Synthesis, structural and conformational properties, and gas phase reactivity of 1,4-dihydropyridine ester and ketone derivatives

Article abstract of DOI:10.1039/c0ob00494d

A new series of 4-aryl-2,6-dimethyl-1,4-dihydropyridines, characterized by ester or ketone functions at positions 3 and 5, has been synthesized. Structural and conformational properties, concerning the dihydropyridine ring and the orientation (synplanar/a

Full text of DOI:10.1039/c0ob00494d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis, structural and conformational properties, and gas phase reactivity
of 1,4-dihydropyridine ester and ketone derivatives†
Gianluca Giorgi,*a Mauro F. A. Adamo,b Fabio Ponticellia and Antonio Venturaa
Received 26th July 2010, Accepted 23rd August 2010
DOI: 10.1039/c0ob00494d
A new series of 4-aryl-2,6-dimethyl-1,4-dihydropyridines, characterized by ester or ketone functions at
positions 3 and 5, has been synthesized. Structural and conformational properties, concerning the
dihydropyridine ring and the orientation (synplanar/antiperiplanar) of the substituents have been
investigated in their crystal structure and in solution by nuclear magnetic resonance. Evaluation of
intermolecular and hydrogen bonding interactions as well as packing features, have been also carried
out, evidencing interesting packing motifs. Their gas phase reactivity, as protonated and deprotonated
molecules, has been investigated by electrospray ionization, high resolution and collision-induced
dissociation multiple stage mass spectrometry. Deydrogenation reactions have been observed as a
function of the capillary voltage.
Considering the promising activity of DP7, we have embarked
on a research program aimed at introducing additional diversity
in the 1,4-dihydropyridine moiety with the obvious tasks of (i)
Introduction
1,4-Dihydropyridines (1,4-DHPs) are an important class of chem-
icals widely used as drugs or their precursors.1 The DHP moiety
obtaining more powerful P-gp inhibitors; (ii) gaining an insight
is common to numerous bioactive compounds such as antihy-
on the tridimensional properties of these products, as their
pertensive, vasodilator, antimutagenic and antidiabetic agents.2,3
chemical properties are linked to the observed biological activity.
Nifedipine, nitrendipine and nimodipine are example of commer-
Modifications of the aromatic group present at position 4 and/or
cially available calcium channel blockers used for the treatment
of cardiovascular diseases and containing the DHPs motif.4,5 1,4-
of the 3,5-diacyl groups were performed to create a small library
of compounds (Scheme 1, 1–6) characterized by either an ester or
Dihydropyridines containing different ester moieties and diethyl
a ketone functionality at positions 3 and 5.
carbamoyl groups are potential antitubercular agents,6 while
The conformation of the dihydropyridine ring, the nature of the
differently functionalized 1,4-DHPs are useful for regeneration of
substituents and their mutual orientation play a key role for the
the reduced form of nicotinamide adenine dinucleotide (NADH),
an essential compound for living organisms.7,8 The use of this class
biological activity of 1,4-DHPs. For this reason, a detailed study
of the crystal structures of compounds 1, 2 and 6 has been carried
of molecules as a scaffold to develop novel antitumor therapies
out. We have also studied the gas phase properties and reaction
has been recently proposed.9 For example, the dihydropyridine
DP7 (Scheme 1) has been shown to be a potent inhibitor of P-gb
and therefore has potential to become a good candidate in novel
treatments for cancers that have developed multi drug resistance
(MDR).10,11
pathways of protonated [M+H]+ and deprotonated [M - H]- ions
produced by 1–6 under electrospray ionization (ESI). This study
was then complemented by multistage mass spectrometry (MSn)
experiments and theoretical calculations.
Results and Discussion
Synthetic approach
Compounds 1–6 were prepared according to the classical
Hantzsch condensation of one equivalent of an aryl aldehyde
with two equivalents of a 1,3-dioxo compound and ammonia,
as reported in Scheme 2. Satisfactory yields were obtained for the
preparation of esters 1, 3, 5 and 6, whereas compounds 2 and 4
were formed in only modest yields in a complex reaction mixture.
Scheme 1
X-Ray crystallography
aDipartimento di Chimica, Universita` di Siena, via Aldo Moro, 53100, Siena,
Italy. E-mail: gianluca.giorgi@unisi.it; Fax: +39 0577 234233; Tel: +39
0577 234241
In the X-ray structures of 1, 2 and 6 (Fig. 1) the 1,4-DHP ring
has a shallow boat conformation. Atoms N(1) and C(4) show
small displacements from the base of the boat plane defined by
C(2), C(3), C(5) and C(6). As already observed in other 1,4-DHP
structures,12,13 as well as in the present crystal structures, N(1)
bCentre for Synthesis and Chemical Biology (CSCB), Department of
Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons
in Ireland, 123 St. Stephen’s Green, Dublin, Ireland
† CCDC reference numbers 770770–770772. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob00494d
˚
shows a smaller deviation from that plane (average 0.112(3) A)
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Scheme 2
˚
compared to C(4) (average 0.273(3) A). The shallowness of the
boat is indicated by the puckering parameters ◦(Table 1) that differ
from those characterizing an ideal boat (q = 90 and j2 = n¥60◦).14
The sum of the absolute values of the ring internal torsion angles
(P) is another quantitative measure suggested for the evaluation of
the flatness of the six-membered ring.15 These values range from
75.6(4) (2) to 89.0(3)◦ (1) (Table 1), indicating a significant amount
of flattening from the ideal boat conformation. In nifedipine, a
calcium channel blocking drug, the value of P is 72◦.16–19 The
phenyl ring at C(4) almost bisects the 1,4-dihydropyridine ring
both in 1 and in the two molecules of 6, while the dihedral angle
between the two planes is 76.41(12)◦ in 2 (Table 2). Similarly to
other 1,4-dihydro-pyridine derivatives,12,18 in all the compounds
the two exocyclic substituents at C(3) and C(5) show the opposite
orientation with synplanar/antiperiplanar conformation at the
two double bonds (Table 2) that imparts chiral character to the 1,4-
dihydropyridine ring. 1 and 2 are a racemic mixture in the crystal,
as it results by the centrosymmetric space groups (P21/c and
Pbca, respectively) in which they crystallize, while 6 crystallizes
in a chiral space group (P21) (see below). The ester groups in 1
are almost coplanar with the 1,4-DHP ring due to the electron
delocalization of the conjugated double bond system involving
Table 1 Geometric and puckering parameters for the 1,4-dihydropyridine
ring in compounds 1, 2 and 6
Fig. 1 ORTEP view of the crystal structures of 1 (top), 2 (middle), and
of the two molecules constituting the asymmetric unit of 6 (bottom).
Ellipsoids enclose 50% probability.
N(1) deva C(4) deva Pb
Q(A)
q(◦)
j2 (◦)
˚
Compd
1
2
0.117(2) 0.308(2) 89.0(3) 0.253 (2) 72.2(4) 183.4 (4)
0.097(2) 0.262(3) 75.6(4) 0.215 (3) 71.9(8) 187.1 (7)
6 (mol A) 0.115(3) 0.262(3) 77.5(5) 0.222 (4) 75.0 (10) 178.1 (10)
6 (mol B) 0.120(3) 0.258(3) 77.3(5) 0.222 (4) 75.6 (10) 178.9 (10)
C(2)–C(3)–C(9)–O(1) and C(6)–C(5)–C(19)–O(5) (Table 2). When
the substituents of the exocyclic carbonyl or carboxy groups are
larger than a methyl group, the steric hindrance plays a key role
on the conformational features. The orientation of the cyclohexyl
group is very similar in the two molecules of the asymmetric unit
a
˚
Deviation (A) from the least square plane defined by C(2),C(3),C(5), C(6)
b P = sum of the absolute values of the ring internal torsion angles of the
1,4-dihydropyridine ring
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Table 2 Significant torsion and dihedral angles (◦) in compounds 1, 2
and 6
different 1H and 13C NMR signals. On the other hand, this effect
is absent in the case of the remaining 1,4-DHP (1–5).
The study of crystal packing of 1 and 2 reveals an interesting
feature due to molecular associations that yield a one-dimensional
extended chain. This chain is characterized as the C(6) packing
motif,19 via intermolecular N(1)–H ◊ ◊ ◊ O(1) hydrogen bonds in-
volving the nitrogen atom of the 1,4-dihydropyridine moiety and
the oxygen atom of the carbonyl group in ap conformation. The
C(2) C(3)– C(6) C(5)–
Compd C(9) O(1)
C
O
Ua
Da
Pa
1
2
177.1(2)
153.7(3)
6 (molA) 150.4(4)
6 (molB) 149.7(4)
8.8(3)
43.4(4)
1.8(6)
1.8(6)
87.69(9)
—
—
76.41 (12) 74.43 (15) 59.44(13)
87.97 (18) 54.87 (18) 85.54(19)
88.18 (18) 55.29 (18) 85.47(19)
˚
N ◊ ◊ ◊ O distances are equal to 2.886(2) and 3.012(3) A in 1 and 2,
respectively (Table 3).
a U = dihedral angle between the 4-aryl and the 1,4-dihydropyridine ring;
D = dihedral angle between 1,4-DHP and the ap-Ph/cHex; P = dihedral
angle between 1,4-DHP and the sp-Ph/cHex
In 2, two hydrogen bonding interacting molecules are in
positions (x, y, z) and (x, 1+y, z) and, as a consequence, they
are coplanar with each other and translated along the b axis. In
1, two adjacent molecules are in positions (x, y, z) and (12 -x,
of 6 and close to the orientation of the phenyl ring in 2. The ring
bound to the syn periplanar ester (in 6) or to the carbonyl group (in
2) is almost perpendicular to the 1,4-DHP ring, while when the ring
is bound to the anti periplanar ester/carbonyl group its orientation
is further from perpendicularity (Table 2). The m-methoxy group
in the dimethoxyphenyl ring has a different orientation in the three
crystal structures. In fact in both the molecules of 6 it is directed
over the 1,4-DHP ring and it has a anti periplanar orientation with
respect to the C(4)–H bond.
1
-2 +y, z), thus causing an almost orthogonal orientation of the
two molecules (Table 3).
In both the molecules of 6, the hydrogen bonding pattern is
different. In fact the hydrogen bonds involve the nitrogen atom and
the oxygen atoms of the m- and p-methoxy group, thus forming
five-membered chelate rings. In the two molecules the N(1) ◊ ◊ ◊ O(3)
˚
distances average 3.133(4) A while those N(1) ◊ ◊ ◊ O(4) average
˚
3.065(4) A (Table 3).
In contrast, in both 1 and 2 the m-methoxy group is directed
away from the 1,4-DHP ring with a syn periplanar orientation
with respect to the C(4)–H bond.
In addition to classical hydrogen bonding interactions, there
are several intermolecular interactions, such as –C–H ◊ ◊ ◊ O in-
teractions. In 2 these involve C(30)–H (x,y,z) that interacts with
both O(2) and O(3) of a molecule at 1-x,-y,-z, thus causing the
formation of a chelate five membered ring and a dimeric structure.
It is worth noting that in the two molecules of 6 the isopropyl
groups are oriented towards the centroid of the phenyl ring
at position 4 of the 1,4-DHP, thus forming C–H ◊ ◊ ◊ p ◊ ◊ ◊ H–C
interactions20 (Fig. 2). These interactions produce conformational
rigidity for the phenyl ring that imparts chiral character to 6.
Conformational rigidity seems to occur also in solution. In fact
this feature, together with the different orientation of the carboxy
groups, causes the two methyl groups in position 2 and 6 of the
1,4-DHP ring, as well as those of the isopropyl group, to produce
Gas phase behavior of protonated and deprotonated molecules
The characterization of the structure and reactivity of cationic and
anionic species produced in the gas phase from compounds 1–6
have been carried out by electrospray ionization, using positive and
negative mode, and by tandem mass spectrometry through MSn
experiments. Elemental compositions of ions have been attributed
by means of high resolution-accurate mass measurements per-
formed with a FT-ICR coupled to an ion trap mass spectrometer.
The ESI(+) mass spectra of compounds 1–6 show the presence
of [M+H]+ and the adduct [M+Na]+ while fragment ions are
undetectable, in agreement with the soft nature of electrospray
ionization.
An interesting feature is the dehydrogenation process that occurs
as a function of the capillary voltage. As an example, in the case
of compound 1, at low capillary voltage values, the ESI(+) mass
spectrum shows abundant [M+H]+ ions at m/z 362. By increasing
the capillary voltage, the elimination of two hydrogen atoms occurs
yielding ions at m/z 360. It is likely that the dehydrogenation
reaction involves the dihydropyridine ring that is aromatized to a
pyridine ring by loss of a molecule of hydrogen. The resulting
Fig. 2 C–H ◊ ◊ ◊ p interactions in one molecule of the asymmetric unit of
6. Distances are in A.
˚
Table 3 Intermolecular hydrogen-bonding interactions in compounds 1, 2 and 6
D–H ◊ ◊ ◊ A (◦)
˚
˚
#
Donor-H
Acceptor/A
Symmetry
H ◊ ◊ ◊ A (A)
D ◊ ◊ ◊ A (A)
1
2
6
N(1)–H
N(1)–H
N(1A)–H
N(1A)–H
N(1B)–H
N(1B)–H
O(1)
O(1)
O(3B)
O(4B)
O(3A)
O(4A)
12 -x,-12 +y, z
x, 1+y, z
2.03
2.12(3)
2.44
2.26
2.43
2.26
2.886 (2)
3.012 (3)
3.140 (4)
3.067 (4)
3.127 (4)
3.064 (4)
178
165(2)
139
156
138
156
-1+x,y,1+z
-1+x y,1+z
1+x,y,z
1+x, y, z
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ions are considerably stabilized by their aromatic conjugated
system. Elimination of H2 also occurs under electron ionization
of analogous 1,4 dihydropyridines.21
benzaldehyde from [2+H]+ produces ions at m/z 348 with relative
abundance below 5%.
Mass spectrometry has been also used to study the gas phase
reactivity of anions derived from compounds 1–6. To the best of
our knowledge, this is the first investigation concerning deproto-
nated 1,4-dihydropyridines. Their ESI(-) mass spectra show only
the species [M - H]- and [M+Cl]-. When the anions [M - H]- are
submitted to CID experiments, their MSn spectra show interesting
features. In contrast to the protonated molecules, whose gas phase
reactions follow few decomposition pathways, deprotonation
followed by CID gives a lot of abundant product ions. Most of
them are produced by loss of some or all substituents at positions
2, 3, 5, 6 of the heterocyclic ring. Loss of the neutral side chain in
position 3 and 5 of the dihydropyridine nucleus from deprotonated
2 yields abundant ions at m/z 346 ([(M-H) – C6H5CHO]-),
Low energy collision induced decompositions of the ions at
m/z 362 cause fragmentation of the carbomethoxy side chains in
positions 3 and 5 with consecutive elimination of two molecules
of methanol, yieding ions at m/z 330 and 298, respectively.
The elimination of alcohols, also described for ESI-MS/MS
experiments on analogous compounds,22 can be rationalized by
assuming an hydrogen atom transfer from each methyl group at
the C-2 and C-6 positions to the methoxy moieties. This should
be favored by the cis configuration of the disubstituted double
bond and by a six-membered transition state, thus resembling an
ortho-elimination in ionized aromatic systems.23
Different structures might be proposed for the ionic
species at m/z 298, such as a (2,6-dimethylenepiperidine-3,5-
diylidene)dimethanone derivative. However, the most reasonable
is that in which the 3,5-di(carboxymethyl)-dihydropyridine moiety
is converted into a tricyclo decadiene system (Fig. 3). This latter
is in agreement with the MS4 spectrum obtained by selecting the
species at m/z 298 whose product ions (m/z 270 and 256) could
be easily formed from the proposed structure (Fig. 3).
∑
∑
while in the case of [1-H]- elimination of OH, CH3/CH3OH
is observed and it gives ions at m/z 328. The decomposition of
these two ionic species involves consecutive eliminations of methyl
radicals, as confirmed by MSn experiments. Losses of radical
species from even-electron ions are uncommon pathways under
electrospray ionization,24 while for these compounds they produce
very abundant species.
Concerning the ions at m/z 346, two possible structures based
on 2-methylene pyridine and on azepine moieties might be
proposed. Theoretical calculations show that the former (Fig. 4,
top) is more stable than the latter, having a heat of formation,
Fig. 3 ESI(+) MS4 product ion spectrum of the ions at m/z 298 obtained
by compound 1. The PM6 energy minimized structure is also depicted.
Also the MS/MS product ion mass spectrum of the oxidized
species at m/z 360 shows consecutive elimination of two methanol
molecules yielding ions at m/z 328 and 296, respectively, together
with other abundant fragment ions at m/z 345 and 330 attributable
∑
to [((M+2H)+H) - CH3]+ and [((M+2H)+H) - 2 CH3]+, respec-
tively.
In contrast, CID decompositions of the protonated dike-
tone 2 (m/z 454) involve almost exclusively the loss of a 1,2-
dimethoxybenzene molecule, yielding ions at m/z 316 whose
abundance is 100%. Owing to this loss, the pyridine ring gains
aromaticity thus forming a thermodynamically stable species. It is
worth noting that in the ester derivatives elimination of the aryl
group in position 4 occurs to only a minor extent, yielding ions
with abundances not higher that 8%. On the other hand, in the keto
derivatives, decompositions involving the substituents at position
3 and 5 are only minor processes. As an example, elimination of
Fig. 4 ESI(-) MS2 product ionspectra ofthe species [M - H]- produced by
compounds 1 (top) and 2 (bottom). The arrows indicate reaction pathways
confirmed by MS3 experiments. PM6 energy minimized ion structures for
ions at m/z 222 (top) and 346 (bottom) are also depicted.
5342 | Org. Biomol. Chem., 2010, 8, 5339–5344
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calculated by PM6, 7.3 kcal mol-1 less than that calculated for the
azepine derivative.
128.8, 131.2, 137.6, 139.0, 147.8, 148.1, 197.9. ESI-MS: m/z 476
[M+Na]+. Anal. Calcd for: C29H27NO4: C, 76.80; H, 6.00; N, 3.09.
Found: C, 77.04; H, 5.92; N, 2.87.
Abundant ions at m/z 420 are present in the CID mass spectrum
of [2-H]-. (Fig. 4, bottom). They correspond to the loss of 32 u
from [M - H]-, easily attributable to CH3OH. But the radical ions
Dimethyl 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (3). Reagents: acetylace-
tone and 1,4-benzodioxane-6-carboxaldehyde, m.p. 223–225 ◦C
∑
at m/z 435 ([(M-H)–CH3]- ) are also produced. Thus it is likely
that ions at m/z 420 may be produced by direct loss of methanol
1
(ethanol). H NMR (CDCl3). d 2.35 (s, 6H, 3 CH3), 3.68 (s, 6H,
∑
∑
and/or by successive eliminations of CH3 and OH. A two step
elimination of methanol is also observed for [1-H]-. In fact, under
CID conditions, ions at m/z 435 and 420, due to consecutive losses
of ∑OH, from the enol form, and ∑CH3, respectively, occur.
Elimination of the neutral substituent at position 4 of the
dihydropyridine ring is an important decomposition pathway for
[1-H]-, yielding ions at m/z 222 (Fig. 4, top). In this case two
possible structures, one with the negative charge formally on C(4)
and another with it on a carboxy group, after methyl transposition,
might be formed. PM6 calculations suggest that the latter (Fig. 4,
top) is 53.7 kcal mol-1 more stable than the former. Elimination
of the neutral aryl substituent at position 4 is only a minor CID
reaction pathway for [2-H]-. In fact the resulting ions (m/z 314)
have relative abundance equal of 15%.
3 CH3), 3.68 (s, 6H, 2 OCH3), 4.25 (s, 4H, 2 OCH2), 4.92 (s, 1H,
CH), 5.68 (s, 1H, NH), 6.70–6.79 (m, 3H, Ph). ESI-MS: m/z 382
[M+Na]+. Anal. Calcd. for C19H21NO6: C, 63.50; H, 5.89; N, 3.90.
Found: C, 63.69; H, 6.04; N, 3.81.
Dimethyl 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (4). Reagents: benzoylace-
tone and 1,4-benzodioxane-6-carboxaldehyde, m.p. 244–246 ◦C
(ethanol). 1H NMR (CDCl3). d 1.99 (s, 6H, 2 CH3), 4.18 (s, 4H, 2
CH2), 5.02 (s, 1H, CH), 5.60 (s, 1H, NH), 6.36–6.39 (dd, J = 8.0,
2.0, 1H), 6.53 (d, J = 2.0, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.36–7.40
(m, 4H, Ph), 7.45–7.49 (m, 2H), 7.59–7.62 (m, 4H). ESI-MS: m/z
452 [M+H]+. Anal. Calcd. for C29H25NO4: C, 77.14; H, 5.58; N,
3.10. Found: C, 77.33; H, 5.60; N, 2.97.
Diethyl 4-(1H-indol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (5). Reagents: indole-4-carboxaldehyde and ethy-
Experimental section
◦
1
lacetate, m.p. 176–178 C (methanol). H NMR (CDCl3): d 1.12
(t, J = 6.8, 6H, 2CH3), 2.36 (s, 6H, 2 CH3), 3.93–4.07 (ABq, J =
10.8, 6.8 Hz, 4H, 2CH2), 5.46 (s, 1H, CH), 5.61 (s, 1H, NH), 6.81–
6.83, 7.07–7.08, 7.17–7.21 (m 5H, indole), 8.03 (s, 1H); 13C NMR
(CDCl3): 13.20, 18.58, 36.47, 58.56, 101.99, 107.89, 118.99, 120.87,
122.16. Anal. Calcd. for C21H24N2O4: C, 68.46; H, 6.57; N, 7.60.
Found: C, 68.38; H, 6.53; N, 7.76. ESI-MS: m/z 391 [M+Na]+.
General information
All the solvents were previously dried according to standard
procedures. Analytical TLC was performed on silica gel 60 F254
plates. Flash column chromatography was carried out on silica gel
(0.040–0.063 mm). Melting points were determined on a Kofler
hot stage and are uncorrected. H and 13C NMR spectra were
1
◦
recorded at 27 C (CDCl3), unless otherwise stated, on a Bruker
1
Bis((1R,2S,5R) - 2 - isopropyl - 5 - methylcyclohexyl) - 4 - (3,4 - di-
methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxy-
late (6). Reagents: 3,4-dimethoxybenzaldehyde and (-)menthol
Avance 400 instrument operating at 400.13 MHz for H and at
100.62 MHz for 13C. The chemical shifts are reported in ppm on
the d scale, using the solvent peak as a reference value. Data are
reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,
dd = doublet of doublet, m = multiplet, b = broad. J are in Hz.
◦
1
acetoacetate, m.p. 191–193 C (methanol). H NMR (CDCl3):
d 0.43, 0.57, 0.68, 0.77, 0.79, 0.80, 0.82 (6d, J = 10.8, 18H, 6
CH3), 0.73–1.95 (m, 18H, CH/CH2), 2.22, 2.33 (2 s, 6H, 2 CH3),
3.75, 3.77 (2 s, 6H, 2 OCH3), 4.62, 4.58 (2td, J = 10.8, 4.4, 2
OCH), 4.91 (s, 1H, CH), 5.49 (s, 1H, NH), 6.63–6.70 (m, 2H,
Ar), 6.79 (d, J = 2 Hz, 1H, Ar). 13C NMR (CDCl3) 15.63, 16.76,
19.52, 19.70, 20.91, 21.02, 22.07, 22.10, 22.80, 23.80, 25.18, 26.56,
31.41, 31.43, 34.38, 34.46, 38.68, 41.23, 41.47, 47.32, 47.62, 55.76,
55.86, 72.97, 73.68, 103.91, 104.98, 110.77, 111.60, 119.81, 140.58,
142.95, 144.22, 147.27, 148.23, 167.09, 167.34. ESI-MS: m/z 632
[M+Na]+. Anal. Calcd. for C37H55NO6: C, 72.87; H, 9.09; N, 2.30.
Found: C, 73.02; H, 8.96; N, 2.41.
General procedure for the preparation of the 1,4-dihydropyridines
(1–6)
A solution of 1,3-dicarbonyl compound (20 mmol), ammonia
28% (1 mL) and the suitable aldehyde (10 mmol) in ethanol
(20 mL) was refluxed for 24 h following the Hantzsch protocol.
Evaporation of the solvent gave an oily residue which was column
chromatographed using light petroleum/ethyl acetate (4 : 1 v/v)
as eluent.
Dimethyl
4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydro-
X-Ray crystallography
pyridine-3,5-dicarboxylate (1). Reagents: acetylacetone and
3,4-dimethoxybenzaldehyde according to the procedure reported
by Ohsumi et al.25 m.p. 144–146 ◦C (ethanol) (lit: 146–147 ◦C).
Single crystals of 1, 2 and 6 were submitted to X-ray data
collections by using a Siemens P4 four-circle diffractometer with
˚
(4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
diyl)-bis(phenylmethanone) (2). Reagents: benzoylacetone and
3,4-dimethoxybenzaldehyde., m.p. 221–223 ◦C (methanol). 1H
NMR (CDCl3): d 1.99 (s, 6H, 2CH3), 3.64, 3.80 (2 s, 6H, 2CH3),
3.64, 3.80 (2 s, 6H, 2 OCH3), 5.13 (s, 1H, CH), 5.65 (s, 1H,
NH), 6.35 (s, 1H), 6.60–6.62 (d, 1H), 6.69–6.71 (d, J = 8.2 Hz,
2H), 7.36–7.47 (m, 6H, Ph), 7,47–7,59 (m, 4H, Ph). 13C NMR
19.0, 43.2, 54.3, 54.7, 110.0, 111.1, 113.4, 118.8, 119.0, 128.6,
graphite monochromated Mo-Ka radiation (l = 0.71073 A).
The structures were solved by direct methods implemented in
SIR 200626 and in SHELXS-9727 programs. The refinements were
carried out by full-matrix anisotropic least-squares on F2 for all
reflections for non-H atoms by using the SHELXL-97 program.28
CCDC-770770, CCDC-770771 and CCDC-770772 contain the
supplementary crystallographic data for compounds 1, 2 and 6,
respectively, described in this paper.†
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Mass spectrometry
species. Nevertheless, elimination of the neutral aryl moiety at
position 4 is a common process for all deprotonated molecules.
ESI measurements have been carried out on a LCQ-DECA
ion trap (Thermo, Bremen, D) in positive and negative modes.
Solutions were introduced into the mass spectrometer using a
syringe pump at a flow rate of 5 mL min-1. Operating conditions of
the ESI source were: spray voltage ( ) 4.5 kV; capillary temperature
200 ◦C; sheath gas (nitrogen) flow rate, ca. 0.75 L min-1. Ultra pure
helium was the collision gas and the CID collision energy was in
the range 0.5–1.0 eV (laboratory frame).
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This study has produced a new series of 1,4-dihydropyridine
derivatives, functionalized as ketones or esters at positions 3 and
5, whose structural and conformational properties, and gas phase
reactivity have been investigated by using X-ray crystallography,
nuclear magnetic resonance spectroscopy, mass spectrometry and
theoretical calculations. The conformational study of their crystal
structures, both concerning the 1,4-dihydropyridine ring and
the substituents at positions 3 and 5, as well as the study of
intermolecular and hydrogen bonding interactions have added
useful information for understanding the features of this class
of compounds.
Investigation of the gas phase ion chemistry of the cations
and anions derived from protonation or deprotonation of these
compounds has been carried out by electrospray and multi-stage
(up to MS4) mass spectrometry. It is of interest the different
reactivity shown in collision-induced dissociation experiments
as a function of the charge of the species. While the loss of
methanol from substituents at position 3 and 5 dominate the
CID spectra of protonated diester cations formed from 1 and
3, for ketone derivatives, elimination of the neutral aryl moiety at
position 4 is highly prevalent over all the other gas phase reactions.
The occurrence of a dehydrogenation process as a function of
the electrospray capillary voltage has been also observed and
discussed.
Deprotonated molecules undergo several kinds of gas phase
decompositions, most of them involving elimination of radical
5344 | Org. Biomol. Chem., 2010, 8, 5339–5344
This journal is
The Royal Society of Chemistry 2010
©