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Synthesis and ReactiVity of Laquinimod
TABLE 4. Alcoholysis of Amide 2 and Trans-Esterification of
Ester 1
amide 13 was not solvolyzed to methyl benzoate when heated
in MeOH at 100 °C. These experiments further underline that
the enol proton, found in compounds 16 and 2, is fundamental
for the reaction with methanol and that amide 2 is more reactive
than ester 16. Apparently, the exocyclic amide bond in 2 is weak
and reactive when the enol proton is present in the molecule
whereas it is very stable when the molecule is in its enolate
form. Compound 2 is rather acidic (pKa ) 4.2), and the stable
enolate form dominates under physiological conditions. In vivo
pharmacokinetic studies on compound 2 have not revealed any
reactions related to those discussed here, and 2 is metabolized
mainly by aryl hydroxylation and oxidative N-dealkylation6 and
the half-life elimination in man is 3 days. Compound 17 is
similar in structure to 2 but is extremely stable when heated in
MeOH at 140 °C and shows no sign of the methanolysis product
or any other byproducts. Unlike compound 2, which is readily
soluble in water at pH 7.5 (100 mg/mL), compound 17 is
virtually insoluble (<0.01 mg/mL). A plausible explanation of
the very different chemical behavior of 2 and 17 is discussed
later in the section about the possible reaction mechanism for
the equilibrium between 1 and 2.
reactant/alcohol
rate constant (h-1
)
ester in % of productsa
2/1.6% n-PrOH
2/0.32% n-PrOH
2/0.064% n-PrOH
2/0.32% MeOH
2/0.32% EtOH
2/0.32% i-PrOH
1/1.6% n-PrOH
1/0.064% n-PrOH
0.232
0.227
0.226
0.219
0.221
0.218
0.00343
0.00303
91
71
32
82
66
60
91
25
a Apart from ester, 7 was also formed from reaction with water. The
found sum of 7 and ester corresponded to the consumed amount of the
reactant.
SCHEME 4. Acetoacetylation of Aniline with tert-Butyl
Acetoacetate
Kinetic Study of the Solvolysis of 1 and 2. The stability of
the amide 2 was studied in various solvents, and it was found
that the polarity of the solvent had a large impact on the stability.
The ratios of the relative degradation rates in water (0.02 M
HCl), DMSO, ethanol, and dichloromethane were approximately
1:5:10:40 (see the Experimental Section for details). Thus, the
reactivity of 2 increases when solvent polarity decreases.
Comparison of these results with the solvent dependence of UV
and NMR spectra of amide 2 (discussed below) led to the
assumption that compound 2 is present in two different forms
in equilibrium. One form is favored in nonpolar solvents and is
highly reactive, while the other form, which is much less
reactive, is favored in polar solvents. Even though we expected
that the reactivity of ester 1 and amide 2 would be caused by
ketene formation rather than by the more common bimolecular
reaction through tetrahedral intermediates, it was necessary to
provide more evidence in order to exclude the latter type.
Therefore, we decided to examine whether the nucleophile was
involved in the rate-determining step or not. One difficulty in
studying the effect of the concentration of the nucleophile was
to distinguish between the direct dependence on the rate of
formation and the impact of the solvent polarity. This was
overcome by the using a solvent mixture (20% DMSO in
acetonitrile) that was “buffered” with respect to polarity by
solvents that do not enter the reaction. Kinetic experiments with
amide 2 were performed using varying amounts of n-propanol
and other alcohols in this mixed medium. In all cases, the
consumption of the reactant followed first-order kinetics,
obviously in favor of a reaction involving an unimolecular rate-
determining step. In addition to the n-propyl ester, the corre-
sponding carboxylic acid 6 was also formed but was decarbox-
ylated to 7 before analysis. This byproduct is formed in a side-
reaction with traces of moisture present in the reaction medium.
In all experiments, the sum of the expected n-propyl ester and
compound 7 corresponded well to the consumed amount of the
reactant. The total rate was virtually independent of the
concentration and type of alcohol used (Table 4), further
indicating that the alcohol does not take part in an initial rate-
determining step. In the same series, experiments were also
made with solvolysis of ester 1 with two different concentrations
of n-propanol. Although the reaction was much slower than for
amide 2, the same products were found, and reaction rate was
of the first order with respect to consumption of the reactant
and this rate was not dependent on the concentration of
n-propanol. Finally, the quotients between the two final products
(n-propyl ester and 7) were nearly the same for both reactions
(Table 4). This strongly indicates the existence of a common
reactive intermediate in the reactions of 1 and 2 respectively.
This intermediate could very well be the ketene 3.
Possible Reaction Mechanism for the Equilibrium between
1 and 2. As previously discussed, the â-ketoesters 1 and 14
were found to be the only esters in this study that reacted with
N-ethylaniline to give their corresponding amides in high yields
(Table 2). A literature search on the subject of reactions between
carboxylic esters and aromatic amines provides further support
for this finding. Most references describe reactions of â-ke-
toesters such as malonic esters or methyl or tert-butyl aceto-
acetate with aromatic amines. A related reaction of phenyl
salicylate with amines is known as the “Salol reaction”.7
Acetoacetylation of nucleophiles (alcohols or amines) with
methyl or tert-butyl acetoacetate 19 (Scheme 4) was found to
obey first-order reaction kinetics, and mechanistic studies have
shown that the reaction probably proceeds via acetylketene 20
instead of via a tetrahedral intermediate.8 Here, strong evidence
for the ketene mechanism also comes from the fact that tert-
butyl acetoacetate 19 was 15-20-fold more reactive than methyl
acetoacetate. A tetrahedral intermediate is unlikely because the
(7) (a) Allen, C. F. H.; VanAllan, J. Organic Syntheses; Wiley: New
York, 1955; Collect. Vol. III, p 765. (b) Black, M.; Cadogan, J. I. G.;
McNab, H. J. Chem. Soc., Perkin Trans. 1994, 155.
(8) (a) Witzeman, J. S. Tetrahedron Lett. 1990, 31, 1401. (b) Witzeman,
J. S.; Nottingham, W. D. J. Org. Chem. 1991, 56, 1713. (c) Clemens, R. J.;
Witzeman, J. S. J. Am. Chem. Soc. 1989, 111, 2186.
(5) Wiseman, E. H.; Chiaini, J.; McManus, J. M. J. Med. Chem. 1973,
16, 131.
(6) Tuvesson, H.; Hallin, I.; Persson, R.; Sparre, B.; Gunnarsson, P. O.;
Seidegård, J. Drug Metab. Dispos. 2005, 33, 866.
J. Org. Chem, Vol. 71, No. 4, 2006 1661