analysis of targets 1 and 2 showed that 3,5-dimethyl-4-
nitroisoxazole 5 could serve as a starting material for a
sequence of anionic driven reactions (Scheme 1).
Scheme 2. Synthesis of Compounds 2a and 1a
Scheme 1. Retrosynthetic Analysis of Targets 1 and 2
obtained in similar yield by reacting together 5, 6, 10, and
9a in a one-pot process (Scheme 3). We then studied the
conversion of 2a to acid 1a. The best results were obtained
with mixtures of ethanol/water as the solvent and a minimum
of 4 equiv of sodium hydroxide. We also established a
protocol for the purification of 1a and 2a that did not involve
the intervention of chromatography. Compound 2a was
purified by crystallization, whereas compound 1a was
obtained pure by mean of an base/acid extraction.
We have recently reported a one-pot procedure by which
adducts 3 (Scheme 1) were obtained in high yields from
commercially available isoxazole 5, an aromatic aldehyde 6
and acetylacetone 10.4 We reasoned that compound 2 could
be prepared using an extension of this procedure that included
the addition of hydroxylamine, hydrazine, or a substituted
hydrazine. Finally, we planned to prepare 3-arylpropionic
acids 1 by hydrolysis of the 3-methyl-4-nitroisoxazol-5-yl
group present in 2. The hydrolysis of the 3-methyl-4-
nitroisoxazol-5-yl core to a carboxylate is a well-documented
process,9,10 and although the mechanistic details of this
reaction have been clarified, its synthetic utility has not been
addressed. From the synthetic standpoint, the 3,5-dimethyl-
4-nitroisoxazol-5-yl core could be considered a masked
carboxylate that is revealed upon hydrolysis. Therefore, the
3,5-dimethyl-4-nitroisoxazolate 7 is formally equivalent to
an acetic acid dianion 8 (Figure 2).
Scheme 3. One-Pot Synthesis of 3-Heteroarylpropionic Acids
1a-i and 4-Nitroisoxazol-5-ethanyl Compounds 2a-i
With a set of experimental conditions in hand, we focused
our attention on a study of the dinucleophile component.
Indeed, â-diketones have been extensively used to generate
heterocycles when reacted with opportune dinucleophiles.11
Compound 3a (Scheme 2) reacted well with hydroxylamine
9a, hydrazine 9b, and phenyl-hydrazine 9c. However, the
reaction of 3a with benzamidine, acetamidine, and methyl
3-aminocronate gave only starting material. Having deter-
mined an appropriate set of reagents and conditions, we
carried out the synthesis of compounds 1a-i in a one-pot
fashion (Scheme 3, Table 1).
Typically 5 (3 mmol) and an aromatic aldehyde 6 (3
mmol) were reacted in the presence of piperidine (0.1 equiv)
in ethanol (10 mL) at 60 °C for 1 h and then acetylacetone
10 (1.5 equiv) was added. The reaction mixture was stirred
at 60 °C for 6 h, then 9a-c (1 equiv) was added, and the
reaction mixture stirred at 60 °C for another 7 h. At this
point water (10 mL) and NaOH (4 equiv) were added, and
the reaction refluxed for 6 h.
Figure 2. 3,5-Dimethyl-4-nitroisoxazolate 7 and acetic acid dianion
8.
We first carried out a stepwise synthesis of compounds
2a and 1a using hydroxylamine 9a as the nucleophile, in
order to determine an optimal set of reaction conditions
(Scheme 2). We were delighted to observe that 1 equiv of
9a was enough to produce 2a in good yield and that 2a was
(7) Krishna, K. S. R.; Rao, M.; Devi, Y. U. Proc. Indian Acad. Sci.,
Sect. A 1976, 84, 79.
(8) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org.
Lett. 2005, 7, 3821.
(9) Chimichi, S.; De Sio, F.; Donati, D.; Fina, G.; Pepino, R.; Sarti-
Fantoni, P. Heterocycles 1983, 20, 263.
(10) Baracchi, A.; Chimichi, S.; De Sio, F.; Donati, D.; Nesi, R.; Sarti-
Fantoni, P.; Torroba, T. J. Labelled Compd. Radiopharm. 1986, 24, 2863.
(11) Gilchrist, T. L. Heterocyclic Chemistry; Longman: Harlow, 1997;
p 61.
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