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Boletín de la Sociedad Chilena de Química

versión impresa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.46 n.4 Concepción dic. 2001

http://dx.doi.org/10.4067/S0366-16442001000400010 

SYNTHESIS OF 1-n-ALKYL-3-METHYL- AND 1-n-ALKYL-3-
PHENYL-5-PYRAZOLONES AND FORMYL DERIVATIVES

J. BELMAR*, J. ALDERETE, C. ZUÑIGA, C. JIMÉNEZ, V. JIMÉNEZ,
H. NÚÑEZ, R. GRANDY, AND A. YORI.

Deparment of Organic Chemistry, Faculty of Chemical Sciences, Universidad de
Concepción. Casilla 160-C, Concepción. Chile.
jbelmar@udec.cl
(Received: March 22, 2001 - Accepted: October 5, 2001)

SUMMARY

3-Methyl- and 3-phenyl-5-pyrazolones were alkylated and formylated. The phenyl derivative was less reactive towards alkylation. However in the formylation step 1-n-alkyl-3-methyl- and 1-n-alkyl-3-phenyl-5-pyrazolones showed no difference in reactivity. The alkylated products exist as 5-pyrazolones in chloroform solutions and in dimethylsulfoxide their structure is a 5-hydroxy-pyrazole. Chloroform and dimethyl sulfoxide solutions of 4-formyl derivatives have a structure that is better described as 4-hydroxymethylene-5-pyrazolone.

Keywords: pyrazolones, tautomers, alkylpyrazolones, formylpyrazolones.

RESUMEN

Se alquiló y formiló 3-metil- y 3-fenil-5-pirazolona. El 3-fenil derivado es menos reactivo en la etapa de alquilación. En la etapa de formilación no hay diferencias entre 1-n-alquil-3-metil- o 1-n-alquil-3-fenil-5-pirazolona. Los productos de alquilación presentan una estructura de 5-pirazolona en cloformo, mientras que en dimetilsulfóxido la estructura es del tipo 5-hidroxipirazol. En estos mismos solventes, los derivados formilados solo presentan una estructura que es descrita como 4-hidroximetilén-5-pirazolona.

Palabras claves: pirazolonas, tautómeros, alquilpirazolonas, formilpirazolonas.

INTRODUCTION

Some interesting features of pyrazolones have been recognized for a long time. They are versatile heterocycles wich have very important applications in both chemistry and biology. For example, some pyrazolones have been widely used as analgesic and anti-inflamatory drugs (1, 3). Also some derivatives have very interesting properties as chelators in liquid-liquid extraction processes (4-5). Moreover the physical and chemical properties of these compounds are modulated by their tautomeric properties. Thus we have found that the nucleophilic character and basicity of the nitrogen atoms in 3-phenyl-5-pyrazolones change from tautomer to tautomer (6).

It is important to note that most part of the information on pyrazolones that is available is related to 1-phenyl derivatives because they are readily obtained through the condensation of a b-keto-ester with phenylhydrazine (7-10). 1-n-Alkyl pyrazolones, on the other side, are seldom mentioned since the required alkylhydrazines are difficult to obtain (11) and only a few of them are commercially available. Considering this fact and our interest in chelating molecules, we focused our attention on 1-n-alkylpyrazolones and their nitroso, azo and acyl derivatives (12-14).

In this paper we expand the information for 1-alkylpyrazolones and report the results obtained with their 4-formyl-derivatives. Some of the results are comparatively discussed with our previous findings in an effort to summarize the information so far obtained for these heterocycles.

RESULTS

Pyrazolones were obtained as outlined in Scheme 1. Ethyl acetoacetate or ethyl benzoylacetate were condensed with hydrazine to obtain 3-methyl-5-pyrazolone (1) or 3-phenyl-5-pyrazolone (2) with very good yields. The alkylation step was carried out by heating to reflux a mixture of the corresponding pyrazolone and an alkyl bromide in dioxane. Compound 1 was alkylated in about 70% yield, while compound 2 underwent alkylation with a modest 40%. Further attempts to improve this yield by using other solvents as ethanol or dimethylformamide and more prolonged reaction times were unsuccessful. Theoretical calculations (14) show that N-1 is a poorer nucleophile in 3-phenyl- than in 1-methyl-5-pyrazolones. This may result from extended conjugation towards the phenyl ring and/or the change of a sp3 methyl carbon by a more electronegative sp2. Formylation with chloroform in basic medium yielded compounds 8 to 12. In this case the yields ranged from 40% to 65% and no difference was observed for 3-methyl or 3-phenyl derivatives. 1-Benzyl-3-methyl-5-pyrazolone (6) was obtained using benzyl chloride not bromide, and that is the reason for the lower yield. This compound was used to obtain a 4-formyl derivative with a higher melting point that could be easily crystallized and in this way obtain information would be useful in structure characterization of 1-n-alkyl derivatives.

TAUTOMERISM

Four tautomeric structures can be drawn for 3-substituted pyrazolones (Figure 1). According to 13C spectroscopic data in DMSO-d6 for compounds 1 and 2 we first suggested that they were present as OH tautomers in this solvent. Later, using 15N and theoretical calculations (6) for 1, we found that a NH/OH tautomer was in better agreement with all the information obtained. Since the chemical shifts for compound 2 are very close to that of compound 1, we now suggest that also in this case NH/OH is the better structure. Theoretical calculations for compound 2 turned out to be much time consuming, so they were not carried out.


Fig. 1. Tautomers for 3-Substituted Pyrazolones

For 1,3-disubstituted 5-pyrazolones, there are only three tautomers (Figure 2). The data provided by 13C nmr in CDCl3 shows that all the obtained compounds (3-7) exist as the CH tautomer. The chemical shifts values for compound 5 are 172.0 ppm (C-5, C=O), 155.1 ppm (C-3, C=N), and 41.7 ppm (C-4, CH2). The DEPT spectrum shows that the last signal is a methylene. This is also confirmed in the proton spectrum by a singlet at 3.17 ppm (2H) that corresponds to the methylene a to the carbonyl. Compound 6 shows the same behaviour, as it is expected the phenyl ring does not have a noticeable effect on the tautomeric equilibrium. Compound 7 also exists as a CH tautomer in CDCl3. The 13C chemical shifts for the significant signals are 171.5 ppm (C-5, C=O), 153.9 ppm (C-3, C=N) and 38.1 ppm (C-4, CH2). The proton spectrum shows a singlet at 3.6 ppm (2H) that correlates with the signal at 38.1 ppm in the CH correlation spectrum. It is clear that the phenyl ring at C-3 does not have a measurable effect on the tautomeric equilibrium compared with the compounds bearing a methyl group at the same position.

Fig.2. Tautomers for 1,3-disubstituted Pyrazolones

For compounds 3 to 7, 13C nmr spectra in DMSO-d6 were also recorded. In this case the structure for the tautomer is OH. A signal around 85 ppm that corresponds to C-4 in the ring, can be observed in the four cases. According to their DEPT spectra this is a CH. Singlets between 5 to 6 ppm (1H, =CH) also support the suggested structure. The mentioned signals correlate in the CH-COSY spectrum. Again, the phenyl ring at C-3 does not produce any noticeable change in the tautomeric equilibrium. In addition, as it would be expected, the benzyl at N-1 neither has an effect on the equilibrium.

Regarding the formyl derivatives (8-12), four tautomers can be written (Figure 3). In CDCl3 compound 10 exist as a CO/OH tautomer. The important signals in the 13C spectrum are 161.3 ppm (C-5, C=O), 151.4 ppm (C-3, C=N), 137.5 ppm (=CHOH) and 108.1 (C-4). The signal at 137.5 ppm is a CH according to the DEPT spectrum. In the pmr appears a sharp singlet at 17.7 ppm (1H) that corresponds to the enolic hydroxyl. Another singlet appears at 7.13 ppm (1H) and corresponds to the vinylic proton (=CH).


Fig. 3. Tautomers for 1,3-Disubstituted 4-Formyl-5-Pyrazolones

The nature of the tautomer of the formylated compounds was somewhat surprising considering that 4-acetyl and 4-benzoyl derivatives previously reported (12, 14) have a real acyl substituent and the ring posses an OH structure. Another interesting feature of the formylated compounds was the intense yellow-orange color. 4-Acylpyrazolones are colorless.

Compounds 11 and 12 also have a CO/OH structure and are strongly colored. The 13C for compound 11 in CDCl3 is, of course, similar to that of compound 10 in the same solvent. There is only a small downfield shift for some of the signals due to the phenyl ring. The chemical shifts values are 161.4 ppm (C-5, C=O), 154.3 ppm (C-3, C=N), 142.8 ppm (=CH-OH) and 107.8 ppm (C-4). As it can be followed from the DEPT spectrum the signal at 142.8 ppm is a CH. In a CH COSY this signal correlates with a singlet at 7.63 ppm. (1H) in the pmr spectrum. The enolic proton appears at 17.73 ppm. Again the nature the phenyl ring at C-3 has no measurable effect on the tautomeric equilibrium when compared with the compounds bearing a methyl at the same position. The main signals for 12 in CDCl3 are 161.6 ppm (C-5, C=O), 151.8 ppm (C-3, C=N), 138.2 ppm (=CH-OH) and 108.2 (C-4). The signal at 132.8 ppm correlates with the singlet at 7.14 ppm (1H) in the pmr spectrum. In this case the characteristic singlet for the enolic OH appears at 17.89 ppm.

Compounds 8 to 12 have a CO/OH structure in dimethyl sulfoxide as it was evidenced from their proton spectra in DMSO-d6. The spectra pattern for these compounds are the same in CDCl3 or DMSO, with only very small differences in chemical shifts from one solvent to the other. Consequently the DMSO-d6 data is not included in Experimental.

In conclusion, the phenyl attached to C-3 has an effect that is important on the reactivity of the pyrazolone N-1 towards alkylation, affording poor yields of the 1-alkyl derivatives. There is a clear solvent effect for 1-alkylpyrazolones, where a CH structure is preferred in a lower polarity solvent as CHCl3. In the more polar DMSO, the preferred structure is OH. 4-Formyl derivatives in CDCl3 and DMSO exist as 4-hydroxymethylenepyrazolones where the ring has a CO structure. Finally, substitution of the methyl at C-3 by a phenyl ring does not have effect on the tautomeric equilibriums here presented.

Examples of DEPT (145) and 13C-1H correlation spectra for 1-n-decyl-3-methyl-5-pyrazolone (4) and 1-n-decyl-3-methyl-4-formyl-5-pyrazolone (9) are shown in figures 4 to 9.

EXPERIMENTAL

Fig. 4. DEPT-135 spectrum (CDCl3) of 1-n-decyl-3-methyl-5-pyrazolone (4). The downward signal for C-4 corresponds to a methylene.


Fig. 5. 13C-1H Correlation spectrum (CDCl3) of 1-n-hexyl-3-methyl-5-pyrazolone (4). The signals for CH2 (C-4) are indicated with the dashed lines.


Fig. 6. DEPT-135 spectrum (DMSO-d6) of 1-n-hexyl-3-methyl-5-pyrazolone (4). The upward signal for C-4 is indicative of C-H.


Fig. 7. 13C-1H Correlation spectrum (DMSO-d6) of 1-n-decyl-3-methyl-5-pyrazolone. The signals for CH (C-4) are indicated with dashed lines.


Fig. 8. DEPT-135 spectrum of 1-n-decyl-3-methyl-4-formyl-5-pyrazolone. The upward signal for =CH-O appears at 138.0 ppm.


Fig. 9. 13C-1H Correlation spectrum (CDCl3) of 1-n-decyl-3-methyl-4-formyl-5-pyrazolone. The dashed lines connect the chemical shifts corresponding to =CH-O- group.

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 correlation (16) and DEPT (17) 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. Chemical shifts for nmr spectra (d) are quoted in ppm. Infrared values (n) are quoted in reciprocal centimeters (cm-1) and are reported just to complete the characterization data because they are not very useful in assesing the taumer structures. Boiling and melting points are reported in Celcius degrees.

Bol. Soc. Chil. Quím., 46, N 4 (2001)

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

To a magnetically stirred solution of ethyl acetylacetate (1.0 mole, 129 ml) in 500 ml of ethanol, 80% aqueous hydrazine (1.0 mole, 61 ml) was added dropwise. Stirring was continued for an hour after the addition was finished. The white solid was filtered and recrystallized from ethanol. Yield: 94%, mp: 217, lit. 215 (7).

Anal. Calcd. for C4H6N2O: C, 48.97; H, 6.16. Found: C, 48.60; H, 6.23.

1H NMR (DMSO-d6) d: 10.43 (s, OH, NH broad), 5.03 (s, 1H, H-4), 2.17 (s, 3H, Me).

13C NMR (DMSO-d6) d: 161.3 (1C, C-5, =C-OH), 139.9 (1C, C-3), 89.1 (1C, C-4), 11.3 (1C, CH3).

IR (KBr) n: 3500 (NH), 1620 (C=O).

Synthesis of 3-phenyl-5-pyrazolone (2)

The same procedure described for 1 was followed. Ethyl benzoylacetate (0.47 mole, 81 ml), hydrazine (0.47 mole, 23 ml) were used. Yield: 80%, mp: 245-246.

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

1H NMR (DMSO-d6) d: 11.20 (1H, OH, broad), 7.31-7.81 (m, 5H, C6H5), 6.04 (s, 1H, CH, H-4), 3.80 (1H, NH, broad).

13C NMR (DMSO-d6) d: 161.5 (1C, C-5, C=O), 144.8 (1C, C-3), 130.8, 129.4, 128.6, 125.4 (6C, C6H5), 87.6 (1C, C-4, =CH).

IR (KBr) n: 3200-3210 (O-H, N-H), 3118 (=C-H), 1624 (C=O), 1589 (C=C).

Alkylation of 3-methyl-5-pyrazolone. General procedure

In 300 ml of dioxane, 3-methyl-5-pyrazolone (18.5 g, 0.188 mole) and n-alkylbromide (0.188 mole) were heated to reflux during 48 hours. Then the solvent was evaporated and the remaining material poured over a mixture of ice and 10% NaHCO3. The mixture was diluted with ether and washed with water until neutral pH. The organic phase was dried with sodium sulphate evaporating the solvent. The crude was distillated under reduced pressure.

This reaction was carried out with different ammounts of reagents without affecting the yields. In some of the runs we were able to prepare about 80 to 100 grams of the alkylated product.

Synthesis of 1-n-hexyl-3-methyl-5-pyrazolone (3)

Obtained following the general procedure. Yield 70%, bp: 100-115 (0.1 mmHg).

Anal. Calcd. for C10H18N2O: C, 65.89; H, 9.95. Found: C, 65.84; H, 10.14.

1H NMR (CDCl3) d: 3.61 (t, 7.22 Hz, 2H, CH2 a to N-1), 3.20 (s, 2H, CH2-C=O), 2.10 (s, 3H, CH3 at C-3), 1.66 (m, 2H, CH2 b to N-1), 1.31 (wide singlet, 6H, 3CH2, alkyl chain), 0.87 (t, 6.49 Hz, 3H, CH3, alkyl chain).

13C NMR (CDCl3) d: 171.9 (1C, C-5, C=O), 155.1 (1C, C-3), 43.9 (1C, CH2, C-4), 31.2, 28.1, 26.2, 22.3 (4C, 4CH2, alkyl chain), 16.8 (1C, CH3 at C-3), 13.8 (1C, CH3, alkyl chain).

1H NMR (DMSO-d6) d: 10.30 (broad singlet, 1H, OH), 5.13 (s, 1H, =CH at C-4), 3.74 (t, 7.00 Hz, 2H, CH2 a to N-1), 2.04 (s, 3H, CH3 at C-3), 1.63 (q, not well resolved, 2H, CH2 b to N-1), 1.25 (broad singlet, 6H, 3 CH2, alkyl chain), 0.85 (t, 6.07 Hz, 3H, CH3, alkyl chain).

13C NMR (DMSO-d6) d: 154.7 (1C, C-5, =C-OH), 145.2 (1C, C-3), 86.7 (1C, C-4, =CH), 44.8 (1C, CH2 a to N-1), 30.8, 28.9, 25.7, 22.0 (4C, CH2, alkyl chain), 13.7, 13.5 (2C, CH3).

IR (KBr) n: 2960-2860 (C-H), 1550 (C=N).

Synthesis of 1-n-decyl-3-methyl-5-pyrazolone (4)

Yield: 65%, bp: 135-140 , (0.01 mmHg).

Anal. Cald. for C14H26N2O: C, 70.54; H, 11.00. Found: C, 70.53; H, 11.02.

1H NMR (CDCl3) d: 3.57 (t, 7.07 Hz, 2H, CH2 a to N-1), 3.36 (s, 2H, CH2-C=O), 2.06 (s, 3H, CH3 at C-3), 1.63 (wide signal, 2H, CH2 b to N-1) 1.23 (wide signal, 14H, 7CH2, alkyl chain), 0.84 (t, 6.60 Hz, 3H, CH3, alkyl chain).

13C NMR (CDCl3) d: 171.8 (1C, C-5, C=O), 155.1 (1C, C-3), 43.8 (1C, CH2 a to N-1), 41.6 (1C, C-4), 31.7, 29.3, 29.1, 28.1, 26.5, 22.5 (8C, 8CH2, alkyl chain), 16.7 (1C, CH3 at C-3), 13.9 (1C, CH3, alkyl chain).

1H NMR (DMSO-d6) d: 10.3 (broad singlet, 1H, OH), 5.06 (s, 1H, =CH), 3.69 (t, 6.85 Hz, 2H, CH2 a to N-1), 1.98 (s, 3H, CH3 at C-3), 1.60 (broad signal, 2H, CH2 b to N-1), 1.20 (broad singlet, 14H, 7CH2, alkyl chain), 0.81(t, not well resolved, 3H, CH3, alkyl chain).

13C NMR (DMSO-d6) d: 154.3 (1C, C-5, C-OH), 145.0 (1C, C-3), 86.4 (1C, C-4, =CH), 44.5 (1C, CH2 a to N-1), 31.0, 28.7, 28.4, 25.8, 21.8 (8C, 8CH2), 13.4 (2C, 2CH3).

IR (film) n: 2918, 2850 (sat CH), 1544 (C=O, C=N).

Synthesis of 1-n-dodecyl-3-methyl-5-pyrazolone (5)

Synthesized following the general procedure with some variations in the work up. The cooled reacting mixture was neutralized with 10% NaOH, poured over ice and filtered. The solid was crystallized from EtOH-H2O. Yield: 70%, mp: 73-74.

Anal. Calcd. for C16H30N2O: C, 72.13; H, 11.35. Found: C, 72.15; H, 11.36.

1H NMR (CDCl3) d: 3.60 (t, 7.25 Hz, 2H, CH2 a to N-1), 3.17 (s, 2H, CH2-C=O, C-4), 2.08 (s, 3H, CH3 at C-3), 1.66 (m, 2H, CH2 b to N-1), 1.25 (broad singlet, 18 H, 9CH2, alkyl chain), 0.88 (t, 6.40 Hz, 3H, CH3, alkyl chain).

13C NMR (CDCl3) d: 172.0 (1C, C-5, C=O), 155.1 (1C, C-3), 44.1 (1C, CH2 a to N-1), 41.7 (1C, C-4, CH2), 31.9, 29.6, 29.2, 28.3, 26.7, 22.7 (10C, CH2, alkyl chain), 16.9 (1C, CH3 at C-3), 14.0 (1C, CH3, alkyl chain).

1HNMR (DMSO-d6) d: 10.28 (broad signal, 1H, OH), 5.08 (s, 1H, =CH), 3.68 (t, 6.93 Hz, 2H, CH2 a to N-1), 1.98 (s, 3H, CH3 at C-3), 1.59 (wide singlet, 2H, CH2 b to N-1), 1.23 (broad singlet, 18H, 9CH2, alkyl chain), 0.85 (t, 6.73 Hz, 3H, CH3, alkyl chain).

Owing to the extremely low solubility of the compound in dimethylsulfoxide it was not possible to obtain a fairly good 13C spectrum.

IR (film) n: 2920, 2852 (sat. CH), 1550 (C=O, C=N).

Synthesis of 1-benzyl-3-methyl-5-pyrazolone (6)

Obtained following the general procedure and the same work up as compound 5. Yield: 45%, mp: 178-179.

Anal. Calcd. for C11H12N2O: C, 71.98; H, 6.04. Found: C, 71.96; H, 6.02.

1H NMR (CDCl3) d: 7.32 (complex signal, 5H, C6H5), 4.79 (s, 2H, CH2, benzylic), 3.20 (s, 2H, CH2, C-4), 2.05 (s, 3H, CH3).

13C NMR (CDCl3) d: 172.0 (1C, C-5, C=O), 155.5 (1C, C-3), 136.7, 128.6, 128.2, 127.6 (6C, C6H5), 47.8

Bol. Soc. Chil. Quím., 46, N 4 (2001)

(1C, CH2, benzylic), 41.5 (1C, CH2, C-4), 16.9 (1C, CH3).

1H NMR (DMSO-d6) d: 10.91 (broad singlet, 1H, OH), 7.33-7.13 (complex signal, 5H, C6H5), 5.17 (s, 1H, =CH, C-4), 4.94 (s, 2H, CH2, benzylic), 2.01 (s, 3H, CH3).

13C NMR (DMSO-d6) d: 156.8 (1C, C-5,C-OH), 146.0 (1C, C-3), 138.1, 128.33, 127.2 (6C, C6H5), 86.2 (1C, C-4), 48.5 (1C, CH2), 13.9 (1C, CH3).

IR (KBr) n: 3490 (OH, NH), 3032 (=CH), 2935 (sat. CH), 1779 (C=O), 1549 (C=C).

Synthesis of 1-n-hexyl-3-phenyl-5-pyrazolone (7)

The same general procedure for the alkylation of 3-methyl-5-pyrazolones was followed with a different work up. After reflux was finished, the solvent was evaporated and the remaining material poured over ice, neutralized with 10% NaHCO3 and filtered. The solid was dried and then extracted with chloroform in a soxhlet apparatus. The chloroform solution was evaporated and the crude crystallized from EtOH-H2O. Yield: 40%, mp: 161-164.

Anal Calcd. for C15H20N2O: C, 73.17; H, 8.25. Found: C, 73.69; H, 8.26.

1H NMR (CDCl3) d: 7.69-7.39 (m, 5H, C6H5), 3.75 (t, 7.14 Hz, CH2 a to N-1), 3.62 (s, 2H, CH2C=O), 1.73 (m, 2H, CH2), 1.37 (m, 6H, 3CH2), 0.89 (t, 6.83 Hz, 3H, CH3).

13C NMR (CDCl3) d: 171.5 (1C, C-5, C=O), 153.9 (1C, C-3), 131.2, 130.1, 128.7, 125.5 (6C, C6H5), 44.3 (1C, CH2 a to N-1), 38.1 (1C, C-4, CH2), 31.3, 28.3, 26.3, 22.4 (4C, 4CH2, alkyl chain), 13.9 (1C, CH3).

1H NMR (DMSO-d6) d: 11.08 (s, 1H, OH, at C-5), 7.80-7.33 (m, 5H, C6H5), 5.87 (s, 1H, =CH 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, 3CH2), 0.93 (t, 6.79 Hz, 3H, CH3).

13C NMR (DMSO-d6) d: 153.0 (1C, C-5, C-OH), 147.7 (1C, C-3), 134.3, 128.5, 127.1, 124.7 (6C, C6H5), 83.1 (1C, C-4), 45.8, 30.8, 29.2, 25.8, 22.1 (5C, 5CH2), 13.9 (1C, CH3).

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

Formylation Reaction. General Procedure.

A flask containing a mixture of pyrazolone (0.17 mole) and 54 g (1.35 mole) of NaOH dissolved in 54 ml of water was heated between 65 and 70 C and then 27 ml (40 g, 0.33 mole) of chloroform were added in small portions. The mixture was then heated to reflux during 1h.

After the reflux, the solution was cooled with an ice bath and neutralized with 10% HCl. Extra chloroform (100 ml) was then added. The organic phase was washed with water until pH neutral in a separatory funnel and after separation the solvent evaporated in a rotary evaporator. The crude was crystallized with EtOH-H2O.

Synthesis of 1-n-hexyl-3-methyl-4-formyl-5-pyrazolone (8).

This compound was obtained following the general procedure but some changes were introduced in the work-up. The organic phase was washed and then dried with sodium sulfate. The solvent was evaporated and the remaining crude was chromatographed using a silica column and chloroform as the mobil phase. Elemental analysis for this compound was not obtained because more purification would have been required. Purity was enough to get the nmr spectra, however. Yield: 40%. Reddish oil.

1H NMR (CDCl3) d: 17.86 (s, 1H, OH), 7.13 (s, 1H, =CH-O), 3.80 (t, 7.13 Hz, CH2 a to N-1), 2.24 (s, 3H, CH3 at C-3), 1.75 (broad singlet, 2H, CH2 b to N-1), 1.32 (broad singlet, 6H, 3CH2), 0.88 (t, 6.33 Hz, 3H, CH3, alkyl chain).

13C NMR (CDCl3) d: 161.0 (1C, C-5, C=O), 151.0 (1C, C-3), 137.7 (1C, =CH-OH), 107.8 (1C, C-4), 45.4

(1C, CH2 a to N-1), 31.1, 28.3, 26.0, 22.2 (4C, CH2, alkyl chain), 13.7 (1C, CH3, alkyl chain), 12.46 (1C, CH3 at C-3).

IR (film) n: 2928, 2861 (sat. CH), 3500 (OH), 1614 (C=O).

Synthesis of 1-n-decyl-3-methyl-4-formyl-5-pyrazolone (9).

Obtained as described in the general procedure. Yield: 50%, mp: 43-44.

Anal. Calcd. for C15H26N2O2 : C, 67.63; H, 9.83. Found: C, 67.63; H, 9.81.

1H NMR (CDCl3) d: 17.8 (s, 1H, OH), 7.14 (s, 1H, =CH-O), 3.82 (t, 7.18 Hz, 2H, CH2 a to N-1), 2.56 (s, 3H, CH3 at C-3), 1.75 (m, 2H, CH2 b to N-1), 1.26 (wide singlet, 14H, 7CH2), 0.88 (t, 6.49 Hz, 3H, CH3, alkyl chain).

13C NMR (CDCl3) d: 161.3 (1C, C-5, C=O), 151.3 (1C, C-3), 138.0 (1C, =CHOH), 108.1 (1C, C-4), 45.7 (1C, CH2, a to N-1), 31.9, 29.5, 29.4, 29.3, 29.1, 28.5, 26.6, 22.6 (8C, CH2), 14.1 (1C, CH3, alkyl chain), 12.7 (1C, CH3 at C-3).

IR (film) n: 2925, 2857 (sat. CH), 1613 (C=O), 1565 (C=C).

Synthesis of 1-n-dodecyl-3-methyl-4-formyl-5-pyrazolone (10).

Obtained as described in the general procedure. Yield: 65 %, mp: 56-57.

Anal. Cald. for C17H30N2O2 : C, 69.35; H, 10.27. Found: C, 69.37; H, 10.25.

1H NMR (CDCl3) d: 17.74 (s, 1H, OH), 7.13 (s, 1H, =CH-O), 3.81 (t, 7.18 Hz, 2H, CH2 a to N-1), 2.25 (s, 3H, CH3 at C-3), 1.75 (m, 2H, CH2 b to N-1), 1.25 (wide singlet, 18H, 9CH2), 0.88 (t, 6.41 Hz, 3H, CH3, alkyl chain).

13C NMR (CDCl3) d: 161.3 (1C, C-5, C=O), 151.4 (1C, C-3), 137.5 (1C, =CH-OH), 108.1 (1C, C-4), 45.6 (1C, CH2 a to N-1), 31.9, 29.6, 28.6, 26.6, 22.7 (10C, CH2, alkyl chain), 14.1 (1C, CH3, alkyl chain), 12.8 (1C, CH3 at C-3).

IR (film) n: 2922, 2853 (sat. CH), 1625 (C=O), 1538 (C=C, C=N).

Synthesis of 1-n-hexyl-3-phenyl-4-formyl-5-pyrazolone (11).

Obtained as described in the general procedure. Yield: 58%, mp: 82-85.

Anal. Cald. for C16H20N2O2 : C, 70.56; H, 7.40. Found: C, 70.54; H, 7.38.

1H NMR (CDCl3) d: 17.73 (s, 1H, OH), 7.63 (s, 1H, = CH-O), 7.47-7.35 (complex signal, 5H, C6H5), 3.97 (t, 7.19 Hz, 2H, CH2 a to N-1), 1.84 (m, 2H, CH2 b to N-1), 1.35 (wide singlet, 6H, 3CH2), 0.89 (t, 6.48 Hz, 3H, CH3).

13C NMR (CDCl3) d: 161.4 (1C, C-5, C=O), 154.3 (1C, C-3), 142.8 (1C, =CH-OH), 131.3, 129.1, 128.8, 128.6 (6C, C6H5), 107.8 (1C, C-4), 46.1 (1C, CH2 a to N-1), 31.3, 28.5, 26.3, 22.4 (4C, 4CH2), 13.9 (1C, CH3).

IR (film) n: 2928, 2861 (sat. CH), 1700 (C=O, shoulder), 1614 (C=N, C=C).

Synthesis of 1-benzyl-3-methyl-4-formyl-5-pyrazolone (12).

Obtained following the general procedure. Yield: 70%, mp: 119-120.

Anal. Calcd. for C12H12N2O2 : C, 66.66; H, 5.59. Found: C, 66.68; H, 5.61.

1H NMR (CDCl3) d: 17.89 (s, 1H, OH), 7.33-7.27 (complex signal, 5H, C6H5), 7.14 (s, 1H, =CH-O), 5.00 (s,

2H, CH2), 2.22 (s, 3H, CH3).

13C NMR (CDCl3) d: 161.6 (1C, C-5, C=O), 151.8 (1C, C-3), 138.2 (1C, =CH-OH); 136.1, 128.0, 127.8 (6C, C6H5), 108.2 (1C, C-4), 49.5 (1C, CH2), 12.7 (1C, CH3).

IR (KBr) n: 3418 (OH), 3052 (=CH), 2933 (sat CH), 1616 (C=O), 1546 (C=C).

ACKNOWLEDGEMENTS

This work was supported by "Dirección de Investigación", Research Grant P.98.23.22-1

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