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Boletín de la Sociedad Chilena de Química

versión impresa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.44 n.4 Concepción dic. 1999 



Departamento de Química, Facultad de Ciencas, Universidad de Chile, Casilla 653, Santiago, Chile.
(Recieved: November 5, 1998 - Accepted: August 23, 1999)


The N-acylation reaction of a series of lactams of biological interest, derived from 2-benzoxazolinones and 1,4-benzoxazin-3-one, with acetic anhydride has been studied. The reaction yields show the same tendency as that observed for AM1 calculated DH for the deprotonation reaction of the heterocyclic nitrogen atom.

KEY WORDS: 2-benzoxazolinones, 1,4- benzoxazin-3-one, acylation reaction.


Se estudió la reacción de N-acilación con anhídrido acético, de una serie de lactamas de interés biológico derivadas de 2-benzoxazolinonas y 1,4-benzoxazin-3-onas. Los rendimientos de las reacciones muestran la misma tendencia que los valores de DH de desprotonación del nitrógeno heterocíclico, calculados empleando el método AM1.

PALABRAS CLAVES: Reacción de acilación, 2-benzoxazolinonas, 1,4-benzoxazin-3-onas.

*To whom correspondence should be addressed.


Cyclic hydroxamic acids, Hx, 1,4-benzoxazin-3-one (Fig. 1A), are found in gramineae of agricultural importance, such as maize, wheat and rye, and their presence in these living organisms is related to a natural resistance factor against pathogens attack1,2). The chemical behavior of these molecules are known in some detail3-7). The corresponding lactams (Fig. 1, R3 = H) should be the natural biosynthetic precursors of these Hx, and little is known about their chemical properties.

DIMBOA: R1 = MeO; R2 = R3 = OH
DIBOA: R1 = H; R2 = R3 = OH
MBOA: R1 = MeO
BOA: R1 = H

FIG. 1.

Solutions of 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), and the demethoxylated deriative (DIBOA) decompose to produce the respective 2-benzoxazolinones MBOA and BOA (Fig. 1B). MBOA and BOA are also found in these gramineae and other species of superior plants8-11). These lactams show important and diverse bioactivity12-20).

Studies oriented to determine the mode of biological action and chemical reactivity of these structures at molecular level, require the synthesis of derivatives with structural changes in both, the heterocyclic and the aromatic rings. Of particular importance are modifications on the nitrogen atom, since it has been suggested that the chemical and bological activity could be determined by the electronic characteristics of this atom21-23). For instance, the N-acetyl derivatives increase significantly the electrophilic reactivity24,25). N-acetyl derivatives are easily obtained from the reaction of acetic anhydride and the respective Hx17,25). Acetic anhydride has also been used as an acylation reagent of lactams, not always successfully. For example, MBOA is easily N-acylated17), however N-acylation of lactams derived from DIMBOA do not occur26), or the yields are low17).

For a deeper understanding of the reactivity behavior of these two kinds of lactams of biological interest, we report comparative yields obtained for the N-acylation reaction of 7-substituted 1,4-benzoxazin-3-ones and 6-substituted 2-benzoxazolinones. The observed differences are discussed in terms of the acid characteristics of the N-H bond of these compounds. To assist the interpretation of the experimental results, AM127) molecular orbital calculations were performed.


Lactams, 6-substituted 2-benzoxazolinones and 7-benzoxazin-3-ones, were synthesized using previously described methodologies28,29). MBOA was obtained from the decomposition of natural DIMBA in pyridine, as reported before30). BOA and oxindol, an analog structure of BOA, are commercial products (Aldrich).

General acylation procedure for 6-substituted-2-benzoxazolinones

To a stirred and cooled (273 K) solution of the corresponding 6-substituted 2-benzoxazolinone (0.7 mmol) in aqueous solution of potassium carbonate (0.37 g in 5 mL of water), a solution of acetic anhydride (2 mmol) in ethyl ether (10 mL) was dropped for a period of 30 minutes, with strong stirring. The reaction was complete before 2.5 hours. The two phases were separated and the aqueous phase extracted 3 times with ethyl ether. The ethereal extracts were evaporated "in vacuo" and the residues purified by preparative chromatography in silica gel G60-F254 (CHCl3: MeOH 10 : 1 as eluent). The yields reported in Table I are averages of 3 independent experiments. The structures of the products were characterized employing 1H-NMR and IR spectroscopies. The spectra of N-acyl-BOA are shown in Figure 2 as an example. The NMR peaks at 2.8 ppm arises from the methyl group and between 7.2 and 7.4 appears the aromatic multiplet. The IR spectrum evidence the presence of two carbnyl groups and the absence of the N-H stretching frequency confirms the structure of the N-acyl derivative. The N-acylation of 7-substituted 1,4-benzoxazin-3-ones and oxindol did not proceed under this experimental conditions.

TABLE I. Yields for the N-acylation and DH values, defined in the text, of 2-benzoxazolinones and oxindol (this work) and pKa of BOA and model molecules 6, 7 and 8 (Refs. 31 and 32).

FIG. 2. 300 MHz 1H-NMR (CDCl3) and FT-IR (KBr pellet) spectra of N-acyl-2-benzoxazolinone.


General acylation procedure for 7-substituted-1,4-benzoxazin-3-ones

0.1 mmol of derivative were dissolved in 6 mL of a mixture benzene : pyridine 1 : 1, and allowed to react with acetic anhydride (1 mmol) during 90 hours at 333 K. The mixture was washed with 20 mL of water and the organic phase evaporated "in vacuo". The residues were purified by preparative chromatography in silica gel G60-F254 (CHCl3:MeOH 10:1 as eluent). The yields reported in Table I are averages of 3 independent experiments. The structures of othe products were characterized employing 1H-NMR and IR spectroscopies. The spectra of N-acyl-7-methoxy-1,4-benzoxazin-3-one are shown in Figure 3 as an example. The NMR peaks at 2.5, 3.7 and 4.5 ppm arise from the acetyl, methoxy and methylene groups, respectively. The aromatic signals are observed at 6.6 and 7.6 ppm. The IR spectrum evidence the presence of carbonyl groups and the absence of the N-H stretching frequency confirms the structure of the N-acyl derivative.

FIG. 3. 300 MHz 1 H-NMR (CDCl3) and FT-IR (KBr pellet) spectra of N-acyl-7-methoxy-1,4-benzoxazin-3-one.


The acylation reaction of 2-benzoxazolinones occurs easily at 273 K in a heterogeneous mixture of ethyl ether/water, in the presence of potassium carbonate. The obtained yields are shown in Table I. The N-acylation of oxindol (Table I: compound 6), an analog structure of BOA, did not proceed under this condition. This result strongly suggests that the oxygen atom in the heterocycle plays a fundamental role in the reactivity of these molecules with acetic anhydride. Essentially, this reaction can be rationalized as a nucleophile-electrophile intraction between the heterocyclic nitrogen atom and one of the carbonyl groups in acetic anhydride, respectively. Therefore, it is reasonable to expect that the reactivity is mainly determined by the nucleophilic characteristics of the nitrogen atom. Dissociation of the N-H bond is essential to increase this character, and consequently the reactivity. The observed differences in reactivity between BOA and oxindol could be attributed to a greater electron density on the nitrogen atom, due to the delocalization of the non-bonded electrons from the oxygen atom. However, the differences between BOA and the rest of the molecules in this series, should be attributed to the effect of the substituents on the nitrogen atom. The electronic characteristics of the substituents suggest that this is not the only parameter that influences the reactivity of these molecules. Another interpretation of our results can be suggested by analyzing the frontier orbitals of the anions, since according to frontier orbitals theory, chemical reactions occur through them. A plot of the AM1 calculated electron density of the HOMO orbitals of BOA and oxindol anions are shown in Figure 4. The electron density of the reactive orbital of BOA is more delocalized than in oxindol, influencing the stability of the anions. Additional evidence to support our proposition has been obtained from the pKa values of BOA, oxindol and molecules 7 and 8 of Table I, which were determined by Bordwell et al.31,332). The pKa value of oxindol is 6 units greater than the pKa of BOA. The importance of charge delocalization can be better appreciated from the pKA of molecules 7 and 8. The pKa of compound 8, where extended charge delocalization is not allowed, is 5 units greater than the pKa of molecule 7, where the charge is delocalized over the complete molecule. The electron density of the HOMO orbitals of molecules 7 and 8 anions are shown in Figure 4b.

FIG. 4.AM1 calculated electron density of othe HOMO orbitals of anions of BOA and oxindol (a) and structures 7 and 8 of Table I (b).

Further evidence was obtained from AM1 full geometry optimization calculations of gas phase heats of formation. Neglecting entropy effects, the equilibrium position of any chemical reaction depends on the reaction enthalpy. The enthalpy of an acid-base reaction is defined by the following equations:

(1) HA ® H- + A-

(2) DH° = Df(A-) + Df(H-) - Df (HA)

In order to compare the relative acidity among the different derivatives, we can simply define DH = DHf°(A-) - DHf°(HA) , and since Df(H+) is approximately the same for all derivatives, this contribution will be just a constant added in all cases. We assume that solvent effects are the same in all cases.

The values of DH listed in Table I, indicate that all 2-benzoxazolinones should be more acid than oxindol, which is supported by the pKa values of oxindol and BOA. These results also show that substitution in position 6 do not play a significant role in the acid characteristics of these structures.

1,4-benzoxazin-3-ones substituted in position 7, do not react with acetic anhydride in the conditions employed with 2-benzoxazolinones. For this reason we have employed more drastic conditions, which are detailed previously. Even in these conditions, low yields were obtained (Table II). Our hypothesis implies that the acidic character of these structures should be influenced by stabilization of the anion by conjugation through the heterocycle. In the case of 1,4-benzoxazin-3-ones, the electron delocalization should not be favored because of the presence of a neighbor methylene group. This group, with a sp3 carbon, precludes electron delocalization over the heterocycle and possibly modifies the electronic structure of the adjacent heterocyclic oxygen, as compared with the situation of 2-benzoxazolinones, where there is a carbonyl group instead. Therefore, it is reasonable to relate the low yields obtained for these structures to the less dissociated N-H bond. Consistent with this, the pKa values of the analog molecules 13 and 14 in Table II, are even greater than the correspponding value of oxindol. We have also calculated earlier defined DH values for this series. The obtained values, listed in Table II, are always significantly smaller than the 2-benzoxazolinones value, and also suggest that substitution in the aromatic ring do not have a significant effect on the acid character of othese structures. Consequently, 1,4-benzoxazin-3-ones should be less reactive than 2-benzoxazolinones, which is observed experimentally.

TABLE II. Yields for the N-acylation and DH values, defined in the text, of 1,4-benzoxazin-3-ones (this work) and pKa values of model molecules 13 and 14 (Refs. 31 and 32).

Finally, the presented evidence seems to indicate that a possible mechanism for the N-acylation of these lactams should involve a first step related to the acid-base reaction of the N-H bond, followed by a nucleophylic attack of the negatively charged nitrogen atom to one of the carbonyl carbons of acetic anhydride, however other possibilities cannot be discarded.


The authors are pleased to acknowledge financial assistance from D.I.D., Universidad de Chile.


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