Synthesis of new vinylpyridinium salts

Article abstract of DOI:10.1002/jhet.616

This article reports the reactions of salts of 4-ureylmethylpyridinium and 4-ethoxycarbonylaminomethylpyridinium with carbonylic compounds, performed with the aim of obtaining new vinylpyridinium salts. These reactions can lead to the formation of both co

Full text of DOI:10.1002/jhet.616

May 2011
Synthesis of New Vinylpyridinium Salts
Paloma Posada,a* Miguel F. Bran˜a,b Antonio L. Villarino,a
549
c
Vicente Domınguez, Ismael Ortun˜o, and Carmen Martınez
a
a
´
´
a
´ ´ ´
Departamento de Enfermerıa, Escuela Universitaria de Enfermerıa, Fisioterapia y Podologıa,
Universidad Complutense de Madrid, 28040 Madrid, Spain
´
Departamento de Medicina Preventiva y Salud Publica, Facultad de Medicina, Universidad
b
´
Instituto Canario de Investigacion del Cancer (ICIC), Brasil 25, 28110 Algete, Spain
´
c
Complutense de Madrid, 28040 Madrid, Spain
*E-mail: kekule34@hotmail.com
Received May 20, 2010
DOI 10.1002/jhet.616
Published online 22 February 2011 in Wiley Online Library (wileyonlinelibrary.com).
This article reports the reactions of salts of 4-ureylmethylpyridinium and 4-ethoxycarbonylaminome-
thylpyridinium with carbonylic compounds, performed with the aim of obtaining new vinylpyridinium
salts. These reactions can lead to the formation of both condensation and dimerization products. The
type of products formed is conditioned by the nature of the salts and carbonyl groups involved. The in-
terest generated by the condensation products formed lies in their potential cholinergic activity.
J. Heterocyclic Chem., 48, 549 (2011)
INTRODUCTION
4-Acylaminomethylpyridinium salts 1 show interesting
behavior in their reaction with acid anhydrides. Small dif-
ferences in temperature yield very different compounds
[6]; at 100ꢀC, dimeric compounds 2 are obtained, whereas
at 140ꢀC the main reaction products are oxazoles 3
(Scheme 1). The reaction in Scheme 1 describes a proce-
dure for preparing oxazoles of structure 3, some of which
have shown interesting antitumoral activity [7].
Pyridinium salts (PSs) are a class of ammonium qua-
ternary compounds with many applications in different
areas of chemistry [1,2]. From the point of view of me-
dicinal chemistry, PSs are very well known for their
germicidal properties and their cholinergic activity as
inhibitors of acetylcholinesterase (AChE) (EC 3.1.1.7)
and/or cholineacetyltransferase (CAT) (EC 2.3.1.6). The
dysfunction of these enzyme systems has been associ-
ated with several degenerative diseases [3–5].
This article reports reactions between 4-acylaminome-
thylpyridinium salts 1, where the acyl group is an
C
V
2011 HeteroCorporation

´ ´
P. Posada, M. F. Bran˜a, A. L. Villarino, V. Domınguez, I. Ortun˜o, and C. Martınez
550
Vol 48
Scheme 1
ethylcarbamate or urea with carbonylic compounds. Eth-
ylcarbamate group has very well-known AChE-inhibi-
ting properties [8]. When 4-acylaminomethylpyridinium
salts 1 react with carbonylic compounds, products of
general structure 4 are obtained (Fig. 1). The main inter-
est in these lies in their structural similarity to those
described by DeBernardis et al., and therefore their
potential to inhibit CAT and AChE [9]. DeBernardis et
al. established four structural moieties for the structure
shown in Figure 2 as potentially responsible for strong
inhibitory activity: (a) a mono or bicyclic aromatic sys-
tem, [10]; (b) a double bond; (c) a pyridinium or quino-
linium moiety; and (d) an alkylic chain. Other PSs, how-
ever, have shown low CAT inhibition activity [11].
The salts produced in the reactions studied in this
work show features similar to those of other synthesized
cholinergic/anticholinergic agents that have been phar-
macologically evaluated [12]. This work also reports ini-
tial investigations into the biological activity of one of
the vinylpyridinium salt produced.
RESULTS AND DISCUSSION
The synthesis of 4-ethoxycarbonylaminomethylpyridi-
nium and 4-ureylmethylpyridinium salts 1 was per-
formed according to a previously published procedure
Figure 1. General structure of vinylpyridinium salts.
Figure 2. General structure of CAT inhibitors.
Journal of Heterocyclic Chemistry
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May 2011
Synthesis of New Vinylpyridinium Salts
551
Scheme 2
[6]. The reaction of 1 with aromatic aldehydes selected
from those available in our laboratory (2-methoxy,
4-methoxy, 4-hydroxy, 4-nitro, 3,4,5-trimethoxy, and
2-hydroxy-5-nitrobenzaldehyde) in the presence of
piperidine or morpholine gave a mixture of the corre-
sponding condensation 4 and dimerization 2 products
(Scheme 2). These dimers are very insoluble and thus
easily separated out by filtration. Thus, during the reac-
tion, two competitive processes take place: the forma-
tion of condensation product 4 and the production of
dimer 2, both at low-medium yields (see Table 1).
The formation of condensation products is characteris-
tic of aromatic aldehydes; when the reaction was per-
formed with aliphatic aldehydes or ketones, only the
dimerization product was obtained.
elimination from adduct 7 to yield compound 4 (Scheme
3).
The dimerization reaction may occur through a mech-
anism involving the initial formation of anhydrobase 6,
which would be in equilibrium with the corresponding
acylimine 8. The nucleophilic attack of 6 on 8 would
give Michael type adduct 9, which would lose a hydride
ion that might be captured by the carbonyl compound in
the medium (Scheme 4).
To show the formation of the hydride ion, PS 1 (R ¼
NH2; R0 ¼ C2H5 and C3H7) was reacted with piperidine
in the presence of an oxidant such as nitrobenzene [6],
obtaining dimer 2 in improved yields (Scheme 5).
It is difficult to explain why, in two cases (4e and 4g;
Table 1), only the condensation product was obtained.
The presence of the nitro group in 2-hydroxy-5-nitro-
benzaldehyde would be expected to increase the dimer
yield, but none was detected. More research is needed
for any reliable conclusion to be drawn.
The production of 4 can be explained by the classical
mechanism of addition–elimination via the formation of
anhydrobase 6. The latter is involved in a nucleophilic
attack on the corresponding aldehyde, followed by water
Table 1
Vinylpyridinium 4 and dimer 2 salts yields.
Entry
R
R0
Ar
X
Yield (%) 4
Yield (%) 2
a
b
c
d
e
f
NH2
NH2
C2H5
C2H5
C2H5
C2H5
CH3
C2H5
C2H5
n-C3H7
CH3
2-Methoxyphenyl
4-Methoxyphenyl
4-Hydroxyphenyl
Br
Br
Br
Br
I
Br
Br
Br
I
24
16
33
18
64
20
71
46
21
12
23
17
57
0
NH2
NH2
4-Nitrophenyl
NH2
NH2
3,4,5-Trimethoxyphenyl
3,4,5-Trimethoxyphenyl
2-Hydroxy-5-nitrophenyl
3,4,5-Trimethoxyphenyl
3,4,5-Trimethoxyphenyl
36
0
g
h
i
NH2
NH2
OAC2H5
21
52
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P. Posada, M. F. Bran˜a, A. L. Villarino, V. Domınguez, I. Ortun˜o, and C. Martınez
552
Vol 48
Scheme 3
monitored by thin layer chromatography using silica gel plates
(Merck 60 F254) and ethyl acetate as an eluent.
Double-bond configuration was investigated by NOESY
using specific software: SYBYL [15], gopenMol [16,17], and
Molekel [18].
The stereochemistry of the double bond in 4f–i was
investigated by NOESY; these results will be published
elsewhere [13].
Vinylpyridinium salt 4i shows the optimum groups
(carbamate and quaternary ammonium) affording cholin-
ergic/anticholinergic properties. The behavior of this
compound was compared to that of acetylcholine using
the isolated organ technique [14].
General procedure (A) for the preparation of (Z)-1-
alkyl-4-(2-aryl-1-acylvinyl)pyridinium halide 4. A solution
containing 3 mM of PS, 3 mM of the corresponding aldehyde,
25 mL of absolute ethanol, and four drops of piperidine was
refluxed for 4 h. The solid obtained was collected by suction
filtration and purified by recrystallization (dimer 2). The filtrate
was collected, and the solvent was evaporated to dryness. The
residual solid was purified by recrystallization (condensation
product 4).
General procedure (B) for the preparation of N, N0-dia-
minocarbonyl-1,2-di(1-alkyl-4-pyridinium)ethylenediamine
dihalides 2 [6]. A solution containing 3.4 mM of PS, 15 mL
of absolute ethanol, four drops of piperidine, and four drops of
nitrobenzene was refluxed for 4 h. After cooling, the solid was
filtered and purified by recrystallization.
Salt 4i is remarkable as it behaves per se in the same
way as acetylcholine (the product has a similar concen-
tration-effect curve), with a corresponding pD2 of 5.95.
In conclusion, this work opens up new avenues for
the development of vinylpyridinium salts that may be
useful as cholinergic agents.
EXPERIMENTAL
(Z)-1-Ethyl-4-[2-(2-methoxyphenyl)-1-ureylvinyl]pyridinium
bromide 4a. This compound was obtained by general proce-
dure A. Yield: 24%; mp 154–156ꢀC (isopropanol); IR (potas-
sium bromide) 3400 (NH), 3230, 3160 (NH2), 1665 (C¼¼O),
Melting points were determined using a Bu¨chi 510 capillary
melting point apparatus and are uncorrected. Infrared spectra
1
were recorded using a Perkin-Elmer 297 spectrophotometer. H-
1640 (C¼¼N), 1610 (C¼¼C), 1255, 1025 (ArOCH3) cmꢁ1
;
1H-
NMR spectra were obtained using a Varian T-60 (60 MHz) and
T-90 (90 MHz) using deuterated dimethylsulfoxide or trifluoro-
acetic acid. NOESY experiments were performed using a Varian
XL-300 operating at 300 MHz. Chemical shifts (d) are reported
in parts per million relative to an internal standard of tetramethyl-
silane. Coupling constants (J) are expressed in Hertz. Elemental
analyses (C, H, N, X) of final compounds were performed by the
NMR (dimethyl sulfoxide-d6) d 1.6 (t, 3H, CH3ACANþ, J ¼
7.0 Hz), 3.8 (s, 3H, CH3AO), 4.6 (q, 2H, CH2ANþ, J ¼ 7.0
Hz), 6.1 (s, 2H, NH2), 6.8–7.5 (m, 5H, CH¼¼C and ArH), 7.8
(d, 2H, H-3, H-5 py, J ¼ 7.0 Hz), 8.0 (s, 1H, NH), 8.7 (d, 2H,
H-2, H-6 py,
J
¼
7.0 Hz) ppm. Anal. Calcd. for
C17H20BrN3O2: C, 53.97; H, 5.29; N, 11.11; Br, 21.13. Found:
C, 53.69; H, 5.27; N, 10.90; Br, 20.98.
´ ´
Centro Nacional de Quımica Organica. Reaction progress was
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Synthesis of New Vinylpyridinium Salts
553
Scheme 5
(C¼¼O), 1640 (C¼¼N), 1600 (C¼¼C), 1270, 1050 (ArOCH3)
cmꢁ1 1H-NMR (dimethyl sulfoxide-d6)
1.5 (t, 3H,
;
d
CH3ACANþ, J ¼ 6.9 Hz), 3.6 (s, 3H, pCH3AO), 3.7 (s, 6H,
2mCH3AO), 4.4–4.6 (m, 2H, CH2ANþ), 6.1 (s, 2H, NH2), 6.9
(s, 2H, H-2, H-6 ArH), 7.0 (s, 1H, CH¼¼C), 7.8 (d, 2H, H-3,
H-5 py, J ¼ 6.0 Hz), 8.2 (s, 1H, NH), 8.7 (d, 2H, H-2, H-6
py, J ¼ 6.0 Hz) ppm. Anal. Calcd. for C19H24BrN3O4: C,
52.05; H, 5.48; N, 9.59; Br, 18.26. Found: C, 52.20; H, 5.30;
N, 9.50; Br, 18.10.
(Z)-1-Ethyl-4-[2-(2-hidroxy-5-nitrophenyl)-1-ureylvinyl]-
pyridinium bromide 4g. This compound was obtained by
general procedure A. Yield: 71%; mp 201–203ꢀC (methanol);
IR (potassium bromide) 3400 (NH), 3240, 3180 (NH2), 1660
(C¼¼O), 1640 (C¼¼N), 1600 (C¼¼C), 1510, 1310 (NO2), 1180
CH3ACANþ, J ¼ 7.0 Hz), 4.6 (q, 2H, CH2ANþ, J ¼ 7.0 Hz),
7.0 (d, 1H, H-3 ArH, J ¼ 8.0 Hz), 7.3 (s, 1H, CH¼¼C), 8.0–
8.3 (m, 4H, NH, H-5 ArH and H-3, H-5 py), 8.3–8.5 (m, 1H,
H-6 ArH), 8.6 (d, 2H, H-2, H-6 py, J ¼ 7.0 Hz) ppm. Anal.
Calcd. for C16H17BrN4O4: C, 46.98; H, 4.16; N, 13.69; Br,
19.53. Found: C, 46.80; H, 4.35; N, 13.48; Br, 19.40.
(Z)-1-Ethyl-4-[2-(4-methoxyphenyl)-1-ureylvinyl]pyridinium
bromide 4b. This compound was obtained by general proce-
dure A. Yield: 16%; mp 206–208ꢀC (methanol-ethylic ether);
IR (potassium bromide) 3380 (NH), 3240, 3180 (NH2), 1660
(C¼¼O), 1640 (C¼¼N), 1600 (C¼¼C), 1255, 1020 (ArOCH3)
CH3ACANþ, J ¼ 7.0 Hz), 3.9 (s, 3H, CH3AO), 4.5 (q, 2H,
CH2ANþ, J ¼ 7.0 Hz), 7.1 (d, 2H, H-3, H-5 ArH, J ¼ 8.0
Hz), 7.5–7.8 (m, 3H, CH¼¼C and H-2, H-6 ArH), 8.0–8.3 (m,
3H, NH and H-3, H-5 py), 8.5 (d, 2H, H-2, H-6 py, J ¼ 7.0
Hz) ppm. Anal. Calcd. for C17H20BrN3O2: C, 53.97; H, 5.29;
N, 11.11; Br, 21.13. Found: C, 53.60; H, 5.34; N, 10.80; Br,
21.20.
(ArOH) cmꢁ1 1H-NMR (trifluoroacetic acid) d 1.8 (t, 3H,
;
cmꢁ1
;
1H-NMR (trifluoroacetic acid)
d
1.8 (t, 3H,
(Z)-1-Propyl-4-[2-(3,4,5-trimethoxyphenyl)-1-ureylvinyl]-
pyridinium bromide 4h. This compound was obtained by gen-
eral procedure A. Yield: 46%; mp 217–219ꢀC (ethanol); IR (po-
tassium bromide) 3360 (NH), 3280, 3170 (NH2), 1690 (C¼¼O),
(Z)-1-Ethyl-4-[2-(4-hydroxyphenyl)-1-ureylvinyl]pyridinium
bromide 4c. This compound was obtained by general proce-
dure A. Yield: 33%; mp 260–262ꢀC (ethanol); IR (potassium
bromide) 3410 (NH), 3300, 3140 (NH2), 1660 (C¼¼O), 1640
1645 (C¼¼N), 1610 (C¼¼C), 1280, 1010 (ArOCH3) cmꢁ1
;
1H-
NMR (trifluoroacetic acid) d 1.1 (t, 3H, CH3ACACANþ, J ¼
7.0 Hz), 1.9–2.3 (m, 2H, CH2ACANþ), 4.0 (s, 3H, pCH3AO),
4.1 (s, 6H, 2mCH3AO), 4.6 (t, 2H, CH2ANþ, J ¼ 7.0 Hz), 7.1
(s, 2H, H-2, H-6 ArH), 7.5 (s, 1H, CH¼¼C), 8,2 (d, 2H, H-3, H-5
py, J ¼ 7.0 Hz), 8.4 (s, 1H, NH), 8.6 (d, 2H, H-2, H-6 py, J ¼
7.0 Hz) ppm. Anal. Calcd. for C20H26BrN3O4: C, 53.09; H, 5.75;
N, 9.29; Br, 17.70. Found: C, 53.22; H, 5.85; N, 9.04; Br, 17.33.
(Z)-4-[1-Ethoxycarbonylamine-2-(3,4,5-trimethoxyphenyl)-vinyl]-
1-methylpyridinium iodide 4i. This compound was obtained by
general procedure A. Yield: 21%; mp 210–212ꢀC (ethanol); IR
(potassium bromide) 3180 (NH), 1715 (C¼¼O), 1645 (C¼¼N),
1
(C¼¼N), 1595 (C¼¼C), 1170 (ArOH) cmꢁ1; H-NMR (dimethyl
sulfoxide-d6) d 1.5 (t, 3H, CH3ACANþ, J ¼ 7.0 Hz), 4.5 (q,
2H, CH2ANþ, J ¼ 7.0 Hz), 6.1 (s, 2H, NH2), 6.8 (d, 2H, H-3,
H-5 ArH, J ¼ 8.0 Hz), 7.1 (s, 1H, CH¼¼C), 7.3 (s, 1H, OH),
7,5 (d, 2H, H-2, H-6 ArH, J ¼ 8.0 Hz), 7.9–8.2 (m, 3H, NH
and H-3, H-5 py), 8.9 (d, 2H, H-2, H-6 py, J ¼ 7.0 Hz) ppm.
Anal. Calcd. for C16H18BrN3O2: C, 52.75; H, 4.94; N, 11.54;
Br, 21.98. Found: C, 52.80; H, 5.02; N, 11.60; Br, 21.85.
(Z)-1-Ethyl-4-[2-(4-nitrophenyl)-1-ureylvinyl]pyridinium bro-
mide 4d. This compound was obtained by general procedure
A. Yield: 18%; mp 196–198ꢀC (ethanol); IR (potassium bro-
mide) 3380 (NH), 3220, 3170 (NH2), 1660 (C¼¼O), 1640
1
1610 (C¼¼C), 1270, 1050 (ArOCH3) cmꢁ1; H-NMR (trifluoro-
acetic acid) d 1.3 (t, 3H, CH3O, J ¼ 7.0 Hz), 3.9 (s, 3H,
pCH3AO), 4.0 (s, 6H, 2mCH3AO),4.2 (q, 2H, CH2, J ¼ 7.0
Hz), 4.3 (s, 3H, CH3ANþ), 6.8 (s, 2H, H-2, H-6 ArH), 7.1 (s,
1H, CH¼¼C), 7.5 (s, 1H, NH), 7.9 (d, 2H, H-3, H-5 py, J ¼
7.0 Hz), 8.3 (d, 2H, H-2, H-6 py, J ¼ 7.0 Hz) ppm. Anal.
Calcd. for C20H25IN2O5: C, 48.00; H, 5.00; N, 5.60; I, 25.40.
Found: C, 47.65; H, 5.27; N, 5.84; I, 25.23.
(C¼¼N), 1610 (C¼¼C), 1510, 1345 (NO2) cmꢁ1
;
1H-NMR (di-
methyl sulfoxide-d6) d 1.5 (t, 3H, CH3ACANþ, J ¼ 7.0 Hz),
4.6 (q, 2H, CH2ANþ, J ¼ 7.0 Hz), 6.3 (s, 2H, NH2), 7.1 (s,
1H, CH¼¼C), 7.8–8.4 (m, 6H, 4 ArH and H-3, H-5 py), 8.8 (s,
1H, NH), 9.0 (d, 2H, H-2, H-6 py, J ¼ 7.0 Hz) ppm. Anal.
Calcd. for C16H17BrN4O3: C, 48.85; H, 4.32; N, 14.25; Br,
20.36. Found: C, 48.60; H, 4.35; N, 14.20; Br, 20.45.
N,N0-Diaminocarbonyl-1,2-di-(1-ethyl-4-pyridinium)ethyle-
nediamine dibromide 2a. This compound was obtained by
general procedure B. Yield: 69%; mp 245–247ꢀC (methanol);
IR (potassium bromide) 3430 (NH), 3300, 3120 (NH2), 1680
(Z)-1-Methyl-4-[2-(3,4,5-trimethoxyphenyl)-1-ureylvinyl]-
pyridinium iodide 4e. This compound was obtained by gen-
eral procedure A. Yield: 64%; mp 231–233ꢀC (ethanol); IR
(potassium bromide) 3360 (NH), 3260, 3190 (NH2), 1680
(C¼¼O), 1640 (C¼¼N), 1610 (C¼¼C), 1250, 1045 (ArOCH3)
(C¼¼O), 1650 (C¼¼N), 1580, 1510 (Ar) cmꢁ1
;
1H-NMR (tri-
fluoroacetic acid) d 1.8 (t, 6H, 2CH3, J ¼ 7.5 Hz), 4.6 (q, 4H,
2CH2, J ¼ 7.5 Hz), 6.0–6.2 (m, 2H, 2CH), 7.6–7.8 (m, 2H,
2NH), 8.2 (d, 4H, 2H-3, 2H-5 py, J ¼ 6.0 Hz), 8.5 (d, 4H,
cmꢁ1 1H-NMR (trifluoroacetic acid) d 3.7 (s, 3H, pCH3AO),
;
3.8 (s, 6H, 2mCH3AO), 4.2 (s, 3H, CH3ANþ), 6.9 (s, 2H, H-
2, H-6 ArH), 7.2 (s, 1H, CH¼¼C), 7.9 (d, 2H, H-3, H-5 py, J
¼ 6.0 Hz), 8.4 (d, 2H, H-2, H-6 py, J ¼ 6.0 Hz) ppm. Anal.
Calcd. for C18H22IN3O4: C, 45.86; H, 4.67; N, 8.91; I, 26.94.
Found: C, 45.73; H, 4.81; N, 8.62; I, 26.79.
2H-2, 2H-6 py,
J
¼
6.0 Hz) ppm. Anal. Calcd. for
C18H26Br2N6O2: C, 41.74; H, 5.02; N, 16.22; Br, 30.85.
Found: C, 41.50; H, 4.95; N, 15.97; Br, 30.84.
N,N0-Diaminocarbonyl-1,2-di-(1-propyl-4-pyridinium)ethy-
lenediamine dibromide 2b. This compound was obtained by
general procedure B. Yield: 58%; mp 244–246ꢀC (methanol);
IR (potassium bromide) 3390 (NH), 3300, 3210 (NH2), 1680
(Z)-1-Ethyl-4-[2-(3,4,5-trimethoxyphenyl)-1-ureylvinyl]-
pyridinium bromide 4f. This compound was obtained by
general procedure A. Yield: 20%; mp 208–210ꢀC (ethanol); IR
(potassium bromide) 3380 (NH), 3290, 3160 (NH2), 1680
(C¼¼O), 1645 (C¼¼N), 1580, 1525 (Ar) cmꢁ1
;
1H-NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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P. Posada, M. F. Bran˜a, A. L. Villarino, V. Domınguez, I. Ortun˜o, and C. Martınez
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Vol 48
[6] Bran˜a, M. F.; Castellano, J. M.; De Miguel, P.; Posada, P.;
´
Sanz, C. R.; Migallon, A. S. Tetrahedron 1994, 50, 10061.
(trifluoroacetic acid) d 1.0 (t, 6H, 2CH3, J ¼ 6.9 Hz), 1.7–2.4
(m, 4H, 2CH2ACANþ), 4.5 (t, 4H, 2CH2ANþ, J ¼ 6.9 Hz),
5.8–6.0 (m, 2H, 2CH), 7.5–7.8 (m, 2H, 2NH), 8.4 (d, 4H, 2H-3,
2H-5 py, J ¼ 6.0 Hz), 8.7 (d, 4H, 2H-2, 2H-6 py, J ¼ 6.0 Hz)
ppm. Anal. Calcd. for C20H30Br2N6O2: C, 43.99; H, 5.49; N,
15.38; Br, 29.27. Found: C, 43.77; H, 5.42; N, 15.23; Br, 29.17.
N,N0-Diethoxycarbonyl-1,2-di-(1-methyl-4-pyridinium)ethy-
lenediamine diiodide 2c. This compound has been described
previously [6].
´ ´
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Acknowledgment. The authors thank Dr. Antonio Chana for
performing the NOESY study.
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