SciELO - Scientific Electronic Library Online

 
vol.44 número3PARAMETROS DE CALIDAD ANALITICA DE UN METODO DE DETERMINACION MULTIRESIDUOS DE PLAGUICIDAS POR HPLC-DADPROPIEDADES MESOMORFICAS DE 1-(4-n-ALCOXIFENIL)-3-(5-n-ALQUIL-2-TIENIL)-1,3-PROPANODIONAS Y DE SUS DERIVADOS ISOXAZOLICOS Y PIRAZOLICOS índice de autoresíndice de materiabúsqueda de artículos
Home Pagelista alfabética de revistas  

Boletín de la Sociedad Chilena de Química

versión impresa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.44 n.3 Concepción set. 1999

http://dx.doi.org/10.4067/S0366-16441999000300014 

SYNTHESIS AND TAUTOMERISM OF NEW 1-n-ALKYL-5-
PYRAZOLONE DERIVATIVES

J. BELMAR*, J. ALDERETE, M. PARRA, C. ZUÑIGA

Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de
Concepción, Casilla 3-C, Concepción, Chile, jbelmar@udec.cl
(Received: April 23, 1999 - Accepted: July 8, 1999)

SUMMARY

3-Phenyl-5-pyrazolone (1) is selectively alkylated at position 1 in 40% yield. The alkylated compound (2) is acylated (3) in 60% yield and nitrosated (4) in 80% yield. According to the spectroscopic data a N-H or O-H structure can be proposed for 1 in DMSO. The proton may be at N-2 or on the oxygen at C-5, respectively. The alkylated compound 2 exists as 5-pyrazolone in chloroform with a CH2 at C-4. In DMSO, 2 is a 5-hydroxypyrazole. For compound 3 in chloroform the structure corresponds to 4-acyl-5-hydroxypyrazole. For compound 4 in chloroform there is one tautomer with a 4-nitroso-5-hydroxypyrazole structure while in DMSO the same 4-nitroso-5-hydroxypyrazole (92%) and a 4-nitroso-5-pyrazolone (8%) tautomer can be found.

KEY WORDS: Tautomerism, alkylpyrazolones, pyrazolones, chelating pyrazolones, synthesis.

RESUMEN

La alquilación de la 3-fenil-5-pirazolona (1) ocurre selectivamente en la posición 1 con un 40% de rendimiento. El compuesto alquilado (2) que se obtiene fue acilado (3) con 60% de rendimiento y nitrosado (4) con un 80% de rendimiento. De acuerdo con los datos espectroscópicos, se puede proponer una estructura N-H u O-H para el compuesto 1 en DMSO. El protón puede encontrarse en el N-2 o en el oxígeno unido al C-5. El compuesto alquilado 2 existe como 5-pirazolona en cloroformo y el C-4 es un CH2. En DMSO, 2 es un 5-hidroxipirazol. Para el compuesto 3 en cloroformo la estructura corresponde a 4-acil-5-hidroxipirazol. Para el compuesto 4 en cloroformo hay sólo un tautómero con una estructura de 4-nitroso-5-hidroxipirazol mientras que en DMSO se encuentran dos tautómeros, 4-nitroso-5-hidroxipirazol (92%) y 4-nitroso-5-pirazolona (8%).

PALABRAS CLAVES: Tautomerismo, alquilpirazolonas, pirazolonas, pirazolonas quelantes, síntesis.

INTRODUCTION

Pyrazolones have been widely studied because of their applications and the interest in tautomerism that is associated with them. Nevertheless most reports describe 1-phenyl-5-pyrazolone derivatives because the starting pyrazolone can be easily obtained1-4) through the condensation of a b-ketoester with phenylhydrazine. 1-n-Alkylpyrazolones, on the other hand, are seldom mentioned since the required alkylhydrazines are difficult to obtain5) and very few of them are commercially available. Considering this and our interest in chelating molecules we focused our attention on the synthesis of 1-n-alkylpyrazolone derivatives. As a result we have prviously reported the synthesis and tautomerism observed in 1-n-alkyl-3-methyl-5-pyrazolones and their 4-acyl5,6) and 4-ntiroso7) derivatives and some Schiff bases6). In addition we found out that in our laboratory we had a good stock of ethyl benzoylacetate, so we decided to see if a phenyl group at C-3 on the pyrazolone ring would have an effect on tautomerism when compared with 3-methyl-5-pyrazolones.

In this paper the synthesis and structures of the following 1-n-alkyl-3-5-pyrazolones and 4-acetyl, 4-benzoyl and 4-nitroso derivatives are discussed

2a, R: N-CRH9; 2b, R: N-C6H13; 3a, R': CH3, R: n-C4H9; 3b, R': f, R: n-C4H9; 4b, R: C6H13

RESULTS

All the compounds were obtained as outlined in Scheme 1. Parent compound 3-phenyl-5-pyrazolone (1) is obtained in 80% yield by slowly dropping hydrazine into a solution of ethyl benzoylacetate. This reaction works for all small or big runs (we were able to obtain up to 250 g in one batch), provided that good stirring is kept up all the time. Alkylation with n-butyl bromide is selective at N-1, but the yield is rather poor (40%). This contrasts with the 70% yield obtained upon the alkylation of 3-methyl-5-pyrazolones5). We have calculated, in the frame of the Density Functional Theory, condensed Fukui functions by using AM1 8) electronic densities. The tendency of an atom to be attacked by an electrophilic species can be measured by the condensed Fukui function9), fk-. Table I shows the values of the condensed Fukui function for nitrogen atoms in the CH tautomers of 3-methyl- and 3-phenyl-5-pyrazolone. It can be observed that N-1 in 3-methyl-5-pyrazolone is the most reactive site for an electrophilic attack. This result can account for the lower yield observed in the alkylation of 3-phenyl-5-pyrazolone.

SCHEME 1.

TABLE I. Condensed Fukui function, fk-, for the CH tautomer of 3-methyl- and 3-phenyl-5-pyrazolonea


Atom
3-Methyl-5-pyrazolone
3-Phenyl5-pyrazolone

N-1
0.285
0.182
N-2
0.273
0.037


a fk- was evaluated by using finite difference approximation2)

It is necessary to point out that during work up of the alkyltion mixture, in addition to the product and the unreacted 3-phenyl-5-pyrazolone no other compounds were obtained. This shows that only N-1 reacts. Furthermore, considering that starting material is recovered, the 40% yield of the alkylation reaction is not unsatisfactory. The alkylation was carried out using dioxane as solvent. Trying to improve the reaction yield, ethanol and DMF were also tried but they lead to highly colored solutions without any increase in the yield and rendering the purification more difficult. Prolonged reflux up to 60 hours did not improve the yield either.

Compounds 3 were purified preparing their Cu(II) complexes which were crystallized from ethanol-water. Treatment with dilute hydrochloric acid released the products that were obtained as oils. These compounds were used without further purification attempting to obtain the methylimine from 3a and the oxime from 3b, but probably due to steric hindrance these reactions did not took place. The procedure for these reactions is the same as previously used6).

The nitroso derivatives 4 were obtained in 80% yield. It is worth noting that in order to ensure nitrosation, alkylpyrazolone must be dissolved at 0° before sodium nitrite is added. In the first trials we could not obtain the product and it was because pyrazlone had crystallized from the cooled solution. This is another difference with 1-n-alkyl-3-methyl-5-pyrazolones that can be nitrosated from a suspension in alcohol7).

TAUTOMERISM

Three tautomeric structures can be drawn for 1,3-disubstituted pyrazolones:

When compound 1 is considered, the 13C specturm (DMSO-d6) shows a number of signals that correspond to only one tautomer in that solvent. A signal at 87.6 ppm which according to the DEPT spectrum8) corresponds to a CH group is assigned to C-4. The corresponding proton resonance appears at 6.06 ppm (s, 1H) in the pmr spectrum. This information rules out the CH tautomer. The signal of 161.4 ppm corresponds to C-5, but to assign it as a C=O or C-OH is not straightforward. For instance the resonances for C-5 in 3-methyl-5-pyrazolone appears at 135.3 ppm (DMSO-d6), 159.9 ppm (C6D6) in 1-n-octyl-3-methyl-5-pyrazolone, 154.2 ppm (CDCl3) in 1-n-octyl-3-methyl--4-nitroso-5-pyrazolone (OH tautomer), 161.8 ppm 1-n-octyl-3-methyl-5-nitroso-pyrazolone (NH tautomer), 159.3 ppm (CDCl3) in 1-n-hexyl-3-methyl-4-benzoyl-5-pyrazolone5,6,7) . Consequently, with the information available, the nature of this tautomer cannot be unequivocally established; furthermore, a rapid equilibrium NH/OH could be considered as well. The IR spectrum indicates that in solid phase compound 1 exists as either the NH or OH tautomer.

As it can be seen in the data collected in the experimental part, the 13C and 1H spectra for compounds 2 in DMSO-d6 are quite similar. The chemical shifts and the number of signals in the 13C spectra correspond to a single tautomer with a OH structure. For compound 2a the main resonances are at 152.9 (C-5, C-OH) and 83.0 ppm (C-4, =C-H) and for compound 2b the corresponding signals are at 153.0 and 83.1 ppm. A wide signal around11 ppm (OH) and a singlet at 5.9 ppm (1H, C-H at C-4) in their pmr spectra also support this statement.

The 13C spectrum (CDCl3) for 2b shows a signal at 171.5 ppm for C-5 (C=O). The signal for C-4 appears at 38.1 ppm showing that this carbon is saturated. The pmr spectrum shows a singlet at 3.6 ppm (2H, CH2). It is clear that in this solvent the tautomer possesses a CH structure. This result is the same that previously reported for 1-n-alkyl-3-methyl-5-pyrazolones5). The solubility of 2a in chloroform is not enough to obtain the 13C spectrum.

The information obtained from the IR spectra for compounds 2 is not very useful because the signals corresponding to N-H and O-H stretching tend to be very broad and of very low intensity. In addition, the possibility of hydrogen bonding that shifts the carbonyl stretching signals makes any assessment even more difficult and less reliable. Considering this, the data was included only to complete the information without further discussion upon the tautomerism.

Three tautomeric structures can be drawn for the 4-acyl derivatives of alkylpyrazolones:

For compound 3a the 13C spectrum (CDCl3) shows that there is only one OH tautomer. The signal at 195.8 ppm corresponds to the carbonyl group attached to C-4 and since C-5 appears at 159.0 ppm, it must be C-OH. The pmr spectrum also supports this statement, it shows a singlet at 10.9 ppm that corresponds to the OH group that is bonded to C-5. The situation is the same for compound 3b as is the case for 1-n-alkyl-3-methyl-4-acyl-5-pyrazolones as previously reported5,6). In 3a and 3b, the phenyl group does not have any measurable effect on the tautomeric equilibrium.

There are three tautomers for the nitroso derivatives:

For compounds 4 the 13C spectra (CDCl3) show one signal at 157 ppm (C-5) from which the predominance of an OH tautomer can be concluded. The pmr spectra show a signal near 15 ppm that corresponds to the hydroxyl group forming an intramolecular hydrogen bond with the nitroso substituent. This was demonstrated by recording the pmr spectrum at different concentrations without observing any change in chemical shift. For 4b the spectra in DMSO-d6 were also obtained. In the 13C spectrum of 4b in this solvent there are 10 downfield signals that correspond to two tautomers. There is one signal at 161.0 ppm (C-5, C=O) and another at 152.5 (C-5, C-OH). According to the areas of the signals in a quantitative 13C spectrum, there is about 92% of the OH tautomer. The structure of the minor tautomer (8%, NH or Oximino) cannot be fully established with the information available. This result contrasts with those obtained with 1-n-alkyl-3-methyl-4-nitroso-5-pyrazolones7) where it was found that in several solvents there were two tautomers, with the OH form favored only in lower polarity solvents.

In conclusion, It was observed that the phenyl ring attached to C-3 has an important effect on the reactivity of the pyrazolone N-1 towards alkylation, affording relatively poor yields of the 1-alkyl derivatives. There was also a marked effect in the tautomeric equilibrium of the 1-n-alkyl-3-phenyl-4-nitroso derivatives when compared with the 1-n-alkyl-3-methyl-4-nitroso-5-pyrazolones.

EXPERIMENTAL

Compounds were characterized by FTIR (Nicolet, Magna 550) and 13C and 1H-NMR (Bruker AC 250P; 62.9 and 250 MHz respectively, TMS as internal standard). 13C-1H correlation10) and DEPT11) spectra were also used to assign the signals. Melting points were obtained on a Kofler microscope and are uncorrected. To complete the characterization C, H analyses were obtained. Infrared values (v) are quoted in reciprocal centimeters (cm-1) and chemical shifts for nmr spectra (d) are quoted in ppm.

Synthesis of 3-phenyl-5-pyrazolone (1)

To a magnetically stirred solutionof ethyl benzoylacetate (0.47 mole, 81 mL) in 500 mL of methyl alcohol, 80% aqueous hydrazine (0.47 mole, 23 g) was added dropwise. Stirring was continued for an extra hour after addition was finished. The white solid was filtered and recrystallized from ethanol. Yield: 80%, mp: 245-246°.

Anal. Calcd. for C9H8N2O: C, 67.49; H, 5.03. Found: 67.48; H, 5.11.

1H-NMR (DMSO-d6) d: 11.20 (broad signal, 1H, OH), 6.06-7.81 (m, 5H, phenyl), 3.80 (broad singlet, 1H, NH).

13C-NMR (DMSO-d6) d: 161.5 (1C, C-5. C=O or C-OH), 144.8 (1C, C-3), 130.8, 129.4, 128.6, 125.4 (6C, phenyl), 87.6 (1C, C-4, =C-H).

IR(KBr) n: 3200-210 (O-H, N-H), 3118 (=C-H), 1624 (C=O), 1589 (C=C).

Synthesis of 1-n-butyl-3-phenyl-5-pyrazolone (2a)

In 300 mL of dioxane, 3-phenyl-5-pyrazolone (0.188 mole, 30 g) and n-butyl bromide (0.188 mole, 21 mL), were heated to reflux during 48 h. Then the solvent was evaporated and the remaining material poured over a mixture of ice and 10% NaHCO3. The resulting solid was filtered and washed with water. The cake was extracted with chloroform in a Sohxlet apparatus. The chloroform solution was evaporated to dryness and the alkylpyrazolone rrecrystallized from ethanol-water. The unreacted pyrazolone remaining in the extractor was crystallized from ethanol. Yield: 40%, mp: 161-164°.

Anal. Calcd. for C13H16N2O: C, 72.19; H, 7.46. Found: C, 72.19; H, 7.46.

1H-NMR (DMSO-d6) d: 11.75 (s, 1H, OH), 7.80-7.33 (m, 5H, phenyl), 5.87 (s, 1H, methine at C-4), 3.96 (t, 3.69 Hz, 2H, CH2 a to N-1), 1.87 (quintet, 2H, CH2 b to N-1), 1.45 (m, 2H, CH2 g to N-1), 1.03 (t, 7.32 Hz, 3H, Me).

13C-NMR (DMSO-d6) d: 152.9 (1C, C-OH, C-5), 147.6 (1C, C-3), 134.1, 127.7, 126.4, 124.3 (6C, phenyl), 83.0 (1C, C-4, =C-H).

IR(KBr) n: 3050 (=C-H), 2930 (sat. CH), 1566 (C=C).

Synthesis of 1-n-hexyl-3-phenyl-5-pyrazolone (2b)

The same procedure described for 2a was followed. 3-Phenyl-5-pyrazolone (0.125 mole, 20 g) and n-hexyl bromide (0.125 mole, 17.5 mL) were used. Yield: 40%, mp: 118-119°.

Anal Calcd. for C15H20N2O: C, 73.74; H, 8.23. Found: 73.77; H, 8.35.

1H-NMR (DMSO-d6) d: 11.08 (s, 1H, OH at C-5), 7.80-7.33 (m, 5H, phenyl), 5.87 (s, 1H, methine at C-4), 3.96 (t, 6.95 Hz, 2H, CH2 a to N-1), 1.79 (m, 2H, CH2), 1.34 (broad singlet, 6H, three CH2) 0.93 (t, 6.79 Hz, CH3).

1H-NMR (CDCl3) d: 7.69-7.39 (m, 5H, phenyl), 3.75 (t, 7.14 Hz, CH2 a to N-1) 3.62 (s, 2H, CH2- C=O), 1.73 (m, 2H, CH2), 1.37 (m, 6H, 3CH2), 0.89 (t, 6.83 Hz, 3H, CH3).

13C-NMR (DMSO-d6) d: 153.0 (1C, C-OH, C-5), 147.7 (1C, C-3); 134.3, 128.5, 127.1, 124.7 (6C, phenyl), 83.1 (1C, CH at C-4), 45.8, 30.8, 29.2, 25.8, 22.1 (5C, 5CH2), 13.9 (1C, CH3).

13C-NMR (CDCl3) d: 171.5 (1C, C=O, C-5), 153.9 (1C, C-3), 131.2, 130.1, 128.7, 125.5 (6C, phenyl), 44.3 (1C, CH2 a to N-1), 38.1 (1C, CH2, C-4), 31.3, 28.3, 26.3, 22.4 (4C, 4CH2), 13.9 (1C, CH3).

IR (KBr) n: 3065 (=CH), 2930 (sat. CH), 1558 (C=O), 1500 (C=C).

Synthesis of 1-n-butyl-3-phenyl-4-acetyl-5-pyrazolone (3a)

To a flask containing sodium-dried dioxane (200 mL), 2a (0.023 mole, 5.1 g) was added and heated until the solid was dissolved. Once the solution had cooled to room temperature, calcium hydroxide (0.045 mole, 3.39 g) and acetyl chloride (0.028 mole, 2.2 mL) were added. The mixture was heated to reflux during 30 minutes. Then the solvent was evaporated and the residue made acid with 10% aqueous HCl and extracted twice with 100 mL of methylene chloride. The organic extracts were collected and washed two more time with water until the pH was only slightly acid. The organic phase was concentrated and dissolved in ethanol. This solution was heated and treated with copper(II) acetate (0.011 mole, 2.3 g) dissolved in the smallest possible amount of hot water. The new solution was boiled for 5 minutes and then allowed to cool. The solid complex was filtered and recrystallized four times from ethanol-water. Finally the complex was dissolved in 100 mL of methylene chloride and washed twice with 10% aqueous HCl and then with water until neutral pH. The organic phase was dried over sodium sulphate before evaporating the solvent.

With the procedure above described an oil was obtained. This matrial gave good nmr spectra and hence no further purification was attempted. Elemental analyses and IR spectrum were not obtained.

1H-NMR (CDCl3) d: 10.91 (s, 1H, OH), 7.50-7.39 (two multiplets, 5H, phenyl), 4.00 (t, 7.10 Hz, 2H, CH2 a to N-1), 2.09 (s, 3H, CH3-C=O), 1.84 (m, 2H, CH2), 1.37 (m, 2H, CH2), 0.94 (t, 7.33 Hz, 3H, CH3 alkyl chain).

13C-NMR (CDCl3) d: 195.9 (1C, C=O, acetyl), 159.1 (1C, C-5, C-OH), 150.2 (1C, C-3), 133.3, 129.3, 128.7, 128.2 (4C, phenyl), 102.5 (1C, C-4), 45.7 (1C, CH2 a to N-1), 30.8 (1C, CH2), 27.3 (1C, CH3, acetyl), 19.7 (1C, CH2), 13.4 (1C, CH3, alkyl chain).

Synthesis of 1-n-butyl-3-phenyl-4-benzoyl-5-pyrazolone (3b)

The same procedure described for 3a was followed. 1-n-Butyl-3-phenyl-5-pyrazolone (0.014 mole, 3.0 g), benzoyl chloride (0.028 mole, 2 mL) and calcium hydroxide (0.028 mole, 2.07 g) were used. Yield: 65%.

1H-NMR (CDCl3) d: 10.96 (s, 1H, OH), 7.20-7.84 (m, 10H, phenyls), 3.88 (t, 6.13 Hz, 2H, CH2 a to N-1), 1.70 (m, 2H, CH2), 1.23 (m, 2H, CH2), 0.78 (t, 7.26 Hz, 3H, CH3).

13C-NMR (CDCl3) d: 193.0 (1C, C=O, benzoyl), 160.4 (1C, C-OH, C-5), 150.6 (1C, C-3), 137.5, 133.2, 131.7, 129.3, 129.1, 128.2, 127.9, 127.7 (10C, two phenyl rings), 100.9 (1C, C-4), 46.3, 31.1, 20.0 (3C, CH2), 13.8 (1C, CH3).

Synthesis of 1-n-butyl-3-phenyl-4-nitroso-5-pyrazolone (4a)

In a beaker containing 100 mL of hot ethanol and 15 mL of concentrated aqueous HCl, 2a (0.0023 mole, 0.5 g) was dissolved and then cooled in an ice bath. Keeping the solution between 0-5°, sodium nitrite (0.0025 mole, 0.176 g) dissolved in a very small amount of water was dropped in. Then the solution was stirred one more hour and the solvent evaporated. The remaining material was treated with water. The solid was filtered and crystallized from ethanol-water. Yield: 80%, mp: 110-112°.

Anal. Calcd. for C13H15N3O2 : C, 63.40; H, 6.14. Found: C, 63.42; H, 6.15.

1H-NMR (CDCl3) d: 14.8 (wide signal, OH), 8.09-8.06, 7.45-7.43 (m, m, 5H, phenyl), 3.83 (t, 6.90 Hz, 2H, CH2 a to N-1), 1.79 (quintet, 2H, CH2), 1.40 (sextet, 2H, CH2), 0.97 (t, 7.26Hz, 3H, CH3).

13C-NMR (CDCl3) d: 157.0 (1C, C-OH, C-5), 145.7 (two very close signals, 2C, C-3 plus C-4 or the quaternary carbon at the phenyl ring), 130.6, 128.7, 127.3 (6C, phenyl ring or 5 phenyl carbon plus C-4), 44.2, 30.0, 19.8 (3C, 3CH2), 13.5 (1C, CH3).

IR (KBr) n: 3300 (N-H), 3100 (=C-H), 2930 (sat. CH), 1675 (C=O).

Synthesis of 1-n-hexyl-3-phenyl-4-nitroso-5-pyrazolone (4b)

The same procedure described for 4a was followed. 1-n-Hexyl-3-phenyl-5-pyrazolone (0.004 mole, 1.0 g) and sodium nitrite (0.0045 mole, 0.3 g) were used. Yield: 89%, mp: 73-74°.

Anal. Cald. for C15H19N3O2 : C, 65.67; H, 6.98. Found: 65.65; H, 6.99.

1H-NMR (CDCl3) d: 14.73 (broad signal, OH), 8.14-7.45 (m, 5H, phenyl), 3.86 (t, 7.05 Hz, 2H, CH2 a to N-1), 1.83 (m, 2H, CH2), 1.37 (broad signal, 6H, 3CH2), 0.93 (t, 6.85 Hz, 3H, CH3).

1H-NMR (DMSO-d6) d: 14.78 (s, 1H, OH), 8.03-7.52 (m, 5H, phenyl), 3.77 (t, 6.83 Hz, CH2 a to N-1), 1.72 (broad signal, 2H, CH2), 1.34 (broad singlet, 6H, 3CH2), 0.92 (t, 6.40 Hz, 3H, CH3).

13C-NMR (CDCl3) d: 156.5 (1C, C-5, C-OH), 145.7, 145.2 (2C, C-3 plus C-4 or the quaternary carbon in the phenyl ring), 130.4, 128.6, 127.3 (6C, phenyl or 5C from the phenyl ring plus C-4), 44.5 (1C, CH2 a to N-1), 31.2, 27.9, 26.2, 22.4 (4C, 4CH2), 13.9 (1C, CH3).

13C-NMR (DMSO-d6) d: 161.0 (C-5. C=O), 152.6 (C-5, C-OH), 144.1, 143.6 (C-3 plus C-4 or the quaternary carbon in the phenyl ring), 141.6, 140.9 (C-3 plus C-4 or the quaternary carbon in the phenyl ring), 131.5, 129.9, 129.7, 128.5, 127.8, 127.1 (6C, phenyl or 5 phenyl ring carbons plus C-4), 43.6 (1C, CH2 a to N-1), 30.9, 27.8, 25.9, 22.1 (4C, 4CH2), 13.9 (1C, CH3).

IR (KBr) n: 3328 (N-H), 3007 (=C-H), 2929 (sat. C-H), 1678 (C=O), 1617 (C=C).

ACKNOWLEDGEMENTS

The authors thank the Dirección de Investigación, Universidad de Concepción, for financial support (Grant 96.023.009-1).

_____________________________

*To whom correspondence should be addressed.

REFERENCES

1. L. Knorr. Ber., 17, 2032 (1884).         [ Links ]

2. L. Bouvelt, R. Locquin. Bull. Soc. Chim. France, 31, 528(1904).         [ Links ]

3. L. Bouvelt, R. Locquin. Bull. Soc. Chim. France, 27, 1088 (1902).         [ Links ]

4. W. Krhos. Chem. Ber., 88, 866 (1955).         [ Links ]

5. J. Bartulín, J. Belmar, G. León. Bol. Soc. Chil. Quím., 37, 13 (1992).         [ Links ]

6. J. Belmar, J. Alderete, F. Leonardi, G. León, M. Parra, C. Zúñiga. Bol. Soc. Chil. Quím., 42, 355 (1997).         [ Links ]

7. J. Bartulín, J. Belmar, H. Gallardo, G. León. J. Heterocyclic Chem., 31, 561 (1994).         [ Links ]

8. M.J.S. Dewar, E.G. Zoebisch, E.F. Healy, J.J.P. Stewart. J. Am. Chem. Soc., 107, 3902 (1985).         [ Links ]

9. C. Lee, W. Yang, R.G. Parr. J. Mol. Struct. (Theochem), 163, 305 (1988).         [ Links ]

10. S. Braun, H.O. Kalinowski, S. Berger. 100 and More NMR Experiments, VCH Publishers, New York, 1996. 1st Ed. p. 299.         [ Links ]

11. Ibid, p. 144.