Scheme 2. General reaction for substituted hippuric acids
evaluation
reactive aldehyde in order to nullify the effect of aldehyde on
the reaction. If the hippuric acid substituent was affecting the
reaction conversion, this could be detected and then compared
with reaction conversions using the reference substrate 5 (Table
1, entry 1). Thus, the first step of our study was to evaluate the
effect of substituents on the hippuric acids in the presence of
the highly reactive aldehyde 4-nitrobenzaldehyde 6a using
Hu¨nig’s base and acetic anhydride under solvent-free reaction
conditions5 (Table 1).
It was apparent that the presence of an o-substituent
influenced the reaction rate. The observed reactivity was in the
order NO2 , Cl, Br < F, Me (Table 1, entries 2-6). The same
order was observed for p-substitution but with less impact. In
addition, electronic effects seem to have greater influence on
the reaction rate than those from steric factors (Table 1, entries
2-3). Clear examples of these observations are o-fluoro- and
o-nitro-hippuric acids, which require longer reaction times as
compared with their p-analogues (Table 1, entries 3, 13 vs 8,
and 6 vs 7, see Figure 1). Following these observations, it was
expected that 2,6-disubstitution would have the largest effect
on the reaction rate, especially if it is an electron-withdrawing
substituent, and this proved to be the case (Table 1, entries 9,
12, 13).
Knowing the net effect with an activated aldehyde, the next
step was the evaluation of substituted hippuric acids with the
deactivated 4-methoxybenzaldehyde, 6b (Table 1, entries
14-18). The introduction of an extra deactivating group on the
system produced longer reaction times in most of the examples.
A comparison of the relative reaction rate of substituted hippuric
acids with aldehyde 6a versus 6b is shown in Figure 2.
Hu¨nig’s base reaction conditions were subsequently assessed
with the substrates of interest: 3 and 4 (Scheme 1). Taking into
account the observed effects of substituents, slow conversion
was hypothesized because of two main factors: the deactivating
effect of the o-difluoro groups on 3 and the deactivating
characteristics of aldehyde 4. Consequently, when this reaction
was performed under Hu¨nig’s base reaction conditions, only
35% conversion to 2 was observed by HPLC after 12 h. In
addition to the slow conversion, the transacylation byproduct
11 was observed in approximately 17%.21,22 This byproduct
became a significant problem during product isolation, and the
product quality was adversely affected.
Substituted Hippuric Acids Syntheses. 4-Arylidene-2-
phenyl-5(4)-oxazolones are important intermediates for the
synthesis of several fine chemicals9 which are usually obtained
via an Erlenmeyer reaction. This classical method affords a
potential mixture of Z- and E-stereoisomers; however, in most
of the cases the thermodynamically more stable Z-isomer10 is
observed as the main product. Numerous papers have been
published in the recent past evaluating different bases for the
Erlenmeyer reaction.6-8,11-19 Most of the recent reports involved
reactions of hippuric acid with a variety of aromatic aldehydes,
but a detailed study of substituent effects was lacking. To this
end, we undertook studies of both the substituent effects on
the aromatic aldehyde, reported elsewhere,5 and on the hippuric
acid partner. The substituted hippuric acids 3 and 5a-k were
synthesized Via a modified Schotten-Baumann20 reaction with
the appropriate acid chloride 9 and glycine ethyl ester hydro-
chloride, 10, as shown in Scheme 3.
Stereoelectronic Effects in the Hu¨nig’s Base-Catalyzed
Reaction. It was recently reported by our group5 that, compared
to all other bases, Hu¨nig’s base provides fast Erlenmeyer
reaction conversion; nevertheless, the reaction time could be
limited by substituents on the benzaldehyde. Benzaldehydes
containing electron-withdrawing groups (EWGs) were shown
to react faster; meanwhile, electron-donating groups (EDGs)
afforded slower reactions. Taking into account these facts, the
strategy was to react substituted hippuric acids with a highly
(9) (a) Gottward, K.; Seebatch, D. Tetrahedron 1999, 55, 723–738. (b)
Meiwes, J.; Schudock, M.; Kretzschmar, G. Tetrahedron: Asymmetry
1997, 8, 527–536. (c) Cavelier, F.; Verducci, J. Tetrahedron Lett. 1995,
36, 4425–4428. (d) Martinez, A. P.; Lee, W. W.; Goodman, L.
Tetrahedron 1964, 20, 2763–2771. (e) Gelmi, M. L.; Clerici, F.; Melis,
A. Tetrahedron 1997, 53, 1843–1854. (f) Groce, P. D.; Ferraccioli,
R.; La Rosa, C. J. Chem. Soc., Perkin Trans. 1 1994, 2499–2502.
(10) (a) Rao, Y. S. J. Org. Chem. 1976, 41, 722–725. (b) Cativiela, C.;
Diaz de Villegas, M. D.; Mayoral, J. A.; Melendez, E. Synthesis 1983,
899–902.
(11) Tikdari, A. M.; Fozooni, S.; Hamidian, H. Molecules 2008, 13, 3246–
3252.
(12) Rao, P. S.; Venkataratnam, R. V. Indian J. Chem. 1994, 33B (10),
984–985.
(13) Kashyap, J.; Chetry, A. B.; Das, P. J. Synth. Commun. 1998, 28, 4187–
4191.
(14) Bautista, F. M.; Campelo, J. M.; Garcia, A.; Luna, D.; Marinas, J. M.;
Romero, A. A. J. Chem. Soc., Perkin Trans. 2002, 2, 227–234.
(15) Khodaei, M. M.; Khosropour, A. R.; Jomor, S. J. J. Chem. Res. Synop.
2003, 638–641.
Efforts were made to optimize the Hu¨nig’s base reaction
conditions by using elevated temperature (80 °C). Although a
30 °C increase in reaction temperature successfully decreased
the reaction time for hippuric acids containing electron-donating
(16) Mogilajah, K.; Prashanthi, M.; Srinivaseddy, Ch. Indian J. Chem. 2003,
42B, 2126–2128.
(17) Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2004, 45,
425–427.
(18) Karade, N. N.; Shirodkar, S. G.; Dhoot, B. M.; Waghmare, P. B.
J. Chem. Res. 2005, 46–47.
(19) Yu, C.; Zhou, B.; Su, W.; Xu, Z. Synth. Commun. 2006, 36, 3447–
3453.
(21) Bennett, E. L.; Niemann, C. J. Am. Chem. Soc. 1950, 72, 1803–1804.
(22) Large amounts of transacetylation were also observed in reactions using
other bases: NaOAc, Bi(AcO)3, and (NH4)2H(PO)4. When using ZnO2
at room temperature, transacetylation was not detected, but conversion
was also minimal.
(20) (a) Goldmand, L.; Williams, J. H. J. Am. Chem. Soc. 1954, 76, 6078–
6080. (b) Sano, T.; Sugaya, T.; Inoue, K.; Mizutaki, S.; Ono, Y.; Kasai,
M. Org. Process Res. DeV. 2004, 4, 147–152.
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