hz, 1H,
13
CHar), 7.68 (m, 2H, CHar), 7.90 (m, 2H, CHar), 10.79 (s, 1H, SO NH). C NMR (δ ppm):
2
1
1
3
4.4, 20.9, 44.7, 63.8, 111.8, 114.1, 128.7, 129.1, 129.2, 130.5, 134.2, 138.1, 138.9, 150.3,
54.5. Anal. Calcd for C H BrClN O S: C, 44.22, H, 3.93, N, 6.07, found: C, 44.18, H,
17
18
2
4
.88, N, 6.12.
4
.1.5.10. R/S-1-[1-(5-bromo-2-isopropoxyphenyl)ethyl]-3-phenylsulfonylurea (A10)
The title compound was obtained as described for A1, starting from amine 6c (1 g, 3.87
mmol) and benzenesulfonyl isocyanate (0.62 mL, 4.64 mmol). White solid (1.13 g, 66%).
+
+ 1
m.p. 180-181°C. SM (ESI): m/z 441-443 [M+H] , 463-465 [M+Na] . H NMR (δ ppm):
1
.23 (d, J = 6.0 Hz, 3H, CHCH ), 1.26 (d, J = 6.3 Hz, 6H, OCH(CH ) ), 4.63 (sept, J = 6.3
3 3 2
Hz, 1H, OCH(CH ) ), 4.86 (m, 1H, NHCHCH ), 6.96 (d, J = 8.9 Hz, 1H, CHar), 6.98 (d,
ortho
3
2
3
J = 8.2 Hz, 1H, NHCH), 7.30 (d, Jmeta = 2.6 Hz, 1H, CHar), 7.35 (dd, Jortho = 8.9 Hz, Jmeta
=
2
1
1
4
.6 Hz, 1H, CHar), 7.60 (m, 2H, CHar), 7.69 (m, 1H, CHar), 7.89 (m, 2H, CHar), 10.70 (br s,
13
H, SO NH). C NMR (δ ppm): 20.9, 21.5, 21.6, 44.8, 69.8, 111.5, 115.2, 127.0, 127.3,
2
29.0, 130.5, 133.2, 134.9, 140.1, 150.3, 153.5. Anal. Calcd for C H BrN O S: C, 48.99, H,
1
8
21
2
4
.80, N, 6.35, found: C, 48.73, H, 4.76, N, 6.75.

ACCEPTED MANUSCRIPT
4
.1.5.11.
R/S-1-[1-(5-bromo-2-isopropoxyphenyl)ethyl]-3-(4-methylphenyl)sulfonylurea
(A11)
The title compound was obtained as described for A1, starting from amine 6c (1 g, 3.87
mmol) and 4-methylbenzenesulfonyl isocyanate (0.71 mL, 4.64 mmol). White solid (1.34 g,
+
+ 1
7
6
%). m.p. 152-153°C
. SM (ESI): m/z 455-457 [M+H] , 477-479 [M+Na] . H NMR (δ
ppm): 1.24 (d, J = 6.0 Hz, 3H, CHCH ), 1.26 (d, J = 6.0 Hz, 3H, OCH(CH ) ), 1.27 (d, J =
3
3 2
6
.0 Hz, 3H, OCH(CH ) ), 2.39 (s, 3H, PhCH ), 4.63 (sept, J = 6.0 Hz, 1H, OCH(CH ) ), 4.84
3 2 3 3 2
(
m, 1H, NHCHCH ), 6.91 (d, J = 8.3 Hz, 1H, NHCH), 6.96 (d, J
= 8.8 Hz, 1H, CHar),
3
ortho
7
.28 (d, Jmeta = 2.5 Hz, 1H, CHar), 7.34 (dd, Jortho = 8.8 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.39 (d,
13
Jortho = 8.3 Hz, 2H, CHar), 7.77 (d, Jortho = 8.3 Hz, 2H, CHar), 10.58 (br s, 1H, SO NH).
C
2
NMR (ppm): 20.9, 21.0, 21.5, 21.6, 44.8, 69.8, 111.5, 115.2, 127.1, 129.0, 129.4, 130.4,
1
35.0, 137.4, 143.6, 150.4, 153.5. Anal. Calcd for C H BrN O S: C, 50.11, H, 5.09, N, 6.15,
19 23 2 4
found: C, 50.14, H, 5.10, N, 6.11.
4
.1.5.12.
R/S-1-[1-(5-bromo-2-isopropoxyphenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea
(A12)
The title compound was obtained as described for A1, starting from amine 6c (1 g, 3.87
mmol) and 4-chlorobenzenesulfonyl isocyanate (0.7 mL, 4.64 mmol). White solid (1.38 g,
+
+ 1
7
5
%). m.p. 152-153°C
. SM (ESI): m/z 475-477-479 [M+H] , 497-499-501 [M+Na] . H
NMR (δ ppm): 1.22 (d, J = 6.1 Hz, 3H, CHCH ), 1.26 (d, J = 6.3 Hz, 3H, OCH(CH ) ), 1.27
3
3 2
(
d, J = 6.3 Hz, 3H, OCH(CH ) ), 4.62 (sept, J = 6.3 Hz, 1H, OCH(CH ) ), 4.85 (m, 1H,
3 2 3 2
NHCHCH ), 6.95 (d, J
= 8.8 Hz, 1H, CHar), 6.98 (d, J = 8.3 Hz, 1H, NHCH), 7.29 (d,
3
ortho
Jmeta = 2.5 Hz, 1H, CHar), 7.34 (dd, Jortho = 8.8 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.68 (m, 2H,
13
CHar), 7.90 (m, 2H, CHar), 10.75 (br s, 1H, SO NH). C NMR (δ ppm): 20.8, 21.5, 21.6,
2
4
4.7, 69.8, 111.5, 115.2, 128.9, 129.1, 129.3, 130.4, 134.9, 138.1, 139.0, 150.3, 153.4. Anal.
Calcd for C H BrClN O S: C, 45.44, H, 4.24, N, 5.89, found: C, 45.57, H, 4.48, N, 6.08.
1
8
20
2
4
4
.1.5.13. R/S-1-[1-(2-(benzyloxy)-5-bromophenyl)ethyl]-3-phenylsulfonylurea (A13)
The title compound was obtained as described for A1, starting from amine 6d (1 g, 3.26
mmol) and benzenesulfonyl isocyanate (0.52 mL, 3.91 mmol). White solid (1.04 g, 65%).
+
+ 1
m.p. 167-169°C
. SM (ESI): m/z 489-491 [M+H] , 511-513 [M+Na] . H NMR (δ ppm):
1
.28 (d, J = 6.8 Hz, 3H, CHCH ), 4.96 (m, 1H, NHCHCH ), 5.15 (m, 2H, OCH ), 7.01 (d,
3
3
2
Jortho = 9.1 Hz, 1H, CHar), 7.10 (d, J = 8.1 Hz, 1H, NHCH), 7.38 (m, 7H, CHar), 7.59 (m, 2H,

ACCEPTED MANUSCRIPT
13
CHar), 7.67 (m, 1H, CHar), 7.88 (m, 2H, CHar), 10.66 (br s, 1H, SO NH). C NMR (δ
2
ppm): 21.1, 44.3, 69.5, 112.3, 114.5, 127.0, 127.2, 127.8, 128.5, 128.6, 128.9, 130.4, 133.1,
1
34.9, 136.7, 140.3, 150.6, 154.0. Anal. Calcd for C H BrN O S: C, 53.99, H, 4.33, N, 5.72,
22 21 2 4
found: C, 54.00, H, 4.72, N, 5.64.
4
.1.5.14.
R/S-1-[1-(2-(benzyloxy)-5-bromophenyl)ethyl]-3-(4-methylphenyl)sulfonylurea
(A14)
The title compound was obtained as described for A1, starting from amine 6d (1 g, 3.26
mmol) and 4-methylbenzenesulfonyl isocyanate (0.6 mL, 3.91 mmol). White solid (1.2 g,
+
+ 1
7
3
%). m.p. 181-183°C
. SM (ESI): m/z 503-505 [M+H] , 525-527 [M+Na] . H NMR (δ
ppm): 1.28 (d, J = 6.8 Hz, 3H, CHCH ), 2.38 (s, 3H, PhCH ), 4.95 (m, 1H, NHCHCH ), 5.15
3
3
3
(
m, 2H, OCH ), 7.01 (d, Jortho = 8.8 Hz, 1H, CHar), 7.06 (d, J = 8.1 Hz, 1H, NHCH), 7.39 (m,
2
1
3
9
4
1
5
H, CHar), 7.77 (m, 2H, CHar), 10.59 (br s, 1H, SO NH). C NMR (δ ppm): 21.0, 21.1,
2
4.3, 69.5, 112.3, 114.5, 127.1, 127.2, 127.8, 128.5, 128.6, 129.4, 130.4, 134.8, 136.7, 137.3,
43.6, 150.5, 154.1. Anal. Calcd for C H BrN O S: C, 54.88, H, 4.61, N, 5.56, found: C,
2
3
23
2
4
4.64, H, 4.58, N, 5.53.
4
.1.5.15.
R/S-1-[1-(2-(benzyloxy)-5-bromophenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea
(A15)
The title compound was obtained as described for A1, starting from amine 6d (1 g, 3.26
mmol) and 4-chlorobenzenesulfonyl isocyanate (0.58 mL, 3.91 mmol). White solid (1.31 g,
+
+ 1
7
6
%). m.p. 161-162°C
. SM (ESI): m/z 523-525-527 [M+H] , 545-547-549 [M+Na] . H
NMR (δ ppm): 1.28 (d, J = 6.8 Hz, 3H, CHCH ), 4.96 (m, 1H, NHCHCH ), 5.15 (m, 2H,
3
3
OCH ), 7.01 (d, J
= 8.6 Hz, 1H, CHar), 7.15 (d, J = 8.1 Hz, 1H, NHCH), 7.39 (m, 7H,
2
ortho
CHar), 7.66 (d, Jortho = 8.4 Hz, 2H, CHar), 7.89 (d, Jortho = 8.4 Hz, 2H, CHar), 10.77 (br s, 1H,
13
SO NH). C NMR (δ ppm): 21.1, 44.2, 69.5, 112.3, 114.5, 127.2, 127.8, 128.4, 128.5,
2
1
29.1, 130.4, 134.8, 136.7, 138.0, 139.0, 150.5, 154.0. Anal. Calcd for C H BrClN O S: C,
22 20 2 4
5
0.44, H, 3.85, N, 5.35, found: C, 50.83, H, 3.86, N, 5.28.
4
.1.5.16. R/S-1-[1-(5-chloro-2-methoxyphenyl)ethyl]-3-phenylsulfonylurea (A16)
The title compound was obtained as described for A1, starting from amine 6e (1 g, 5.39
mmol) and benzenesulfonyl isocyanate (0.87 mL, 6.47 mmol). White solid (1.6 g, 80%).
+
+ 1
m.p. 167-168°C
.25 (d, J = 6.8 Hz, 3H, CHCH ), 3.79 (s, 3H, OCH ), 4.87 (m, 1H, CHCH ), 7.00 (d, J =
ortho
. SM (ESI): m/z 369-371 [M+H] , 391-393 [M+Na] . H NMR (δ ppm):
1
3
3
3

ACCEPTED MANUSCRIPT
8
.6 Hz, 1H, CHar), 7.07 (d, J = 8.1 Hz, 1H, NHCH), 7.21 (s, 1H, CHar), 7.26 (dd, Jortho = 8.6
Hz, Jmeta = 2.3 Hz, 1H, CHar), 7.60 (m, 2H, CHar), 7.68 (m, 1H, CHar), 7.90 (m, 2H, CHar),
1
3
1
1
4
0.66 (br s, 1H, SO NH). C NMR (δ ppm): 21.2, 44.7, 55.8, 112.8, 124.2, 125.9, 127.0,
2
27.6, 129.0, 133.1, 133.8, 140.2, 150.5, 154.8. Anal. Calcd for C H ClN O S: C, 52.10, H,
1
6
17
2
4
.65, N, 7.60, found: C, 52.12, H, 4.70, N, 7.58.
4
.1.5.17. R/S-1-[1-(5-chloro-2-methoxyphenyl)ethyl]-3-(4-methylphenyl)sulfonylurea (A17)
The title compound was obtained as described for A1, starting from amine 6e (1 g, 5.39
mmol) and 4-methylbenzenesulfonyl isocyanate (0.99 mL, 6.47 mmol). White solid (1.8 g,
+
+ 1
8
7
%). m.p. 194-195°C
. SM (ESI): m/z 383-385 [M+H] , 405-407 [M+Na] . H NMR (δ
ppm): 1.25 (d, J = 6.6 Hz, 3H, CHCH ), 2.38 (s, 3H, PhCH ), 3.79 (s, 3H, OCH ), 4.87 (m,
3
3
3
1
1
2
1
H, NHCHCH ), 6.99 (d, J
= 8.8 Hz, 1H, CHar), 7.04 (d, J = 8.1 Hz, 1H, NHCH), 7.19 (s,
3
ortho
H, CHar), 7.26 (m, 1H, CHar), 7.39 (d, Jortho = 7.7 Hz, 2H, CHar), 7.78 (d, Jortho = 7.7 Hz,
13
H, CHar), 10.57 (br s, 1H, SO NH). C NMR (δ ppm): 21.0, 21.2, 44.7, 55.8, 112.8,
2
24.2, 125.9, 127.1, 127.6, 129.4, 133.8, 137.3, 143.6, 150.4, 154.8. Anal. Calcd for
C H ClN O S: C, 53.33, H, 5.00, N, 7.32, found: C, 53.47, H, 5.25, N, 7.28.
17
19
2
4
4
.1.5.18. R/S-1-[1-(5-chloro-2-methoxyphenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea (A18)
The title compound was obtained as described for A1, starting from amine 6e (1 g, 5.39
mmol) and 4-chlorobenzenesulfonyl isocyanate (0.97 mL, 6.47 mmol). White solid (1.6 g,
+
+ 1
7
3
%). m.p. 195-196°C
. SM (ESI): m/z 403-405-407 [M+H] , 425-427-429 [M+Na] . H
NMR (δ ppm): 1.25 (d, J = 6.8 Hz, 3H, CHCH ), 3.79 (s, 3H, OCH ), 4.87 (m, 1H,
3
3
NHCHCH ), 6.99 (d, J
= 8.8 Hz, 1H, CHar), 7.11 (d, J = 8.3 Hz, 1H, NHCH), 7.18 (d,
3
ortho
Jmeta = 2.8 Hz, 1H, CHar), 7.26 (dd, Jortho = 8.8 Hz, Jmeta = 2.8 Hz, 1H, CHar), 7.68 (d, Jortho
=
13
8
.6 Hz, 2H, CHar), 7.90 (d, Jortho = 8.6 Hz, 2H, CHar), 10.74 (br s, 1H, SO NH). C NMR (δ
2
ppm): 21.1, 44.6, 55.8, 112.8, 124.2, 125.8, 127.6, 129.1, 133.8, 138.1, 138.9, 150.4, 154.8.
Anal. Calcd for C H Cl N O S: C, 47.65, H, 4.00, N, 6.95, found: C, 47.67, H, 4.06, N,
1
6
16
2
2
4
7
.03.
4
.1.5.19. R/S-1-[1-(5-chloro-2-ethoxyphenyl)ethyl]-3-phenylsulfonylurea (A19)
The title compound was obtained as described for A1, starting from amine 6f (1 g,
5 mmol)
and benzenesulfonyl isocyanate (0.8 mL, 6 mmol). White solid (1.68 g, 87%). m.p. 177-
+
+ 1
1
78°C
. SM (ESI): m/z 383-385 [M+H] , 405-407 [M+Na] . H NMR (δ ppm): 1.27 (d, J =
7
.1 Hz, 3H, CHCH ), 1.32 (m, 3H, OCH CH ), 4.03 (m, 2H, OCH CH ), 4.87 (m, 1H,
3
2
3
2
3

ACCEPTED MANUSCRIPT
NHCHCH ), 6.97 (d, J
= 8.6 Hz, 1H, CHar), 7.02 (d, J = 8.3 Hz, 1H, NHCH), 7.19 (d,
3
ortho
Jmeta = 2.5 Hz, 1H, CHar), 7.23 (dd, Jortho = 8.6 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.60 (m, 2H,
13
CHar), 7.68 (m, 1H, CHar), 7.89 (m, 2H, CHar), 10.67 (s, 1H, SO NH). C NMR (δ ppm):
2
1
4.4, 20.9, 44.9, 63.7, 113.6, 124.0, 126.0, 127.0, 127.7, 129.0, 133.2, 133.8, 140.1, 150.4,
54.1. Anal. Calcd for C H ClN O S: C, 53.33, H, 5.00, N, 7.32, found: C, 53.21, H, 4.97,
1
1
7
19
2
4
N, 7.23.
4
.1.5.20. R/S-1-[1-(5-chloro-2-ethoxyphenyl)ethyl]-3-(4-methylphenyl)sulfonylurea (A20)
The title compound was obtained as described for A1, starting from amine 6f (1 g, mmol)
and 4-methylbenzenesulfonyl isocyanate (0.92 mL, 6 mmol). White solid (1.82 g, 91%).
5
+
+ 1
m.p. 187-188°C
.
SM (ESI): m/z 397-399 [M+H] , 419-421 [M+Na] . H NMR (δ ppm):
1
.27 (d, J = 7.1 Hz, 3H, CHCH ), 1.33 (m, 3H, OCH CH ), 2.38 (s, 3H, PhCH ), 4.04 (m,
3
2
3
3
2
H, OCH CH ), 4.86 (m, 1H, NHCHCH ), 6.98 (m, 2H, CHar + NHCH), 7.16 (d, J
= 2.3
2
3
3
meta
Hz, 1H, CHar), 7.23 (dd, Jortho = 8.6 Hz, Jmeta = 2.3 Hz, 1H, CHar), 7.39 (d, Jortho = 8.2 Hz,
1
3
2
1
1
5
H, CHar), 7.77 (d, Jortho = 8.2 Hz, 2H, CHar), 10.58 (s, 1H, SO NH). C NMR (δ ppm):
2
4.4, 21.0, 21.1, 44.9, 63.7, 113.6, 124.0, 126.0, 127.1, 127.5, 129.4, 133.8, 137.3, 143.6,
50.4, 154.1. Anal. Calcd for C H ClN O S: C, 54.47, H, 5.33, N, 7.06, found: C, 54.21, H,
18
21
2
4
.42, N, 7.07.
4
.1.5.21. R/S-1-[1-(5-chloro-2-ethoxyphenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea (A21)
mmol)
and 4-chlorobenzenesulfonyl isocyanate (0.9 mL, 6 mmol). White solid (1.87 g, 89%). m.p.
The title compound was obtained as described for A1, starting from amine 6f (1 g,
5
+
+ 1
1
1
84-185°C. SM (ESI): m/z 417-419-421 [M+H] , 439-441-443 [M+Na] . H NMR (δ ppm):
.27 (d, J = 6.8 Hz, 3H, CHCH ), 1.32 (m, 3H, OCH CH ), 4.03 (m, 2H, OCH CH ), 4.87
3
2
3
2
3
(
m, 1H, NHCHCH ), 6.97 (d, J
= 8.6 Hz, 1H, CHar), 7.05 (d, J = 8.3 Hz, 1H, NHCH),
3
ortho
7
.17 (d, Jmeta = 2.5 Hz, 1H, CHar), 7.23 (dd, Jortho = 8.6 Hz, Jmeta = 2.5 Hz, 1H, CHar), 7.67 (d,
13
Jortho = 8.6 Hz, 2H, CHar), 7.90 (d, Jortho = 8.6 Hz, 2H, CHar), 10.76 (s, 1H, SO NH).
C
2
NMR (δ ppm): 14.4, 20.9, 44.8, 63.3, 113.5, 124.0, 125.9, 127.5, 129.1, 133.8, 138.1, 138.9,
1
50.3, 154.1. Anal. Calcd for C H Cl N O S: C, 48.93, H, 4.35, N, 6.71, found: C, 48.64, H,
17 18 2 2 4
4
.44, N, 6.36.
4
.1.5.22. R/S-1-[1-(5-fluoro-2-methoxyphenyl)ethyl]-3-phenylsulfonylurea (A22)
The title compound was obtained as described for A1, starting from amine 6g (1 g, 5.91
mmol) and benzenesulfonyl isocyanate (0.95 mL, 7.09 mmol). White solid (1.4 g, 67%).

ACCEPTED MANUSCRIPT
+
+ 1
m.p. 139-140°C
. SM (ESI): m/z 353 [M+H] , 375 [M+Na] . H NMR (δ ppm): 1.25 (d, J =
7
.1 Hz, 3H, CHCH ), 3.78 (s, 3H, OCH ), 4.87 (m, 1H, NHCHCH ), 7.01 (m, 4H, 3CHar +
3
3
3
NHCH), 7.59 (m, 2H, CHar), 7.68 (m, 1H, CHar), 7.90 (m, 2H, CHar), 10.64 (s, 1H,
13
3
2
SO NH). C NMR (δ ppm): 21.2, 44.8, 55.9, 112.3 (d, J = 8.1 Hz), 113.0 (d, J = 24.2
2
C-F
C-F
2
3
Hz), 113.7 (d, J = 22.9 Hz), 127.1, 129.0, 133.1, 133.5 (d, J = 6.7 Hz), 140.1, 150.4,
C-F
C-F
4
1
1
52.2 (d, J = 1.3 Hz), 156.3 (d, J = 236.5 Hz). Anal. Calcd for C H FN O S: C,
C-F C-F 16 17 2 4
5
4.54, H, 4.86, N, 7.95, found: C, 54.50, H, 4.88, N, 8.01.
4
.1.5.23. R/S-1-[1-(5-fluoro-2-methoxyphenyl)ethyl]-3-(4-methylphenyl)sulfonylurea (A23)
The title compound was obtained as described for A1, starting from amine 6g (1 g, 5.91
mmol) and 4-methylbenzenesulfonyl isocyanate (1.08 mL, 7.09 mmol). White solid (1.1 g,
+
+ 1
5
1
%). m.p. 159-160°C
. SM (ESI): m/z 367 [M+H] , 389 [M+Na] . H NMR (δ ppm): 1.25
(
d, J = 6.8 Hz, 3H, CHCH ), 2.38 (s, 3H, PhCH ), 3.78 (s, 3H, OCH ), 4.87 (m, 1H,
3
3
3
NHCHCH ), 7.01 (m, 4H, 3CHar + NHCH), 7.39 (d, Jortho = 8.2 Hz, 2H, CHar), 7.77 (d, Jortho
3
13
=
8.2 Hz, 2H, CHar), 10.64 (s, 1H, SO NH). C NMR (δ ppm): 21.0, 21.2, 44.8, 55.9, 112.3
2
3
2
2
(
d, J = 8.1 Hz), 113.0 (d, J = 24.2 Hz), 113.7 (d, J = 22.9 Hz), 127.1, 129.4, 133.6
C-F C-F C-F
3
4
1
(
d, J = 6.1 Hz), 137.3, 143.6, 150.4, 152.2 (d, J = 2.0 Hz), 156.2 (d, J = 235.8 Hz).
C-F
C-F
C-F
Anal. Calcd for C H FN O S: C, 55.73, H, 5.23, N, 7.65, found: C, 55.82, H, 5.32, N, 7.72.
1
7
19
2
4
4
.1.5.24. R/S-1-[1-(5-fluoro-2-methoxyphenyl)ethyl]-3-(4-chlorophenyl)sulfonylurea (A24)
The title compound was obtained as described for A1, starting from amine 6g (1 g, 5.91
mmol) and 4-chlorobenzenesulfonyl isocyanate (1.06 mL, 7.09 mmol). White solid (1 g,
+
+ 1
4
3
%). m.p. 161-162°C
. SM (ESI): m/z 387-389 [M+H] , 409-411 [M+Na] . H NMR (δ
ppm): 1.25 (d, J = 7.1 Hz, 3H, CHCH ), 3.78 (s, 3H, OCH ), 4.87 (m, 1H, NHCHCH ), 7.01
3
3
3
(m, 3H, CHar), 7.09 (d, J = 8.1 Hz, 1H, NHCH), 7.67 (m, 2H, CHar), 7.90 (m, 2H, CHar),
13
3
1
0.72 (s, 1H, SO NH). C NMR (δ ppm): 21.1, 44.7, 55.9, 112.3 (d, J = 8.1 Hz), 113.0
2 C-F
2
2
3
(
d, J = 24.2 Hz), 113.7 (d, J = 22.9 Hz), 129.1, 129.2, 133.5 (d, J = 6.7 Hz), 138.1,
C-F C-F C-F
4
1
1
38.9, 150.4, 152.2 (d, J
= 1.3 Hz), 156.3 (d, J
= 236.5 Hz). Anal. Calcd for
C-F
C-F
C H ClFN O S: C, 49.68, H, 4.17, N, 7.24, found: C, 49.51, H, 4.13, N, 7.29.
16
16
2
4
4
.1.5.25. R/S-1-[1-(2-ethoxy-5-fluorophenyl)ethyl]-3-phenylsulfonylurea (A25)
The title compound was obtained as described for A1, starting from amine 6h (1 g, 5.46
mmol) and benzenesulfonyl isocyanate (0.88 mL, 6.55 mmol). White solid (1.68 g, 84%).
+
+ 1
m.p. 139-140°C. SM (ESI): m/z 367 [M+H] , 389 [M+Na] . H NMR (δ ppm): 1.28 (d, J =