Cinnamic acid derived oxazolinium ions as novel cytotoxic agents.

Article abstract of DOI:10.1016/S0223-5234(02)01375-2

Substituted cinnamoyl chlorides, 11, were converted into (2-hydroxyethyl)-oxazolinium chlorides 14, N,N-bis-(2-chloroethyl)amides 16 and (2-chloroethyl)-oxazolinium chlorides 17. Although derivatives 14 which possess electron-donating substituents (Me or MeO) were more potent than those substituted by electron-withdrawing groups (NO(2), Cl or CF(3)), the difference in cytotoxic actin was not significant. Modification of the lipophilic character in a series of alkoxy-substituted derivatives 14 led to more active compounds, where 14t that possesses a 4-octyloxy-phenyl-substituent was the most potent and displayed cytotoxic activity in the microM range. It is assumed that the oxazolinium salts act as alkylating agents, and undergo nucleophilic attack on the methylene adjacent to the ring oxygen where the oxazolinium ring parallels the aziridinium ring intermediate found in classical alkylating agents.

Full text of DOI:10.1016/S0223-5234(02)01375-2

Eur. J. Med. Chem. 37 (2002) 607–616
www.elsevier.com/locate/ejmech
Preliminary communication
Cinnamic acid derived oxazolinium ions as novel cytotoxic agents
Lilach Hedvati, Abraham Nudelman *, Eliezer Falb, Boris Kraiz, Regina Zhuk,
Milon Sprecher*
Chemistry Department, Bar Ilan Uni6ersity, Ramat Gan 52900, Israel
Received 19 November 2001; accepted 22 March 2002
Abstract
Substituted cinnamoyl chlorides, 11, were converted into (2-hydroxyethyl)-oxazolinium chlorides 14, N,N-bis-(2-
chloroethyl)amides 16 and (2-chloroethyl)-oxazolinium chlorides 17. Although derivatives 14 which possess electron-donating
substituents (Me or MeO) were more potent than those substituted by electron-withdrawing groups (NO2, Cl or CF3), the
difference in cytotoxic actin was not significant. Modification of the lipophilic character in a series of alkoxy-substituted
derivatives 14 led to more active compounds, where 14t that possesses a 4-octyloxy-phenyl-substituent was the most potent and
displayed cytotoxic activity in the mM range. It is assumed that the oxazolinium salts act as alkylating agents, and undergo
nucleophilic attack on the methylene adjacent to the ring oxygen where the oxazolinium ring parallels the aziridinium ring
´
intermediate found in classical alkylating agents. © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: Cinnamic acid; Cytotoxic agents; Oxazolinium salts
philic and the aziridinium intermediate 3 forms readily.
In such cases the nitrogen mustard 2 may be unaccep-
tably toxic due to a lack of in vivo alkylating selectivity
[2], as found in p-amino-substituted-aniline mustard.
High alkylating potency was also observed with p-MeO
and p-Me substituents [3–5]. In these aniline mustards
the antitumour activity parallels toxicity and both
properties correlate with the electronic parameters (|)
of the substituents on the phenyl ring and their hydro-
phobic constants (y). QSAR studies showed the domi-
nant role played by the electronic factor, whereas the
role of the hydrophobic character of the substituent is
not yet clear [6]. N,N-bis-(2-chloroethyl)amides 5 of
aliphatic acids were prepared from the corresponding
acyl chlorides and bis-(2-chloroethyl)amine [7–9]. N-
Methanesulfonyl-N,N-bis-(2-iodoethyl)amides were ob-
tained by displacement of the corresponding
N,N-bis-(2-methanesulfonate)sulfonamides with iodide
[10]. Amides 5 were reported to be less active as well as
less toxic than the corresponding amines due to the
diminished nucleophilic character of the nitrogen atom.
Although bis-(2-chloroethyl)amides of aromatic acids 5
could have been expected to become alkylating agents
upon in vivo hydrolysis to the active N,N-bis-(2-
chloroethyl)amine 6, they were found to be inactive
1. Introduction
Clinically useful chemotherapeutic nitrogen mus-
tards, 2, such as mechloretamine, cyclophosphamide,
ifosfamide, melphalan and chlorambucil, are commonly
prepared from the corresponding substituted-N,N-bis-
(2-hydroxyethyl)amines 1 when treated with SOCl2 or
PCl5. The mechanism by which they elicit their biologi-
cal activity involves initial intramolecular nucleophilic
displacement of a chloride to give reactive aziridinium
intermediates 3 that serve as alkylating species (Fig. 1).
The potency of the nitrogen mustards is frequently a
function of the nucleophilicity of the nitrogen atom [1].
When the R group is strongly electron withdrawing,
the nucleophilicity of the nitrogen atom may diminish
to a point where the aziridinum intermediate 3 does not
form readily and compound 2 thus becomes inactive as
an alkylating agent. In the series of N,N-bis-(2-
chloroethyl)anilines, it was shown that deactivation by
p-NO2 or p-MeSO2 substituents leads to long half life
and low potency. However, when the R group is elec-
tron donating, the nitrogen atom becomes highly nucleo-
* Correspondence and reprints
E-mail address: nudelman@mail.biu.ac.il (A. Nudelman).
´
0223-5234/02/$ - see front matter © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S0223-5234(02)01375-2

608
L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
bis-(2-chloroethyl)amides from the corresponding cin-
namic acids failed [11–13]. Thus, a balance between
electron withdrawing and donating power of the R
group is sought, that will reduce the nucleophilicity of
the nitrogen atom, but only to such an extent that it
will not impair the formation of a reactive aziridinium
ion [14–16].
The aim of these investigations was to evaluate subs-
tituted-cinnamyl-bis-(2-chloroethyl)amides as potential
alkylating agents, taking advantage of the possibility of
modifying the nucleophilicity of the amido nitrogen
atom by introducing a variety of electron withdrawing
and donating substituents on the aromatic ring.
Fig. 1. General mechanism of action of nitrogen mustards.
2. Chemistry
Two alternative pathways have been described for
the preparation of N,N-bis-(2-chloroethyl)amides: (a)
treatment of N,N-bis-(2-hydroxyethyl)amides with thio-
nyl chloride or (b) coupling of an acid chloride with
N,N-bis-(2-chloroethyl)amine. Reaction of a cinnamoyl
chloride 11 with diethanolamine gave the correspon-
ding N,N-bis-(2-hydroxyethyl)cinnamamides 12, ana-
logs of diol precursors of nitrogen mustards (Fig. 3)
Fig. 2. Rearrangement and deactivation of N,N-(bis-2-chloroethyl)-
arylamides.
since they rearranged to esters 9 via an intermediate
oxazolinium ion 7 (Fig. 2). Attempts to obtain stable
Fig. 3. Synthesis of N,N-(bis-2-chloroethyl)-cinnamides (16) and oxazolinium salts (14 and 17).

L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
609
Table 1
1H-NMR and 13C-NMR chemical shifts of compounds 14, 16 and 17
Compound Solvent
1H-NMR
13C-NMR
CH2OH CH2O CHCO ArCH CH2N
CH2N
CH2OH
CH2O CHCO ArCH CNO
14r
14s
14t
DMSO
DMSO
DMSO
3.08, 3.30
3.06, 3.29
3.07, 3.30
3.71
3.70
3.69
4.42
4.40
4.40
6.46
6.47
6.47
7.78
7.78
7.74
48.63+50.33 57.15
45.77+49.15 56.22
45.53+49.11 56.21
59.35 115.90 144.98 165.94
59.36 114.50 145.02 166.01
59.37 114.51 145.00 166.03
CHCO ArCH CNO
CH2Cl+CH2N CHCO ArCH
CH2Cl
CH2N
16j
CDCl3
CDCl3
CDCl3
CDCl3
3.61–3.94
3.64–3.92
3.73–3.96
3.68–3.98
6.72
6.71
6.71
6.76
7.70
7.71
7.69
7.65
41.79+41.90 50.01+50.06 115.19 144.24 166.94
41.72+42.03 50.14+51.18 113.68 143.86 167.40
16n
16o
16p
41.9
41.7
50.17+51.22 114.12 144.11 167.06
49.86+51.03 115.59 146.10 166.71
CH2N+CH2Cl CH2O
CHCO
ArCH CH2Cl
CH2N
CH2O CHCO ArCH CNO
17u
17v
DMSO
3.91–4.5
3.6–4.1
4.43
4.66
6.47
6.36
7.81
7.82
39.52
37.83
47.67+48.19
46.10+48.29
59.37 114.54 145.22 166.08
58.52 113.54 145.22 165.75
CDCl3/
Acetone-d6
CDCl3/
17w
3.35–3.78
4.60
6.30
7.70
38.33
46.78+48.92
59.22 113.94 146.19 166.76
Acetone-d6
[17]. Subsequent reaction of 12 with SOCl2 in acetoni-
trile, in most cases gave mono-chloride products 14,
where only one of the two OH groups was replaced.
Attempts to replace the second OH even under drastic
conditions including reflux in the presence of an excess
of SOCl2, most frequently failed. Only in the single case
of 12h did both OH groups undergo replacement by Cl
to give 17h. Titration of the 17h showed that one
chloride was ionic and the other covalent. Interestingly,
the IR spectra (KBr pellets) of the diols 12 showed the
presence of two distinct OH absorptions at 3386–3344
and 3288–3245 cm−1, respectively, attributed to two
kinds of H-bonded OH groups. The chloride in com-
pounds 14 was also found to be ionic. Compounds 14,
probably because of their ionic character, readily pre-
cipitated from the acetonitrile media in the course of
the reaction. Other oxazolinium salts have also been
reported to precipitate from acetonitrile [18]. The for-
mation of 14 probably took place by cyclisation of an
intermediate imido-yl-onium chloride, its chlorosulphite
precursor or an amide 13, involving displacement of
chloride or chlorosulphite by one of the OH groups
[19], or displacement of the chloride by the amido
oxygen. Analogous cyclisations to oxazolines [20] or
unstable oxazolinium ions [21,22], as well as a single
example of an oxazolinium cinnamyl derivative [23],
have been reported. However, when 12b was treated
with SOCl2 in pyridine, an unexpected cyclisation took
place to give the eight-membered sulphite 18b.
17 (Fig. 3). Compounds 14, 16 and 17 were readily
1
distinguished by their characteristic H- and 13C-NMR
spectra (Table 1). Oxazolinium salts 17 were found to
be stable at room temperature for more than 2 years,
when stored in sealed vials.
3. Biological data
Biological evaluation of compounds 14 was carried
out in the Preclinical Antitumor Drug Discovery Screen
of the National Cancer Institute (NCI) [25,26]. The
data revealed that the most active compound was 14g,
which was substituted by a CF3 group at the 3-position.
Derivatives substituted with electron withdrawing
groups, i.e. NO2, Cl, CF3 at the 2- and 4-positions,
were the least active. This observation supports the
notion that a decrease in electron withdrawing ability
by the aromatic substituent would result in an increase
in biological activity. In fact, compounds possessing
electron-donating substituents were indeed found to be
more active than those possessing electron-withdrawing
substituents. Several of them were active against one or
more tumour cell lines at 10−4 M concentration. The
most active derivative, 14m, displayed activity against
31 out of the 56 cell lines evaluated. In general, the
highest activity was observed against leukaemia cell
lines. Compound 14q bearing a strong electron dona-
ting OH group, displayed poor activity in comparison
with derivatives substituted by less polar alkyl or
alkoxy groups. This fact may be attributed to the
higher hydrophilicity of 14q that interferes with its
ability to cross cell membranes.
The desired N,N-bis-(2-chloroethyl)-cinnamamides
16 could be prepared by treatment of 11 with N,N-bis-
(2-chloroethyl)amine in the presence of triethylamine
and working up the reaction after 0.5 h [24]. However,
when the reaction mixtures were stirred for 1–3 h at
50 °C the products obtained were the oxazolinium salts
Although derivatives possessing Me or MeO subs-
tituents were more potent than those substituted by

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L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
NO2, Cl and CF3 groups, the difference in potency was
not significant. When the difference in the activity of
compounds possessing electron donating or withdra-
wing substituents is small, as found in the present case,
Topliss’ empirical approach suggests modification in
their lipophilic character [27]. Therefore, a series of
alkoxy oxazolinium salts 14r–w of progressively in-
creasing chain length and lipophilicity of the alkyl
group, were prepared. The most active derivative in this
series 14t, having the 4-octyloxy-substituent, displayed
activity at 10−6 M concentration (Fig. 4), whereas the
analogs 14m, 14r and 14s having 4-methoxy, 4-propoxy
and 4-butoxy-substituents, respectively, were active
only at a maximum of 10−5 M concentrations. Subse-
quent modifications involving elongation of the alkyl
chain to 12, 16 and 18 carbons while at the same time
replacing the 2-hydroxyethyl-substituent on nitrogen
with a 2-chloroethyl group led to compounds less active
than 14t.
5.1.1. Alkylation of methyl 4-hydroxycinnamate (15q)
to methyl 4-alkoxycinnamates 15
5.1.1.1. General procedure. To 15q (1.7 g, 10 mmol) in
50% KOH (10 mmol, 1.35 mL), CH2Cl2 (10 mL), an
alkyl iodide (11 mmol) and a surfactant (aliquat or
Bu4N+ Br− 1% mole) were added and the mixture was
refluxed for 72 h. The organic layer was separated and
evaporated to dryness. The residue was extracted
(ether–H2O×3), washed with brine, dried (MgSO4)
and evaporated to give the products as yellow oils,
containing some residual alkyl iodide that was removed
under high vacuum (yields ca. 75%).
5.1.2. Methyl 4-propoxycinnamate (15r)
The crude yellow oil obtained was crystallised from
1
EtOH, m.p. 87 °C; H-NMR (CDCl3) l 1.04 (t, 3H,
J=8 Hz, Me), 1.48 (sextet, 2H, CH2Me), 3.79 (s, 3H,
CO2Me), 3.96 (t, 2H, J=8 Hz, CH2O), 6.26 (d, 1H,
J=16 Hz, CHCO2), 6.84 and 7.47 (AA%XX% system,
J=8 Hz, 4H, ArH), 7.65 (d, 1H, J=16 Hz, ArCH);
13C-NMR (CDCl3) l 10.5 (MeCH2), 22.5 (MeCH2),
51.6 (OMe), 69.6 (CH2O), 114.8 (C-3 and C-3%), 115.1
(CHCO2), 126.9 (C-1), 129.7 (C-2 and C-2%), 144.6
(ArCH), 161.1 (C-4), 167.9 (CO2); MS (CDI, CH4) m/z
221 ([MH]+, 100), 189 ([MH]+ꢀMeOH, 20), 179
([MH]+ꢀC3H6, 20); HRMS (DCI, CH4) Calc. for
C13H17O3 ([MH]+): 221.1178. Found: 221.1240.
4. Conclusions
It may thus be concluded that in this series of
oxazolinium derivatives the lipophilic character of the
4-alkoxy-substituent is the controlling factor in cyto-
toxic activity, and the 4-octyloxy-substituent displayed
an optimal balance of electron donating and lipophilic
characteristics. It is assumed that the oxazolinium salts
act as alkylating agents, and undergo a nucleophilic
attack on the methylene adjacent to the ring oxygen. In
this respect the oxazolinium ring parallels the aziri-
dinium ring intermediate found in classical alkylating
agents.
5.1.3. Methyl 4-butoxycinnamate (15s)
1H-NMR (CDCl3) l 0.89 (t, 3H, J=8 Hz, Me),
1.3–1.9 (m, 4H, CH2CH2Me), 3.79 (s, 3H, CO2Me),
3.99 (t, 2H, J=8 Hz, CH2O), 6.30 (d, 1H, J=16 Hz,
CHCO2), 6.89 and 7.46 (AA%XX% system, J=8 Hz, 4H,
ArH), 7.65 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3)
l 13.8 (MeCH2), 19.2 (MeCH2), 29.4
(CH2CH2O), 51.6 (OMe), 67.9 (CH20), 114.9 (C-3 and
C-3%), 115.0 (CHCO2), 126.9 (C-1), 129.7 (C-2 and
C-2%), 144.7 (ArCH), 161.1 (C-4), 167.9 (CO2); MS
(CDI, CH4) m/z 235 ([MH]+, 100), 203 ([MH]+
ꢀMeOH, 54), 179 ([MH]+ꢀC4H8, 25), 147 ([MH]+
ꢀC5H12O, 18); HRMS (DCI, CH4) Calc. for C14H19O3
([MH]+): 235.1334. Found: 235.1330.
5. Experimental
5.1. General chemistry
1H-NMR and 13C-NMR spectra were obtained on
Bruker AC-200, DPX-300 and DMX-600 spectrome-
ters. For CDCl3 and acetone-d6 solutions, chemical
shifts are expressed in ppm downfield from Me4Si used
as internal standard; for D2O solutions the HOD peak
was taken as l 4.80 (1H-spectra). Multiplicities in the
13C-NMR spectra were determined by off-resonance
decoupling. Mass spectra were obtained on a Finnigan
4021 spectrometer operating in chemical ionisation
(CI), desorption chemical ionisation (DCI) or HRMS
(high-resolution) modes. Melting points were deter-
mined on a Fisher–Johns apparatus. Analyses indi-
cated by the symbols of the elements were within
90.4% of the theoretical values.
5.1.4. Methyl 4-octyloxycinnamate (15t)
1H-NMR (CDCl3) l 0.89 (t, 3H, J=8 Hz, Me),
1.2–1.44 (m, 10H), 1.82 (quintet, 2H, J=8 Hz,
CH2CH2CH2O), 3.79 (s, 3H, Me), 3.98 (t, 2H, J=8
Hz, CH2O), 6.3 (d, 1H, J=16 Hz, CHCO2), 6.89 and
7.46 (AA%XX% system, J=8 Hz, 4H, ArH), 7.67 (d, 1H,
J=16H, ArCH); 13C-NMR (CDCl3) l 14.1 (MeCH2),
22.6, 26.0, 28.2, 28.7, 29.20 (Me(CH2)5), 32.8
(CH2CH2O), 51.54 (OMe), 68.1 (CH2O), 114. (C-3 and
C-3%), 115.0 (CHCO2), 126.5 (C-1), 129.7 (C-2 and
C-2%), 144.8 (ArCH), 161.4 (C-4), 167.8 (CO2); MS
(DCI, CH4) m/z 291 ([MH]+, 100), 259 ([MH]+

L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
611
ꢀMeOH, 25), 178 ([MH]+ꢀC6H17, 30), 113 (C8H17, 26);
HRMS (DCI, CH4) Calc. for C18H26O3 ([MH]+):
291.1960. Found: 291.1960.
CHCO2), 6.88 and 7.45 (AA%XX% system, 4H, J=8 Hz,
ArH), 7.64 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3) l 14.1 and 14.3 (two Me), 22.5 (C11), 26.0 and
29.2–29.7 (C2ꢀC9), 31.9 (C-10), 60.3 (CO2CH2Me), 68.1
(CH2O), 114.8 (C-3 and C-3%), 115.5 (CHCO2), 126.9
(C-1), 129.7 (C-2 and C-2%), 144.3 (ArCH), 161.0 (C-4),
167.4 (CO2); MS (DCI, CH4) m/z 361 ([MH]+, 100),
315 ([MH]+ꢀC2H6O, 18), 193 ([MH]+ꢀC11H23, 27);
HRMS (DCI, CH4) Calc. for C23H37O3 ([MH]+):
361.2743. Found: 361.2760.
5.1.5. Con6ersion of methyl 4-hydroxycinnamate (15q)
to ethyl 4-alkoxycinnamate (15%)
5.1.5.1. General procedure. To a stirred solution of Na
(20 mmol) in dry EtOH (20 mL), methyl 4-hydroxycin-
namate (3.56 g, 20 mmol), and an alkyl bromide (20
mmol) were added. The mixture was refluxed for 24 h,
then cooled and extracted (EtOAc–H2O, Na2CO3). The
organic layer was dried (MgSO4) and evaporated. The
product, purified by silica gel column chromatography
(hexane followed by Et2O), was obtained as a white
solid in ca. 95% yield after evaporation of the solvent.
5.1.7. Ethyl 4-hexadecyloxycinnamate (15%7)
1
M.p. 59 °C; H-NMR (CDCl3) l 0.88 (t, 3H, J=7
Hz, Me(CH2)15), 1.20–1.32 (m, 26H, Me(CH2)13), 1.33
(t, 2H, J=7 Hz, CO2CH2Me), 1.81 (sextet, 2H, J=7
Hz, OCH2CH2), 3.97 (t, 2H, J=7 Hz, OCH2), 4.25 (q,
2H, J=7 Hz, CO2CH2Me), 6.30 (d, 1H, J=16 Hz,
CHCO2), 6.88 and 7.45 (AA%XX% system, 4H, J=8 Hz,
ArH), 7.64 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3) l 14.1 and 14.3 (two Me), 22.7 (C15), 26.0 and
29.1–29.7 (C2ꢀC13), 31.9 (C14), 60.3 (CO2CH2Me), 68.1
(CH2O), 114.8 (C-3 and C-3%), 115.5 (CHCO2), 126.9
(C-1), 129.6 (C-2 and C-2%), 144.3 (ArCH), 160.94
5.1.6. Ethyl 4-dodecyloxycinnamate (15%u)
1
M.p. 53 °C; H-NMR (CDCl3) l 0.90 (t, 3H, J=7
Hz, Me(CH2)11), 1.18–1.50 (m, 18H, Me(CH2)9), 1.33
(t, 2H, J=7 Hz, CO2CH2Me), 1.81 (sextet, 2H, J=7
Hz, OCH2CH2), 3.97 (t, 2H, J=7 Hz, OCH2), 4.25 (q,
2H, J=7 Hz, CO2CH2Me), 6.30 (d, 1H, J=16 Hz,
Fig. 4. Dose response curves for 4,5-dihydro-2-[2-(4-octyloxyphenyl)ethene]-3-(2-hydroxyethyl) oxazolinium chloride 14t.

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L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
(C-4), 167.4 (CO2); MS (DCI, CH4) m/z 417 ([MH]+,
100), 371 ([MH]+ꢀMeCH2OH, 11), 193 ([MH]+
ꢀC16H33, 12); HRMS (DCI, CH4) Calc. for C27H45O3
([MH]+): 417.3369. Found: 417.3410.
(C-4), 172.16 (CO2); MS (DCI, CH4) m/z 221 ([MH]+,
100), 203 ([MH]+ꢀH2O, 30), 165 ([MH]+ꢀC4H8, 12);
HRMS (DCI, CH4) Calc. for C13H17O3 ([MH]+):
221.1178. Found: 221.1140.
5.1.8. Ethyl 4-octadecyloxycinnamate (15%w)
M.p. 63 °C; H-NMR (CDCl3) l 0.88 (t, 3H, J=7
5.1.12. 4-Octyloxycinnamic acid (10t)
M.p. 150 °C; H-NMR (CDCl3) l 0.88 (br t, 3H,
1
1
Hz, Me(CH2)17), 1.21–1.54 (m, 30H, Me(CH2)15), 1.34
(t, 2H, J=7 Hz, CO2CH2Me), 1.78 (sextet, 2H, J=7
Hz, OCH2CH2), 3.98 (t, 2H, J=7 Hz, OCH2), 4.26 (q,
2H, J=7 Hz, CO2CH2Me), 6.30 (d, 1H, J=16 Hz,
CHCO2), 6.89 and 7.47 (AA%XX% system, 4H, J=8 Hz,
ArH), 7.65 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3) l 14.0 and 14.3 (two Me), 22.6 (C17), 25.9 and
29.1–29.8 (C2ꢀC15), 31.8 (C16), 60.2 (CO2CH2Me), 68.0
(CH2O), 114.7 (C-3 and C-3%), 115.4 (CHCO2), 126.8
(C-1), 129.6 (C-2 and C-2%), 144.3 (ArCH), 160.9 (C-4),
167.24 (CO2); MS (DCI, CH4) m/z 445 ([MH]+, 100),
399 ([MH]+, MeCH2OH, 18), 193 ([MH]+C18H35, 28);
HRMS (DCI)CH4) Calc. for C29H49O3 ([MH]+):
445.3682. Found: 445.3690.
J=6 Hz, Me), 1.2-1.65 (m, 10H, Me(CH2)5), 1.79
(quintet, 2H, J=6 Hz, OCH2CH2), 3.99 (t, 2H, J=6
Hz, OCH2), 6.31 (d, 1H, J=16 Hz, CHCO2), 6.90 and
7.50 (AA%XX% system, 4H, J=8 Hz, ArH), 7.40 (d, 1H,
J=16 Hz, ArCH); 13C-NMR (CDCl3)
l 14.08
(MeCH2), 22.64, 25.98, 29.12, 29.21, 29.34 (Me(CH2)5),
31.79 (CH2CH2O), 68.79 (CH2O), 114.38 (CHCO2),
114.88 (C-3 and C-3%), 126.55 (C-1), 130.07 (C-2 and
C-2%), 146.74 (ArCH), 161.37 (C-4), 172.11 (CO2); MS
(DCI, CH4) m/z 277 ([MH]+, 100), 259 ([MH]+ꢀH2O,
26), 165 ([MH]+ꢀC8H16, 12); HRMS (DCI, CH4) Calc.
for C17H25O3 ([MH]+): 277.1804. Found: 277.1800.
5.1.13. 4-Dodecyloxycinnamic acid (10u)
1
M.p. 128 °C; H-NMR (CDCl3) l 0.88 (t, 3H, J=7
5.1.9. Hydrolysis of methyl 4-alkoxycinnamates (15) to
4-alkoxycinnamic acids 10
Hz, Me(CH2)11), 1.85–1.91 (m, 18H, Me(CH2)9), 1.79
(sextet, 2H, J=7 Hz, OCH2CH2), 3.99 (t, 2H, J=7
Hz, OCH2), 4.25 (q, 2H, J=7 Hz, CO2CH2Me), 6.31
(d, 1H, J=16 Hz, CHCO2), 6.90 and 7.49 (AA%XX%
system, 4H, J=8 Hz, ArH), 7.74 (d, 1H, J=16 Hz,
ArCH); 13C-NMR (CDCl3) l 14.13 (Me), 22.70 (C11),
26.00 and 29.1–29.7 (C2ꢀC9), 31.93 (C10), 68.22
(CH2O), 114.39 (CHCO2H), 114.91 (C-3 and C-3%),
126.58 (C-1), 130.10 (C-2 and C-2%), 146.80 (ArCH),
161.41 (C-4), 172.18 (CO2H); MS (DCI, CH4) m/z 333
([MH]+, 100), 315 ([MH]+ꢀH2O, 24), 193 ([MH]+
ꢀC11H23, 7); HRMS (DCI, CH4) Calc. for C21H33O3
([MH]+): 333.2430. Found: 333.2420.
5.1.9.1. General procedure. A methyl 4-alkoxycinnamate
(10 mmol) in EtOH (10 mL) was added to NaOH (5 M,
20 mL, 100 mmol). The solution was refluxed for 4 h
during which the salt precipitated. The mixture was
cooled, acidified (conc. HCl), extracted (EtOAc–H2O),
dried (MgSO4), and evaporated to dryness. The acids
were obtained as solids in quantitative yield.
5.1.10. 4-Propoxycinnamic acid (10r)
1
M.p. 155 °C; H-NMR (CDCl3) l 1.03 (t, 3H, J=8
Hz, Me), 1.82 (sextet, 2H, J=8 Hz, CH2CH2Me), 3.93
(t, 2H, J=8 Hz, OCH2), 6.42 (d, 1H, J=16 Hz,
CHCO2), 6.87 and 7.47 (AA%XX% system, 4H, J=8 Hz,
ArH), 7.66 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3) l 10.4 (Me), 22.5 (CH2CH2O), 69.7 (CH2O),
114.8 (C-3 and C-3%), 116.2 (CHCO2), 129.8 (C-2 and
C-2%), 145.2 (ArCH), 161.0 (C-4), 171.8 (CO2); MS
(DCI, CH4) m/z 207 ([MH]+, 100), 189 ([MH]+ꢀH2O,
36), 165 ([MH]+ꢀC3H6, 9); HRMS (DCI, CH4) Calc.
for C12H15O3 ([MH]+): 207.1021. Found: 207.1020.
5.1.14. 4-Hexadecyloxycinnamic acid (107)
M.p. 125 °C; H-NMR (CDCl3) l 0.88 (t, 3H, J=7
1
Hz, Me(CH2)15), 1.30–1.58 (m, 26H, Me(CH2)13), 1.85
(sextet, 2H, J=7 Hz, OCH2CH2), 3.99 (t, 2H, J=7
Hz, OCH2), 6.31 (d, 1H, J=16 Hz, CHCO2), 6.90 and
7.49 (AA%XX% system, 4H, J=8 Hz, ArH), 7.74 (d, 1H,
J=16 Hz, ArCH); 13C-NMR (CDCl3) l 14.10 (Me),
22.68 (C15), 26.01 and 29.2–29.7 (C2ꢀC13), 31.93 (C14),
68.25 (CH2O), 114.30 (CHCO2H), 114.96 (C-3 and
C-3%), 126.65 (C-1), 130.07 (C-2 and C-2%), 146.77
(ArCH), 161.43 (C-4), 171.53 (CO2H); MS (DCI, CH4)
m/z 389 ([MH]+, 100), 371 ([MH]+ꢀH2O, 18), 193
([MH]+ꢀC16H33, 13); HRMS (DCI, CH4) Calc. for
C25H41O3 ([MH]+): 389.3056. Found: 389.3060.
5.1.11. 4-Butoxycinnamic acid (10s)
1
M.p. 152 °C; H-NMR (CDCl3) l 0.98 (t, 3H, J=7
Hz, Me), 1.50 (sextet, 2H, J=7 Hz, CH2CH2Me), 1.79
(quintet, 2H, J=16 Hz, CH2CH2CH2), 4.00 (t, 2H,
J=7 Hz, OCH2), 6.31 (d, 1H, J=16 Hz, CHCO2),
6.91 and 7.50 (AA%XX% system, 4H, J=8 Hz, ArH),
7.74 (d, 1H, J=16 Hz, ArCH); 13C-NMR (CDCl3) l
13.82 (Me), 19.20 (MeCH2), 31.25 (CH2CH2O), 67.89
(CH2O), 114.38 (C-3 and C-3%) 114.91 (CHCO2), 126.64
(C-1) 130.10 (C-2 and C-2%), 146.82 (ArCH), 161.66
5.1.15. 4-Octadecyloxycinnamic acid (10w)
1
M.p. 119 °C; H-NMR (CDCl3) l 0.88 (t, 3H, J=7
Hz, Me(CH2)17), 1.20–1.62 (m, 30H, Me(CH2)15), 1.78
(sextet, 2H, J=7 Hz, OCH2CH2), 3.99 (t, 2H, J=7
Hz, OCH2), 6.31 (d, 1H, J=16 Hz, CHCO2), 6.90 and

L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
613
7.49 (AA%XX% system, 4H, J=8 Hz, ArH), 7.73 (d, 1H,
J=16 Hz, ArCH); 13C-NMR (CDCl3)
14.12
(C-1), 129.56 (C-2 and C-2%), 143.01 (ArCH), 160.67
(C-4), 169.20 (CO); MS (DCI, CH4) m/z 308 ([MH]+,
40), 243 ([MH]+ꢀC2H602, 10), 221 ([MH]+ꢀC4H7O2,
53), 203 ([MH]+ꢀC4H11NO2, 19), 179 ([MH]+
ꢀC5H7NO3,10); HRMS (DCI, CH4) Calc. for
C17H26NO4 ([MH]+): 308.1861. Found: 308.1878.
l
(Me),22.70 (C17), 26.00 and 29.1–29.7 (C2ꢀC15), 31.94
(C16), 68.22 (CH2O), 114.09 (CHCO2H), 114.91 (C-3
and C-3%), 126.59 (C-1), 130.06 (C-2 and C-2%), 146.70
(ArCH), 161.40 (C-4), 170.68 (CO2H); MS (DCI, CH4)
m/z 399 ([MH]+, 100), 165 ([MH]+ꢀC18H35, 20);
HRMS (DCI, CH4) Calc. for C27H45O3 ([MH]+):
417.3369. Found: 417.3320.
5.1.20. N,N-Bis-(2-hydroxyethyl)-3-(4-octyloxyphenyl)-
2-propenamide (12t)
1
M.p. 85 °C; H-NMR (CDCl3) l 0.98 (t, 2H, J=7
5.1.16. Cinnamoyl chlorides 11
Hz, Me), 1.2–1.43 (m, 10H, (CH2)5Me), 1.56–1.86 (m,
4H, OCH2CH2CH2), 3.61–3.72 (m, 4H, CH2N), 3.82–
3.92 (m, 4H, CH2OH), 3.97 (t, 2H, J=7 Hz, CH2O),
6.78 (d, 1H, J=16 Hz, CHCO2), 6.87 and 7.45
(AA%XX% system, 4H, J=8 Hz, ArH), 7.65 (d, 1H,
J=16 Hz, ArCH); 13C-NMR (CDCl3) l 14.07 (Me),
22.65, 26.03, 29.21, 29.22, 29.35 (Me(CH2)5), 31.81
(CH2CH2O), 51.32 and 52.88 (NCH2), 61,25 and 61.49
(CH2OH), 68.17 (CH2O), 114.79 (C-3 and C-3%), 114.94
(CHCO), 127.57 (C-1), 129.56 (C-2 and C-2%), 143.10
(ArCH), 160.70 (C-4), 169.24 (CO); MS (DCI, CH4)
m/z 364 ([MH]+, 89), 346 ([MH]+ꢀH2O, 10), 318
([MH]+ꢀC2H6O, 5), 259 ([MH]+ꢀC4H11NO2,, 100), 132
(C5H10NO3); HRMS (DCI, CH4) Calc. for C21H34NO4
([MH]+): 364.2488. Found: 364.2500.
5.1.16.1. General procedure. A solution of a cinnamic
acid derivative (8 mmol) and SOCl2 in toluene (13 mL)
was heated at 70 °C for 4–24 h. Evaporation of the
solution gave ca. 80% of the corresponding acyl
chloride.
5.1.17. Cinnamoyl amides 12
5.1.17.1. General procedure. A solution of the crude
cinnamoyl chloride in dry dioxane (7 mL) was added
dropwise (0.5 h) to a stirred, cooled (15 °C) solution of
diethanolamine (1.2 g, 16 mmol) in dry dioxane (14
mL). The mixture was further stirred for 24 h, after
which most of the solvent was evaporated. The residue
was extracted (EtOAc–H2O ×3), dried (MgSO4) and
evaporated. The residue was purified by silica gel
column chromatography (EtOAc), to give 12 in yields
of ca. 12.5%.
5.1.21. N,N-Bis-(2-hydroxyethyl)-3-(4-methoxyphenyl)-
2-propenamide (12n)
M.p. 84 °C; 1H-NMR (CDCl3) l 3.62 (br t, 4H,
NCH2), 3.8 (s, 3H, MeO), 3.83 (br t, 4H, CH2OH), 6.72
(d, 1H, J=16 Hz, CHCO2), 6.84 and 7.43 (AA%XX%
system, J=8 Hz, ArH), 7.58 (d, 1H, J=16 Hz,
ArCH); 13C-NMR (CDCl3) l 51.30 and 52.28 (NCH2),
55.34 (MeO), 61.17 and 61.34 (CH2OH), 114.27 (C-3
and C-3%), 115.25 (CHCO2), 127.63 (C-1), 129.56 (C-2
and C-2%), 142.88 (ArCH), 161.04 (C-4), 169.14 (CO);
MS (DCI, CH4) 266 ([MH]+, 46), 161 ([MH]+
ꢀC4H11NO2, 23); HRMS (DCI, CH4) Calc. for
C14H20NO4 ([MH]+): 266.1392. Found: 266.1400.
5.1.18. N,N-Bis-(2-hydroxyethyl)-3-(4-propoxyphenyl)-
2-propenamide (12r)
1
M.p. 100 °C; H-NMR (CDCl3) l 1.04 (t, 3H, J=7
Hz, Me), 1.82 (sex, 2H, J=7 Hz, CH2CH2Me), 3.65
(m, 4H, NCH2), 3.85 (m, 4H, CH2OH), 3.93 (t, 2H,
J=7 Hz, CH2O), 6.79 (d, 1H, J=16 Hz, CHCO2),
6.85 and 7.44 (AA%XX% system, 4H, J=8 Hz, ArH),
7.62 (d, 2H, J=16 Hz, ArCH); 13C-NMR (CDCl3) l
10.49 (Me), 22.52 (MeCH2), 52.32 and 51.36 (NCH2),
61.54 and 61.28 (CH2OH) 69.61 (CH2O), 114.76 (C-3
and C-3%), 114.91 (CH2O), 127.53 (C-1), 129.57 (C-2
and C-2%), 143.09 (ArCH), 160.67 (C-4), 169.26 (CO);
MS (DCI, CH4) m/z 294 ([MH]+, 100), 276 ([MH]+
ꢀH2O, 24), 252 ([MH]+ꢀC3H6, 6), 189 ([MH]+
ꢀC4H11NO2, 59); HRMS (DCI, CH4) Calc. for
C16H24NO4 ([MH]+): 294.1705. Found: 294.1734.
5.1.22. N,N-Bis-(2-hydroxyethyl)-3-(4-methylphenyl)-
2-propenamide (12j)
1
M.p. 112 °C; H-NMR (CDCl3) l 2.35 (s, 3H, Me),
3.59–3.69 (m, 4H, NCH2), 3.80–3.90 (m, 4H, CH2OH),
6.89 (d, 1H, J=16 Hz, NCH2), 7.14 and 7.39 (AA%XX%
system, 4H, J=8 Hz, ArH), 7.62 (d, 1H, J=16 Hz,
ArCH); 13C-NMR (CDCl3) l 21.40 (Me), 51.31 and
52.32 (NCH2), 61.25 and 61.41 (CH2OH), 116.62
(CHCO2), 127.93 (C-2 and C-2%), 129.53 (C-3 and C-3%),
132.35 (C-1), 140.14 (C-4), 143.24 (ArCH), 169.04
(CNO), MS (DCI, CH4) 250 ([MH]+, 100), 232 ([MH]+
ꢀH2O, 64), 161 ([MH]+ꢀC4H11NO2, 40); HRMS (DCI,
CH4) Calc. for C14H20NO3 ([MH]+): 250.1443. Found:
250.1440.
5.1.19. N,N-Bis-(2-hydroxyethyl)-3-(4-butoxyphenyl)-
2-propenamide (12s)
1
M.p. 94 °C; H-NMR (CDCl3) l 0.98 (t, 3H, J=7
Hz, Me), 1.49 (sex, 2H, J=7 Hz, CH2CH2Me), 1.77
(quintet, 2H, J=7 Hz, 13C-NMR (CDCl3) l 13.81
(Me), 19.22 (MeCH2), 31.25 (CH2CH2O), 51.35 AND
52.29 (NCH2), 61.20 and 61.37 (CH2OH), 67.84
(CH2O), 114.79 (C-3 and C-3%), 115.04 (CHCO), 127.59

614
L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
5.1.23. N,N-Bis-(2-hydroxyethyl)-3-(3-methoxyphenyl)-
2-propenamide (12m)
M.p. 60–63 °C; H-NMR (CDCl3) 3.60 (br t, 4H,
5.1.27. 4,5-Dihydro-2-[2-(4-octyloxyphenyl)ethene]-
3-(2-hydroxyethyl)-oxazolinium chloride (14t)
1H-NMR (DMSO) l 0.87 (br t, 3H, Me), 1.20-1.37
(m, 12H, (CH2)6Me), 3.07 and 3.30 (t, 4H, J=6 Hz,
NCH2), 3.69 (quintet, 2H, J=6 Hz, CH2OH), 4.02 (t,
2H, CH2OAr), 4.40 (t, 2H, J=6 Hz, CH2O), 4.97 (t,
1H, J=6 Hz, OH), 6.47 (d, 1H, J=16 Hz, CHCNO)
6.99 and 7.68 (AA%XX% system, 4H, J=8 Hz, ArH),
7.74 (d, 1H, J=16 Hz, ArCH); 13C-NMR (DMSO) l
13.86 (Me), 22.40, 25.37, 28.46, 28.55, 28.61
(Me(CH2)5) 31.13 (CH2CH2O) 45.53 and 49.11
(NCH2), 56.21 (CH2OH), 59.37 (CH2O), 67.58
(CH2OAr), 114.51 (CHCO), 114.79 (C-3 and C-3%),
126.27 (C-1), 130.10 (C-2 and C-2%), 145.00 (ArCH),
160.66 (C-4), 166.03 (CNO); MS (FAB) m/z 382
([MH]+, 3), 364 ([MH]+ꢀH2O, 13).
1
NCH2), 3.78 (s, 3H, MeO), 3.78–3.86 (m, 4H,
CH2OH), 6.86 (dd, 1H, J=8 Hz, 1 Hz, CH-4), 6.92 (d,
1H, J=16 Hz, NCH2), 6.99 (br t, 1H, J=1 Hz, CH-2),
7.07 (d, 1H, J=8 Hz, CH-6), 7.24 (t, 1H, J=8 Hz,
CH-5), 7.56 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3) 51.06 and 52.16 (NCH2), 55.30 (MeO), 60.87
(two CH2OH), 113.36 (CHCO), 115.27 (C-2), 118.10
(C-4), 120.48 (C-6), 136.38 (C-1), 142.94 (ArCH),
159.78 (C-3), 168.62 (CO); MS (DCI, CH4) m/z 266
([MH]+, 100), 248 ([MH]+ꢀH2O, 19) 161 ([MH]+,
C4H11NO2, 43), 106 (C4H12NO2, 5); HRMS Calc. for
C14H20NO4 ([MH]+): 266.1392. Found: 266.1430.
5.1.24. Oxazolinium salts 14—cyclisation of an amide
upon treatment with SOCl2
5.1.28. N,N-Bis-(2-chloroethyl)-3-(substituted-phenyl)-
2-propenamides (16)
A solution of a substituted propenamide 12 (0.5
mmol), MeCN (15 mL) and SOCl2 (0.15 mL, 2 mmol)
was refluxed for 6 h. The mixture was cooled and
filtered to give the oxazolidinium salts in quantitative
yield.
5.1.28.1. General procedure. A solution of an cinnamoyl
chloride 11 (3 mmol) in dry CHCl3 (7 mL) was added
dropwise (20 min) to a stirred solution of bis-(2-
chloroethyl)amine hydrochloride (625 mg, 3.5 mmol)
and Et3N (1 mL, 7 mmol) in dry CHCl3 (7 mL). The
mixture was further stirred for 0.5 h and was then
extracted with dilute HCl, H2O and dilute NaHCO3.
The organic layer was washed with brine, dried
(MgSO4), and evaporated to dryness. The correspon-
ding amides 16 were obtained as oils in 60–85% yield.
5.1.25. 4,5-Dihydro-2-[2-(4-propoxyphenyl)ethene]-
3-(2-hydroxyethyl)-oxazolinium chloride (14r)
1H-NMR (DMSO) l 0.98 (t, 3H, J=6 Hz, Me), 1.76
(sextet, 2H, J=6 Hz, CH2CH2Me), 3.08 (t, 2H, J=5.4
Hz, NCH2), 3.30 (br t, 2H, NCH2), 3.71 (t, 2H, J=4.7
Hz, CH2OH), 3.98 (t, 2H, J=6.5 Hz, CH2OAr), 4.42
(m, 2H, CH2O), 6.48 (d, 1H, J=16 Hz, CHCO2), 6.99
and 7.68 (AA%XX% system, 4H, J=8 Hz, ArH), 7.80 (d,
2H, J=16 Hz, ArCH); 13C-NMR (DMSO) l 10.21
(Me), 22.22 (MeCH2), 48.63 and 50.33 (NCH2), 57.15
(CH2OH), 59.35 (CH2O), 70.38 (CH2OAr), 115.08 (C-3
and C-3%), 115.90 (CHCO), 127.69 (C-1), 130.04 (C-2
and C-2%), 144.98 (ArCH), 162.45 (C-4), 165.94 (CNO);
MS (FAB) m/z 313 ([MH]+, 1.3), 294 ([MH]+ꢀH2O,
26).
5.1.29. N,N-Bis-(2-chloroethyl)-3-(4-methylphenyl)-
2-propenamide (16j)
1H-NMR (CDCl3) l 3.61–3.94 (m, 8H, four CH2),
6.72 (d, 1H, J=16 Hz, CHCNO), 7.17 and 7.41
(AA%XX% system, 4H, J=8 Hz, ArH), 7.70 (d, 1H,
J=16 Hz, ArCH); 13C-NMR (CDCl3) l 41.79 and
41.90 (CH2Cl), 50.01 and 50.06 (CH2N), 55.39 (Me),
115.19 (CHCO), 127.93 (C-2 and C-2%), 129.59 (C-3 and
C-3%), 132.07 (C-1), 140.39 (C-4), 144.24 (ArCH),
166.94 (CNO); MS (DCI, CH4) m/z 286 ([MH]+, 14),
232 ([MH]+ꢀHCl, 10), 161 ([MH]+ꢀC4H8Cl2N, 100),
142 (C4H8Cl2N, 6); HRMS (DCI, CH4) Calc. for
C14H18Cl2NO ([MH]+): 286.0765. Found: 286.0700.
5.1.26. 4,5-Dihydro-2-[2-(4-butoxyphenyl)ethene]-
3-(2-hydroxyethyl)-oxazolinium chloride (14s)
1H-NMR (DMSO) l 0.92 (t, 3H, J=6 Hz, Me), 1.43
(sextet, 2H, J=6 Hz, CH2CH2Me), 1.70 (quintet, 2H,
J=7 Hz, CH2CH2O), 3.06 (t, 2H, J=5.4 Hz, NCH2),
3.29 (br t, 2H, NCH2), 3.70 (m, 2H, CH2OH), 4.0 (t,
2H, J=6.4 Hz, CH2OAr), 4.40 (br t, 2H, J=5 Hz,
CH2O), 5.32 (t, 1H, J=8 Hz, OH), 6.46 d, 1H, J=16
Hz, CHCNO), 6.97 and 7.66 (AA%XX% system, 4H,
J=8 Hz, ArH), 7.78 (d, 1H, J=16 Hz, ArCH); 13C-
NMR (DMSO) l 13.57 (Me), 22.40 (MeCH2), 30.53
(MeCH2CH2) 45.77 and 49.15 (NCH2), 56.22
(CH2OH), 59.36 (CH2O), 67.28 (CH2OAr), 114.50
(CHCO), 114.78 (C-3 and C-3%), 127.69 (C-1), 130.10
(C-2 and C-2%), 145.02 (ArCH), 160.65 (C-4), 166.01
(CNO); MS (FAB) m/z 326 ([MH]+, 0.5), 308 ([MH]+
ꢀH2O, 3).
5.1.30. N,N-Bis-(2-chloroethyl)-3-(4-methoxyphenyl)-
2-propenamide (16n)
1H-NMR (CDCl3) l 3.64–3.92 (m, 8H, four CH2),
3.84 (s, 3H, MeO), 6.71 (d, 1H, J=16 Hz, CHCNO),
6.91 and 7.49 (AA%XX% system, 4H, J=8 Hz, ArH),
7.71 (d, 1H, J=16 Hz, ArCH); 13C-NMR (CDCl3) l
41.72 and 42.03 (CH2Cl), 50.14 and 51.18 (NCH2),
113.68 (CHCO), 114.32 (C-3 and C-3%), 127.57 (C-1),
129.62 (C-2 and C-2%), 143.86 (ArCH), 161.21 (C-4),
167.10 (CNO); MS (DCI, CH4) m/z 302 ([MH]+, 47),
266 ([MH]+ꢀHCl, 18), 161 ([MH]+ꢀC4H8Cl2N, 100);

L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
615
HRMS (DCI, CH4) Calc. for C14H18Cl2NO2 ([MH]+):
302.0715. Found: 302.0640.
5.1.35. 4,5-Dihydro-2-[2-(4-hexadecyloxyphenyl)-
ethene]-3-(2-chloroethyl)-oxazolinium chloride (177)
1H-NMR (CDCl3/acetone-d6) l 0.88 (t, 3H, J=7 Hz,
Me), 1.13–1.54 (m, 28H, (CH2)9Me), 1.79 (quintet, 2H,
J=7 Hz, CH2CH2O), 3.56 (m, 2H, CH2Cl), 3.56–4.10
(m, 4H, two NCH2), 4.14 (t, 2H, J=7 Hz, CH2OAr),
4.66 (br t, 2H, NCH2CH2O), 6.36 (d, 1H, J=16 Hz,
CHCNO), 6.89 and 7.54 (AA%XX% system, 4H, J=8
Hz, ArH), 7.82 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3/acetone-d6) l 13.12 (Me), 21.83 (C15), 25.21 and
28.1–30.0 (C2ꢀC13), 31.30 (C14), 37.83 (CH2Cl), 46.10
and 48.29 (NCH2), 58.52 (CH2O), 67.32 (CH2OAr)
113.54 (CHCO), 114.12 (C-3 and C-3%), 126.06 (C-1),
129.27 (C-2 and C-2%), 145.22 (ArCH), 160.59 (C-4),
165.75 (CNO).
5.1.31. N,N-Bis-(2-chloroethyl)-3-(2,4-dimethoxy-
phenyl)-2-propenamide (16p)
1H-NMR (CDCl3) l 3.73–3.96 (m, 8H, four CH2),
3.92 (s, 3H, p-MeO), 3.93 (s, 3H, m-MeO) 6.71 (d, 1H,
J=16 Hz, CHCNO), 6.88 (d, 1H, J=8 Hz, H-5), 6.88
(d, 1H, J=8 Hz, H-2), 7.15 (dd, 1H, J=8 Hz, 2 Hz,
H-6), 7.69 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3) l 41.9 (two CH2Cl), 50.17 and 51.22 (NCH2),
56.01 (two MeO), 110.40 (C-2), 111.27 (C-5), 114.12
(CHCO), 122.01 (C-6), 127.94 (C-1), 144.11 (ArCH),
149.26 (C-4), 151.00 (C-3), 167.06 (CNO); MS (DCI,
CH4) m/z 332 ([MH]+, 4), 296 ([MH]+ꢀHCl, 2), 190
([MH]+ꢀC4H8Cl2N, 100); HRMS (DCI, CH4) Calc. for
C15H20Cl2NO3 ([MH]+): 332.0820. Found: 332.0820.
5.1.36. 4,5-Dihydro-2-[2-(4-octadecyloxyphenyl)ethene]-
3-(2-chloroethyl)-oxazolinium chloride (17w)
1H-NMR (CDCl3/acetone-d6) l 0.78 (t, 3H, J=7 Hz,
Me), 1.02–1.43 (m, 30H, (CH2)15Me), 1.78 (quintet,
2H, J=7 Hz, CH2CH2O), 3.35–3.78 (m, 6H, two
NCH2 and CH2Cl), 3.88 (t, 2H, J=7 Hz, CH2OAr),
4.60 (br t, 2H, NCH2CH2O), 6.30 (d, 1H, J=16 Hz,
CHCO), 6.80 and 7.43 (AA%XX% system, 4H, J=8 Hz,
ArH), 7.70 (d, 1H, J=16 Hz, ArCH); 13C-NMR
(CDCl3/acetone-d6) l 14.07 (Me), 22.64 (C17), 25.96 and
29.1–29.6 (C2ꢀC 15), 31.87 (C16), 38.33 (CH2Cl), 46.78
and 48.92 (NCH2), 59.22 (CH2O), 68.11 (CH2OAr)
113.94 (CHCO), 114.78 (C-3 and C-3%), 126.56 (C-1),
129.94 (C-2 and C-2%), 146.19 (ArCH), 161.27 (C-4),
166.76 (CNO).
5.1.32. N,N-Bis-(2-chloroethyl)-3-(3,4,5-trimethoxy-
phenyl)-2-propenamide (16p)
1H-NMR (CDCl3) l 3.68–3.98 (m, 8H, four CH2),
3.87 (s, 3H, p-MeO), 3.88(s, 6H, two m-MeO), 6.75 (s,
2H, C-2 and C-5), 6.76 (d, 1H, J=16 Hz, CHCNO),
7.65 (d, 1H, J=16 Hz, ArCH); 13C-NMR (CDCl3) l
41.7 (two CH2Cl), 49.86 and 51.03 (NCH2), 56.12 (three
MeO), 105.14 (C-2 and C-6), 115.59 (CHCO), 130.33
(C-4), 146.10 (ArCH), 153.32 (C-3 and C-5), 166.71
(CNO); MS (DCI, CH4) m/z 362 ([MH]+, 4), 221
([MH]+ꢀC4H9Cl2N, 100); HRMS (DCI, CH4) Calc. for
C16H22Cl2NO4 ([MH]+, 362.0926. Found: 332.0910.
5.1.33. Oxazolidinium chlorides 17
5.1.37. 1-(2-oxo-2u4-[1,3,2,6]dioxathiazocan-6-yl)-
3-(3-nitro-phenyl)-Propenone (18)
5.1.33.1. General procedure. A cinnamoyl chloride 11 (8
mmol) in CHCl3 (10 mL) was added dropwise to a
solution of bis-(2-chloroethyl)amine hydrochloride
(1.43 g, 8 mmol), Et3N (2.8 mL, 20 mmol) in CHCl3 (10
mL). The mixture was stirred for 0.5–1 h at r.t. then
extracted (HCl 3N, NaHCO3). The organic layer was
washed with brine, dried (MgSO4) and heated for 1–3
h at 50 °C. Evaporation of the solvent gave the corres-
ponding product 17 in ca. 70% yield.
To a solution of 12b (100 mg, 0.35 mmol) [9] in dry
pyridine (2 mL) SOCl2 (53.8 mL, 0.73 mmol) was
added. The mixture was stirred for 3 days at r.t., it was
then filtered and the filtrate was extracted with CH2Cl2.
The organic phase was washed with water, separated,
dried (MgSO4) and evaporated to give an orange
residue that after a few hours under high vacuum it
1
solidified, 27 mg (23% yield). H-NMR (DMSO) l 3.60
(m, 1H), 3.75 (m, 1H), 4.0 (m, 4H), 4.70 (m, 2H), 6.91
(d, 1H, J=11 Hz, Ha), 7.60 (t, 1H, J=6 Hz, H4), 7.80
(d, 1H, J=11 Hz, Hb), 7.81 (t, 1H, J=6 Hz, H5), 8.21
(t, 1H, J=6 Hz, H5), 8.40 (br s, 1H, H2). MS (CI,
butane) m/z 327 ([MH]+, 100), 297 ([MH]+ꢀH2CO, 2),
281 ([MH]+ꢀEtOH, 4), 263 ([MH]+ꢀSO2, 5).
5.1.34. 4,5-Dihydro-2-[2-(4-dodecyloxyphenyl)ethene]-
3-(2-chloroethyl)-oxazolinium chloride (17u)
1H-NMR (DMSO) l 0.85 (t, 3H, J=7 Hz, Me),
1.28–1.47 (m, 18H, (CH2)9Me), 1.70 (quintet, 2H, J=7
Hz, CH2CH2O), 3.91–4.5 (m, 8H, NCH2CH2Cl,
CH2OAr, NCH2CH2O), 4.43 (t, 2H, J=7 Hz,
NCH2CH2O), 6.47 (d, 1H, J=16 Hz, CHCNO), 6.97
and 7.67 (AA%XX% system, 4H, J=8 Hz, ArH), 7.81 (d,
1H, J=16 Hz, ArCH); 13C-NMR (DMSO) l 13.95
Acknowledgements
(Me), 22.09 (C11), 25.45 and 28.6–29.0 (C2ꢀC ), 31.30
Generous support for this work by the ‘Marcus
Centre for Pharmaceutical and Medicinal Chemistry’
and the ‘Bronia and Samuel Hacker Fund for Scientific
Instrumentation’ at Bar Ilan University, are gratefully
acknowledged.
9
(C10), 39.52 (CH2Cl), 47.67 and 48.19 (NCH2), 59.37
(CH2O), 67.67 (CH2OAr) 114.54 (CHCO), 114.87 (C-3
and C-3%), 126.43 (C-1), 130.20 (C-2 and C-2%), 145.22
(ArCH), 160.76 (C-4), 166.08 (CNO).

616
L. Hed6ati et al. / European Journal of Medicinal Chemistry 37 (2002) 607–616
[14] A. Panthanickal, C. Hansch, A. Leo, F.R. Quinn, J. Med. Chem.
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