Synthesis of 1,4-dihydro-2-methyl-4-oxo-nicotinic acid: Ochiai's route failed

Article abstract of DOI:10.1016/j.tet.2006.04.053

The synthesis of 1,4-dihydro-2-methyl- and 1,4-dihydro-1,2-dimethyl-4-oxo-nicotinic acids was accomplished following a route other than Ochiai's procedure, which yielded the isomer 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl ester, and not the 4-oxo-derivative, as reported. Analytical data confirmed the identity of the two isomer oxo-nicotinic acids. UV-vis and potentiometric preliminary data showed that Al(III) does not form complexes with 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl ester in solution, as expected, but with 1,4-dihydro-2-methyl-4-oxo-nicotinic acid.

Full text of DOI:10.1016/j.tet.2006.04.053

Tetrahedron 62 (2006) 6222–6227
Synthesis of 1,4-dihydro-2-methyl-4-oxo-nicotinic acid:
Ochiai’s route failed
b
b
Maria Grazia Ferlin,a, Valerio B. Di Marco and Annalisa Dean
*
aDepartment of Pharmaceutical Sciences, Faculty of Pharmacy, University of Padova, Via Marzolo 5, 35131 Padova, Italy
bDepartment of Chemical Sciences, University of Padova, Padova, Italy
Received 13 February 2006; revised 11 April 2006; accepted 20 April 2006
Available online 15 May 2006
Abstract—The synthesis of 1,4-dihydro-2-methyl- and 1,4-dihydro-1,2-dimethyl-4-oxo-nicotinic acids was accomplished following a route
other than Ochiai’s procedure, which yielded the isomer 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl ester, and not the 4-oxo-derivative,
as reported. Analytical data confirmed the identity of the two isomer oxo-nicotinic acids. UV–vis and potentiometric preliminary data showed
that Al(III) does not form complexes with 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl ester in solution, as expected, but with 1,4-di-
hydro-2-methyl-4-oxo-nicotinic acid.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
isomer 1,6-dihydro-2-methyl-6-oxo-nicotinic acid ethyl
ester 1. In the present work, we intend to demonstrate that
the compound obtained using Ochiai’s method is not the
ethyl ester 1,4-dihydro-2-methyl-4-oxo-nicotinic acid but
its isomer 1. In this connection, we report a successful
multi-step synthesis providing 1,4-dihydro-2-methyl-4-oxo-
nicotinic acid (7) and its N-methyl derivative. Exhaustive
analytical data (NMR, IR, UV, MS, mp) and preliminary
potentiometric and UV–vis results on the complexation
properties of the two ligands toward Al(III) are reported.
Therapy for metal overload pathologies usually involves ad-
ministration of suitable chelating agents to remove the metal
from the body selectively. Regarding aluminum(III) and
iron(III), medical research constantly emphasizes the need
for new safe, efficient, and orally effective chelators.1–3
Hydroxypyridinecarboxyl acids are a class of compounds,
which have been considered for metal chelation therapy.
Their structure suggests good binding capacity toward
aluminum(III) and iron(III), and interactions between 2,3
and 3,2- and 3,4 and 4,3-hydroxypyridinecarboxyl acids
with aluminum(III) and iron(III) have been studied.4,5 The
thermodynamic data and chelation efficiencies of these
compounds are such that they cannot be considered in
aluminum(III) chelation therapy. Synthesis of more lipo-
philic compounds was indicated and thus, in analogy with
deferiprone or 1,2-dimethyl-3-hydroxy-pyridin-4-one, an
effective oral chelation therapy, monomethyl- and di-
methyl-derivatives of hydroxypyridinecarboxyl acids, was
designed. Among these acids, new 1,4-dihydro-2-methyl-
4-oxo-nicotinic acid 7 and the corresponding N-methyl de-
rivative 8 were proposed for synthesis. At first, we adopted
Ochiai’s procedure, the only one reported in the literature,6
which would have allowed us to prepare the methyl ester
of the desired hydroxypyridinecarboxyl acid by only one re-
action between aminomethylenemalonate and ethyl acetoa-
cetate. However, in all conditions applied, we obtained the
2. Results and discussion
In our first attempt at synthesizing 1,4-dihydro-2-methyl-4-
oxo-nicotinic acid 7, we adopted the one-step method de-
scribed by Ochiai6 for synthesis of its ethyl ester, by reacting
diethyl aminomethylenemalonate and ethyl acetoacetate in
the presence of bubbled HCl dry gas at room temperature
(Scheme 1), and easily obtained the corresponding acid by
alkaline hydrolysis. Ochiai conditions allowed us to isolate
only the isomer 1,6-dihydro-2-methyl-6-oxo-pyridine-3-
carboxyl acid ethyl ester (1) in 44% yield. Varying the molar
ratio of the two reagents or increasing/decreasing the reac-
tion temperature never isolated the desired ethyl ester of 7.
Very recently, researchers have obtained identical results
with Ochiai’s reaction for 1,4-dihydro-2-methyl-4-oxo-pyri-
dine-3-carboxyl acid ethyl ester and proposed a four-step
pathway leading to the target.7
Keywords: Oxo-nicotinic acids; Chelating agents.
* Corresponding author. Tel.: +39 049 8275718; fax: +39 049 8275366;
e-mail: mariagrazia.ferlin@unipd.it
Analytical data for isomer ester 1 were consistent with
those reported in the literature for the same compound (IR,
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.053

M. G. Ferlin et al. / Tetrahedron 62 (2006) 6222–6227
6223
Table 1. Comparison of significant analytical data of the two isomer acids 2
and 7
O
COOEt
O
EtOOC COOEt
C
a)
COOEt
H C
2
COOH
O
CH
C
N
H
H N
2
CH
3
H C
COOH
CH
3
CH
3
N
H
O
Analysis
N
H
3
a) HCl
2
7
UV (H2O) (nm) 262 (14,209)
pH 1
245 (6162)
COOH
CH
COOEt
IR (KBr) (cmꢀ1
)
1668 (carboxyl C]O),
1650 (amide C]O)
1721.27 (carboxyl
C]O), 1646.41 (carbonyl
C]O)
N
H
O
O
N
CH
3
3
b) NaOH
H
1
1H NMR (d)
6.16 (d, 1H, J¼9.72 Hz, 6.66 (d, 1H, J¼7.5 Hz,
2
HC-5), 7.79 (d, 1H,
J¼9.72 Hz, HC-4)
HC-5), 7.96 (d, 1H,
J¼7.5 Hz, HC-6)
Scheme 1.
13C NMR (d)
165.6 (carboxyl C]O), 167 (carboxyl C]O), 180
(carbonyl C]O)
180 ꢁC dec
155.9 (amide C]O)
153 ꢁC dec
1H NMR, mp) which, however, had been synthesized by
means of other methods.8–11 In particular, it has been ob-
tained by cyclization of a dienamino ester, which resulted
from the reaction between a b-amino-croton ester and a pro-
piol ester.8
Mp
HRMS
MH+ 154
MH+ 154
malonate derivative and ring closure (d, e). An alternative
(which leads to the same thing) is first alkylation of ethyl
3-amino-butenoate by the formyl group in malonate (f) and
then ring closure by amide formation (g, h). Lastly, water
loss, ester hydrolysis, and carbon dioxide loss (i) affords
compound 1.
It is not the aim of this paper to speculate on the mechanism
involved in the formation of 6-oxo-nicotinic derivative 1 by
means of a reaction between aminomethylenmalonate and
ethyl acetoacetate, but we suggest two similar possible
mechanisms, described in Scheme 2. Briefly, after conden-
sation between aminomethylenmalonate and ethyl aceto-
acetate (a), transamination may occur (a plus b), forming
ethyl 3-amino-butenoate and formyl malonate, followed by
amide formation (c) with one of the ester functions in the
Subsequently, 5-carboxyl ethyl ester 1 is transformed by
means of alkaline hydrolysis (NaOH 2 N) into the corre-
sponding acid 2, to yield a compound to compare with target
acid 7 (Table 1).
COOEt EtOOC COOEt
C
H C
2
H
CH
C
O
H N
2
H C
a
3
COOC H
C H OOC
2
5
2
5
ethyl
aminomethylene
malonate
COOC H
2
5
acetoacetate
N
H O
b
2
COOC H
2
5
O
H
H
COOEt
O
H
c
H C
HC
C
CH
CH
COOEt
3
f
OH
H
C H OOC
2
5
COOC H
C
2
5
H
O
NH
NH EtOOC
2
C
N
H
H C
3
-C H OH
2
5
COOC H
2
C H OOC
5
H C
3
2
5
d
g
COOC H
2
5
OH
H
H C
3
HO
H
OH
H
C H OOC
2
5
COOC H
2
C2H5OOC
H3C
COOC H
2
5
H
5
e
h
H
NH
H
O
2
COOC H
C H OOC
H C
3
N
2
5
2
5
O
N
H
-C H OH
2
5
-H O, -C H OH, -CO
i
2
2
2 5
EtOOC
O
H C
3
N
H
1
Scheme 2.

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M. G. Ferlin et al. / Tetrahedron 62 (2006) 6222–6227
The synthesis of definite 1,4-dihydro-2-methyl-4-oxo-nico-
tinic acid 7 was accomplished partly by taking advantage
of a known method already used by us to prepare 4-oxo-
nicotinic acid5,12 (Scheme 3). We obtained a useful inter-
mediate, 2-chloro-4-methoxy-nicotinonitrile 5, starting from
condensation of malodinitrile and triethyl orthoacetate to
give 1,1-dicyano-2-ethoxypropene (3), which was reacted
with DMF–DMA in methanol, yielding 1,1-dicyano-4-
(N,N-dimethylamino)-2-methoxy-1,3-butadiene (4). The
latter was cyclized to chloro-derivative 5 (70%), the key pre-
cursor for target acid 7, which was obtained from it in two
steps: (a) introduction of a methyl group by the cross-cou-
pling reaction of 5 with Al(CH3)3 and (Ph)3P4Pd as catalyst
in dry dioxane to give 2-methyl-4-methoxy-nicotinonitrile
(6) in optimum yield; (b) hydrolysis by HBr 48% to the final
compound 7 (40% yield). Acid 7 was also N-methylated by
the conventional method,13 using CH3I in DMF to furnish
1,2-dimethyl-4-oxo-nicotinic acid 8.
NC
NC
OCH CH
2
NC
NC
OCH CH
3
2
3
CH
+
OCH CH
3
C
C
CH C
2
3
3
CH
OCH
CH
3
3
3
3
a) DFMDMA
OCH
OCH3
3
CN
NC
NC
OCH
3
b) HCl
CN
c) Al(CH )
3 3
C
C
C
C
N
CH
[(Ph) P] Pd
3 4
N
Cl
3
N CH
3
5
4
CH
6
3
d) HBr 48%
COOH
O
O
OH
N
COOH
COOH
CH I
3
N
CH
CH
3
N
H
CH
3
CH
3
3
7
8
Scheme 3.
Figure 1. (a) NOESY and HMBC spectra of compound 1; (b) Blue arrow:
NOESY correlation; red arrows: diagnostic HMBC correlations described
in text.
Data on the characterization of the two isomer acids 2 and 7
by UV, IR, 1H, and 13C NMR, plus melting points, are listed
in Table 1, so that, by comparing their analytical data, we can
state that the Ochiai compound is the isomer 1,6-dihydro-6-
oxo-pyridine derivative 1. As shown, the IR and 13C NMR
values for the carbonyl C]O of 2, 1665 cmꢀ1 and d 167, re-
spectively, are consistent with an amide C]O, whereas for 7
the same signals occur at 1646.5 cmꢀ1 and d 180, according
at d 7.79 (H-4) and the carbon resonances at d 155.9 (C-6)
and 165.6 (carboxyl C]O) and between the CH2 of the
ethoxy group at d 4.18 and the carbon resonance at d 165.6
(C]O) (Fig. 1, a and b).
1
to a cyclic ketone structure. Moreover, H NMR coupling
Lastly, as regards melting points, the breakdown of 2 at
153 ꢁC is consistent with its decarboxylation, which occurs
more readily than in 7 (180 ꢁC), in which the carbonyl and
carboxyl groups are next to each other.
constants for H-4 and H-5 (9.5 Hz) of 2 are higher than those
for H-5 and H-6 (7.5 Hz) of 7, in agreement with literature
data on a-pyridinone.8
NOESY, HMQC, and HMBC 2D NMR experiments were
also performed with 1 in order to confirm further the struc-
ture of the obtained compounds. In the NOESY spectrum,
a weak correlation was observed between the doublet at
d 7.79 (H-4) and the triplet at d 1.26 (methyl signal of the
ethyl residue). Further evidence was represented by the
diagnostic HMBC correlations between the proton signal
Further evidence of the identity of the two isomers came
from comparing their capacity to form complexes with
a hard metal ion like aluminum(III). Hard metal ions can
form reasonably stable complexes with hard functional
groups, such as phenol and carboxyl oxygens, provided
that a chelated complex forms, i.e., that two or more groups
can bind simultaneously with the metal ion14 to form a

M. G. Ferlin et al. / Tetrahedron 62 (2006) 6222–6227
6225
5.0
4.5
4.0
3.5
3.0
2.5
2.0
five- or six-membered ring. If this is not the case then very
weak monodentate complexes form (the only exceptions be-
ing phosphonate oxygens at acidic pH values, which form
reasonably stable monodentate complexes). This property
can be used to discriminate between isomers 2 and 7, as
only 7 has the carboxyl and phenol groups in ortho, and is
thus able to chelate the metal ion.
The formation of complexes is easily detected by UV–vis
analysis. Figure 2 shows UV–vis spectra obtained at the
same pH value (4.1) for one solution containing 2 and
Al(III) and another containing only 2. A pH value of 4.1
was chosen to ensure reasonable complex formation (com-
plexes may not form at more acidic values) and to avoid
the precipitation of aluminum hydroxide (expected at
pH>4.5–5 if complex stability constants are not sufficiently
high). Nevertheless, the two spectra are practically identical,
indicating that the ligand is not complexed.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
V
(ml)
NaOH
Figure 3. Theoretical (line) and experimental (circles) potentiometric titra-
tion curves for a solution containing Al3+ (3.81ꢃ10ꢀ4 m) and 2 (1.14ꢃ
10ꢀ3 m).
a solution containing 7 and Al3+. The overlapping theoretical
curve was calculated presuming no complex formation. The
differences between the two curves are large, especially at
higher pH values. Assuming the formation of strong com-
plexes of the type AlL, AlL2, and AlL3 leads to a far better
match between the two curves.16 Moreover, in solutions
containing 7 and Al3+, precipitation of Al(OH)3 was only
observed at [L]/[Al] ratios of less than 3.
0.5
0.4
0.3
0.2
0.1
0.0
5.0
4.5
4.0
3.5
3.0
2.5
2.0
200
220
240
260
280
300
320
340
nm
Figure 2. UV–vis spectra for one solution containing ligand alone,
pH¼4.08 (solid line) ([L]0¼3.39ꢃ10ꢀ4 m), and another containing ligand
with metal ion, pH¼4.13 (dash-dotted line) ([L]0¼3.39ꢃ10ꢀ4 m,
[Al3+]0¼9.86ꢃ10ꢀ5 m).
As regards potentiometric titrations, formation of the com-
plexes is competitive with acid–base equilibria, so that the
acidity constants of the ligand were determined first (the
acid–base properties of Al3+ were known from previous
data15). The results were pK1¼0.308ꢂ0.008 (OH),
pK2¼3.758ꢂ0.008 (COOH), pK3¼11.63ꢂ0.02 (NH) (note
that pKa values alone cannot discriminate between 2 and 7,
as very similar values are expected from both isomers).
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
V
(ml)
NaOH
Figure 4. Theoretical(line)andexperimental(circles)potentiometrictitration
curve for a solution containing Al3+ (3.11ꢃ10ꢀ3 m) and 7 (9.70ꢃ10ꢀ3 m).
These preliminary complexometric results undoubtedly sup-
port our structural assignments for 2 and 7. The significant
complexation ability of 7 toward Al3+ confirms that, in this
compound, the two coordinating groups, COOH and OH,
are in ortho, whereas this is not the case for 2.
Figure 3 shows an experimental potentiometric titration for
a solution containing 2 and Al3+. The overlapping theoretical
curve was calculated solely on the basis of the acid–base
properties of the ligand and the metal ion, thus assuming
no metal–ligand species. The theoretical curve almost coin-
cides with the experimental data, demonstrating that, in this
system, there is no (or very little) complexation at any pH
(values higher than 4.5–5 could not be reached, due to pre-
cipitation of Al(OH)3).
3. Experimental
3.1. General
Different results were obtained for isomer 7. The complete
results and discussion will be provided elsewhere.16
Figure 4 shows an experimental potentiometric titration for
Melting points were determined on a Gallenkamp MFB 595
010M/B capillary melting point apparatus, and are not cor-
rected. Infrared spectra were recorded on a Perkin–Elmer

6226
M. G. Ferlin et al. / Tetrahedron 62 (2006) 6222–6227
1760 FTIR spectrometer using potassium bromide pressed
disks; all values are expressed in cmꢀ1. UV–vis spectra
were recorded on a Perkin–Elmer Lambda UV/VIS spec-
trometer. 1H NMR spectra were recorded on Varian
Gemini (200 MHz) and Bruker (300 MHz) spectrometers,
using the indicated solvents; chemical shifts are reported
in d (parts per million) downfield from tetramethylsilane
as internal reference. Coupling constants are given in hertz.
In the case of multiplets, chemical shift was measured start-
ing from the approximate center. Integrals were satisfacto-
rily in line with those expected on the basis of compound
structure. Elemental analyses were performed in the
Microanalytical Laboratory, Department of Pharmaceutical
Sciences, University of Padova, using a Perkin–Elmer ele-
mental analyzer model 240B; results fell in the range of cal-
culated values ꢂ0.4%. Mass spectra were obtained on a Mat
112 Varian Mat Bremen (70 eV) mass spectrometer and
Applied Biosystems Mariner System 5220 LC/Ms (nozzle
potential 250.00). Column flash chromatography was per-
formed on Merck silica gels (250–400 mesh ASTM).
Chemical reactions were monitored by analytical thin-layer
chromatography (TLC) using Merck silica gel 60 F-254
glass plates with a 9:1 dichloromethane/methanol mixture
as eluant, unless otherwise specified.
IR (KBr) 3320 (NH), 1668 (carboxyl C]O), 1650 (amide
1
C]O) cmꢀ1; H NMR (DMSO-d6) d 2.52 (s, 3H, CH3),
6.1 (d, 1H, J5,4¼9.66 Hz, H-5), 7.81 (d, 1H, J4,5¼9.66 Hz,
1
H-4), 11.96 (s, 1H, HN-1); H NMR (MeOD) d 2.63 (s,
3H, CH3), 6.33 (d, 1H, J4,5¼9.70 Hz, HC-4), 8.04 (d, 1H,
J5,4¼9.72 Hz, HC-5); 13C NMR (DMSO-d6) d 170.37 (car-
boxyl C]O), 163.45 (C-6), 143.5 (C-2), 142.8 (C-4),
117.96 (C-5), 115.82 (C-3), 15.96 (CH3); HRMS [MH+]
154.129; Anal. Calcd for C7H7NO3: C, 54.90; H, 4.61; N,
9.15; found: C, 54.78; H, 4.33; N, 9.00.
3.1.3. Synthesis of 2-chloro-4-methoxy-nicotinonitrile
(5). Following the reported route,12 10 g (151.37 mmol) of
malodinitrile were reacted with 27.1 g (167.05 mmol) of tri-
ethyl orthoacetate at 90–95 ꢁC for 45 min. The mixture was
then evaporated at 60 ꢁC, giving a pink product of 1,1-
dicyano-2-ethoxypropene (3). Yield 99%; mp 91–92 ꢁC
[lit.17 88.5–89.5 ꢁC].
A solution obtained by heating a mixture of 3 (7.4 g,
54.35 mmol) in 17 ml of MeOH at 50 ꢁC, was added with
DMF–DMA (10.92 g, 82.05 mmol) and the resulting mix-
ture was refluxed for 1.5 h. After cooling at room tempera-
ture, a dark red precipitate formed, which was collected,
washed with cold MeOH, and dried, yielding 52% of 4,
mp 133 ꢁC (lit.12 130 ꢁC).
Solutions were concentrated in a rotary evaporator under
reduced pressure. Starting materials were purchased from
Aldrich Chimica and Acros, and solvents from Carlo Erba,
Fluka and Lab-Scan. DMSO was made anhydrous by reflux-
ing with CaO for 8 h and then by distillation under vacuum
andstorageonmolecularsieves. Dioxanewasdriedbyleaving
it on KOH pellets overnight and then storing it on metallic Na.
1,1-Dicyano-4-(N,N-dimethylamino)-2-methoxy-1,3-buta-
diene (4) (5 g, 28.21 mmol) in 100 ml of MeOH was sub-
mitted to cyclization in acid conditions by HCl gas, with
vigorous stirring, at 15 ꢁC. At the end of the reaction, water/
ice (800 g) was added and a white precipitate separated
from the solution. This was collected, washed with cold water,
and dried. The filtrate was concentrated under vacuum
and basified with NaOH 2 N, and a further product formed.
Overall yield was 70% of almost pure 5; mp 175–176 ꢁC
(methanol) (lit.12 168 ꢁC).
3.1.1. Synthesis of 1,6-dihydro-2-methyl-6-oxo-nicotinic
acid ethyl ester (1): Ochiai’s procedure. A mixture of ami-
nomethylenemalonic acid diethyl ester (1 g, 5.34 mmol) and
ethyl acetoacetate (0.68 ml, 5.34 mmol) was stirred at room
temperature to give a homogeneous suspension and then,
after cooling at 0 ꢁC, HCl gas was bubbled until saturation
and complete solubilization. The yellow solution was then
allowed to reach room temperature and left for 4–5 days.
By this time, a yellow crystalline product had formed, which
was collected and recrystallized from methanol/acetone
2:8, yielding 44% of pure compound. Mp 213 ꢁC (lit.6,7,10
207 ꢁC, lit.10 222 ꢁC); Rf 0.34 (chloroform/methanol 95:5);
IR (KBr) 3350 (NH), 1705 (ester CO), 1645 (amide
3.1.4. Synthesis of 2-methyl-4-methoxy-nicotinonitrile
(6). 2-Chloro-4-methoxy-nicotinonitrile (2 g, 11.86 mmol)
and 85 ml of anhydrous dioxane (KOH, Na) were placed
in a 250-ml two-necked round-bottomed flask. After dissolv-
ing by slight heating, 6 ml (56.84 mmol) of (CH3)3Al, 2 M
n-hexane solution and then 0.224 g (0.1916 mmol) of
[(Ph3)P]4Pd as catalyst were added. The mixture was re-
fluxed for 4 h under an inert atmosphere of N2, checking
the ongoing reaction by TLC analysis (chloroform/methanol
95:5). At the end, the cooled reaction mixture was acidified
with HCl 2 N and the solvent evaporated off. The residue
was treated with water, basified with NaOH 20%, and the
mixture extracted with diethyl ether. The combined extracts,
washed with water and dried over anhydrous Na2SO4, were
evaporated until dry. Yield 99%; mp 117 ꢁC; Rf (CHCl3/
1
CO) cmꢀ1; H NMR (DMSO-d6) d 1.26 (t, 3H, CH3), 2.52
(s, 3H, CH3), 4.18 (q, 2H, J¼7.0 Hz, CH2O), 6.19 (d, 1H,
J4,5¼9.66 Hz, H-5), 7.79 (d, 1H, J5,4¼9.59 Hz, H-4), 12.02
(s, 1H, H-1); 13C NMR (DMSO-d6) d 165.6 (carboxyl
C]O), 155.9 (C-6), 142.8 (C-4), 140.66 (C-2), 117.96 (C-
5), 115.82 (C-3), 60.87 (CH2), 15.96 (CH3), 14.28 (CH3);
HRMS [MH+] 182.12; Anal. Calcd for C9H11NO3: C,
59.66; H, 6.12; N, 7.73; found: C, 59.45; H, 6.13; N, 7.64.
1
MeOH 95:5); H NMR (DMSO-d6) d 2.53 (s, 3H, CH3),
4.05 (s, 3H, OCH3), 7.39 (d, 1H, J5,6¼6.1 Hz, H-5), 8.56
(d, 1H, J6,5¼6.1 Hz, H-6); HRMS [MH+] 147.15; Anal.
Calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91; found:
C, 64.69; H, 5.38; N, 18.86.
3.1.2. Synthesis of 1,6-dihydro-2-methyl-6-oxo-nicotinic
acid (2). A solution of 1.2 g (6.62 mmol) of ethyl ester 1
in NaOH 0.5 M (3–4 ml) was heated at 70–80 ꢁC for 3 h.
After cooling, the solution was slowly acidified with HCl
2 N until precipitation was complete, and placed at 0 ꢁC
overnight. The white precipitate was collected, washed
with water, and recrystallized from water. Yield 74%; mp
153 ꢁC (dec); Rf 0.2 (methanol); UV–vis 262 (14,209) nm;
3.1.5. Synthesis of 1,4-dihydro-2-methyl-4-oxo-nicotinic
acid (7). In a 50-ml flask, 1 g (6.84 mmol) of 2-methyl-4-
methoxy-nicotinonitrile and 17 ml of HBr 48% water solu-
tion were heated at 70–80 ꢁC for 1 h and then refluxed,

M. G. Ferlin et al. / Tetrahedron 62 (2006) 6222–6227
6227
checking the course of reaction by TLC analysis (chloro-
form/methanol 9:1). Although refluxing lasted some days,
the reaction had not finished, so refluxing was stopped, the
mixture cooled, and worked up as follows. It was basified
with NaOH 20% (pH 8–9), extracted with ethyl acetate in
order to remove the starting material, and the aqueous phase
acidified with HCl 2 N (pH 3). In this way, a fine white pre-
cipitate formed, which was left at 0–4 ꢁC overnight. The
next day, it was collected, washed with water, and dried.
Yield 45%; mp 180 ꢁC (dec); Rf 0.2 (methanol); UV–vis
245 nm (6162); IR (KBr) 3395 (NH), 1721 (carboxyl
standardized as previously described.4 The water solubility
of 2 and 7 is low (<2ꢃ10ꢀ3 m): working solutions at higher
concentrations (4.4ꢃ10ꢀ3 m and 6.5ꢃ10ꢀ3 m) could be
prepared upon slight basification. The ionic strength of all
solutions was adjusted to 0.6 m (z0.594 M) (Na)Cl.
Potentiometric titrations were carried out at 25ꢂ0.1 ꢁC.
Duplicate potentiometric measurements were carried out
using two glass electrodes (Radiometer pHG201 and BDH
309/1015/02) and a Ag/AgCl/0.6 m NaCl reference elec-
trode.
C]O), 1646.41 (carbonyl C]O) cmꢀ1
;
(DMSO-d6) 2.76 (s, 3H, CH3), 6.66 (d, 1H,
1H NMR
d
Solutions for UV–vis analysis were prepared in the same cell
used for potentiometric titrations and, after fixing the pH, the
solutions were transferred into a cuvette (1 cm path length).
A 0.6 m NaCl solution was used as blank.
J5,6¼7.06 Hz, H-5), 7.96 (d, 1H, J6,5¼7.25 Hz, H-6), 12.82
(s, 1H, HN-1), 16.15 (s, 1H, OH); 13C NMR (DMSO-d6)
d 180 (C-4), 167.1 (carboxyl C]O), 156.59 (C-2), 139.45
(C-6), 116.36 (C-5), 113.50 (C-3), 20.16 (CH3); HRMS
[MH+] 154.12, [Mꢀ1] 152.0; Anal. Calcd for C7H7NO3:
C, 54.90; H, 4.61; N, 9.15; found: C, 54.95; H, 4.53; N, 9.02.
All stability constants were calculated using the PITMAP
program.18
3.1.6. Synthesis of 1,4-dihydro-1,2-dimethyl-4-oxo-nico-
tinic acid (8). 2-Methyl-4-oxo-1,4-dihydro-pyridine-3-car-
boxyl acid (7) (0.900 g, 5.88 mmol) in 45 ml of DMF was
added with 1.8 ml (29.1 mmol) of CH3I and the mixture
heated at 100 ꢁC for 2 h. After cooling, the solvent was evapo-
rated off and the residue was recrystallized with methanol.
Yield 60%; mp 271 ꢁC; Rf 0.2 (methanol); IR (KBr)
1718.6 (CO), 1655.6 (carbonyl); 1H NMR (DMSO-d6)
d 2.76 (s, 3H, CH3), 3.45 (s, 3H, N–CH3), 6.66 (d, 1H,
J5,6¼7.06 Hz, H-5), 7.96 (d, 1H, J6,5¼7.25 Hz, H-6), 16.15
(s, 1H, COOH); 13C NMR (DMSO-d6) d 180 (C-4), 170.1
(carboxyl C]O), 163.4 (C-2), 142.2 (C-6), 116.2 (C-5),
114.6 (C-3), 33.2 (CH3), 19.3 (CH3); HRMS [MH+]
168.05; Anal. Calcd for C6H9NO3: C, 57.48; H, 5.43; N,
8.38; found: C, 57.32; H, 5.41; N, 8.25.
References and notes
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4. Complexometric measurements
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1985, 50, 1512–1516.
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Coord. Chem. Rev. 1996, 149, 311–328.
The experimental apparatus, reagents, and measurement
methods were almost the same as those previously reported.4
A summary follows, with details given only when they differ
from those already described.
All analyte concentrations are expressed in the molality
scale (mol/kg of water).
Potentiometric measurements were performed on
a Radiometer ABU93 Triburette apparatus; UV–vis spectra
were recorded on a Perkin–Elmer Lambda 25 instrument.
¨
15. Ohman, L. O. Inorg. Chem. 1988, 27, 2565–2570.
16. Di Marco, V. B.; Dean, A.; Ferlin, M. G., et al., in preparation.
17. Schmidt, H. W.; Junek, H. Monatsh. Chem. 1977, 108,
895–900.
Working solutions of HCl (0.2 m), NaOH (0.2 m), and AlCl3
(0.1 m, containing HCl 0.3 m) were prepared and
18. Di Marco, V. B. Ph.D. Thesis, University of Padova, 1998.