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Journal of the Brazilian Chemical Society

versión impresa ISSN 0103-5053

J. Braz. Chem. Soc. v.15 n.6 São Paulo nov./dic. 2004

http://dx.doi.org/10.1590/S0103-50532004000600027 

SHORT REPORT

 

An easy and efficient method to produce g-amino alcohols by reduction of b-enamino ketones

 

 

Maria Inês N. C. Harris; Antonio C. H. Braga*

Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970 Campinas -SP, Brazil

 

 


ABSTRACT

Reduction of b-enamino ketones 2 with NaBH4 in glacial acetic acid gave g-amino alcohols 1 in 70% to 98% yield with diastereomeric excesses, preferentially the syn product, from 44% to 90%. The stereochemistry of these compounds was confirmed by analysis of their tetrahydro-1,3-oxazine derivatives 3.

Keywords: amino alcohols, enamino ketones, oxazines, stereoselective reduction


RESUMO

A redução de b-enamino cetonas 2 com NaBH4 em ácido acético glacial produziu g-amino álcoois 1 em 70% a 98% de rendimento, com excessos diastereoméricos, preferencialmente o produto syn, de 44% a 90%. A estereoquímica desses compostos foi confirmada pela análise de seus derivados tetraidro-1,3-oxazinas 3.


 

 

Introduction

The synthesis of g-amino alcohols 1 is of great interest due to the pharmacology of these compounds and their derivatives. This functionality is found in several antibiotics and other biologically active natural products.1 Several synthetic methods have been described for the synthesis of g-amino alcohols 1 from diols,2 hydroxazols,3 lactams4 and lactones,5 but the more important methods are those where one can obtain g-amino alcohols 1 by reduction of 1,3-difunctionalized unsaturated compounds containing nitrogen and oxygen, such as b-hydroxy oximes,6 b-enamino ketones 2,7-11 and, more frequently, by the reduction of b-amino ketones.1,12-15

g-Amino alcohols 1, mainly syn, can be synthesized by reduction of b-enamino ketones 2 with Na in PriOH/tetrahydrofuran or with CeCl3/ LiBH4/tetrahydrofuran.9 On the other hand, the combination of NaBH4 in a carboxylic acid media has yielded an efficient reducing reagent.16

We wish to report herein a simple and efficient method to produce g-amino alcohols 1 through the reduction of b-enamino ketones 2 with NaBH4 in glacial acetic acid, which has been sucessfully used in our laboratory.17

 

Results and Discussion

Difficulties in reduction of b-enamino ketones 2 have been reported.10 The use of NaBH4 in a carboxylic acid medium is well known,16 but its use in the reduction of b-enamino ketones 2 has not been explored. Our results show that the reaction of b-enamino ketones 2 with NaBH4 in glacial acetic acid (3 hours at room temperature, Scheme 1), produces a mixture of syn/anti g-amino alcohols 1, the syn isomer being the major product (Table 1).18

 

 

 

 

When the reaction is carried out without temperature control, the reaction produces the a,b-unsaturated ketone 6 while at 0 °C (hexane/HOAc, CH2Cl2/HOAc or HOAc as solvent) the product is a mixture of reactant 2, g-amino alcohol 1 and the corresponding Mannich base 5. Another important observation is that, by this methodology, it is impossible to reduce 3-(N-benzylamino)-2-cyclohexen-1-one.

A mechanism is suggested where chelated intermediate 4 is reduced to produce b-amino ketone 5 and g-amino alcohol 1 (Scheme 2).

 

 

Quantitative conversion of g-amino alcohols 1 to the corresponding tetrahydro-1,3-oxazine derivatives 3 (formol in diethyl ether, Scheme 3),19 allow us to assign the syn stereochemistry to the major g-amino alcohol 1 after inspection of their 1H and 13C NMR spectra. Using the syn-3a compound as an example (Scheme 4), we can see the hydrogen atoms H4 and H6 as a double quartet of doublets at 3.27 ppm (J 3.3, 6.3, 11.1 Hz) and 3.68 ppm (J 2.7, 6.3, 12.3 Hz) respectively. These hydrogen atoms and H5e are in a axial-equatorial situation (q @ 60°), with coupling constants 2.7 Hz (JH4-H5e) and 3.3 Hz (JH6-H5e). The 1H NMR spectrum shows the axial-axial (q @ 180°) relation between H5a and hydrogen atoms H6 and H4 (JH4-H5a 11.1 Hz; JH6-H5a 12.5 Hz). Furthermore we can see H5e and H5a as a double triplet at 1.57 ppm (J 2.7, 13.5 Hz) and 1.42 ppm (J 11.1, 13.0 Hz), respectively. The analysis of the 13C NMR spectrum (Scheme 5) allows the assignement of the secondary carbons at 40.03 ppm and 85.76 ppm (C5 and C2 respectively), and the tertiary carbons at 53.90 ppm and 73.43 ppm (C4 and C6 respectively). The chemical shifts of the methyl groups were assigned mainly based on the protective anisotropic effect of the phenyl group at C4. The chemical shift of the carbon C6 in the syn-3a isomer and in the anti-3a isomer are 73.43 and 68.14 ppm respectively. This upfield shift (ca. 5 ppm) is compatible with a g-gauche exocyclic interaction, showing the axial methyl group at C4.

 

 

 

 

 

 

In conclusion, the reduction of b-enamino ketones 2 with NaBH4 in acetic acid is a very simple and fast method to obtain g-amino alcohols 1 (with preferential syn configuration) in good chemical yields.

 

Experimental

General

1H NMR and 13C NMR spectra were recorded on a GEMINI-300 MHz instrument, using CDCl3 as a solvent and TMS as internal reference. The IR spectra were recorded on a Perkin Elmer 1600-FTIR (film in NaCl cell) instrument. Elemental analyses were performed on a Perkin Elmer 2400 instrument. The mass spectra were recorded on a HP 5988ª instrument. The gas chromatographic analysis were performed on a Shimadzu GC/MS Class 5000 chromatograph equipped with a Simplicity-1 (SUPELCO) column. The products were purified by flash chromatography or PLC using SiO2 as a stationary phase.

General procedure to obtain g-amino alcohol, (1). To a solution of b-enamino ketone (2, 1 mmol) in glacial acetic acid (6 mL), was slowly added NaBH4 (4 mmol). The reaction was kept at 18-20 °C. The reaction was stirred for 3 hours, and then neutralized with an aqueous solution of 30% NaOH (approximatelly 12 mL) in an ice bath. The reaction mixture was extracted with CH2Cl2, the organic phases were combined, dried over MgSO4, and concentrated.

4-(N-Phenylamino)-pentan-2-ol, (1a). IR (neat) nmax/cm-1: 3350, 3050, 3025, 2970, 2925, 1600, 1500, 1320, 1250, 1130, 750, 690. MS m/z (%): 179(37), 164(15), 120(100), 104(7.6), 93(24), 77(22), 45(24). 1H NMR syn-1a d: 1.14(d, J 6.2 Hz, 3H), 1.18(d, J 6.2 Hz, 3H), 1.57(AA'XY, 2H), 3.41(s, large, 2H), 3.66(sext, J 6.5 Hz, 1H), 4.01(sext, J 6.0 Hz, 1H), 6.57-6.79(m, 3H), 7.12-7.24(m, 2H). 13C NMR syn-1a d: 147.13, 129.46, 118.98, 115.29, 67.97, 49.89, 45.76, 23.98, 21.46. 1H NMR anti-1a d: 1.17(2 d, 6H), 1.43-1.70(m, 2H), 3.20(s, large, 2H), 3.76(m, 1H), 3.91(m, 1H), 6.49-6.67(m, 3H), 7.00-7.10(m, 2H). 13C NMR anti-1a d: 147.73, 129.37, 117.61, 113.73, 67.25, 46.05, 45.70, 24.04, 21.32. Anal. Calc. for C11H17NO: C, 73.70; H, 9.56; N, 7.82%. Found: C, 73.91; H, 9.56; N, 7.62%.

4-(N-Benzylamino)-pentan-2-ol, (1b). IR (neat) nmax/cm-1: 3346, 3286, 3076, 2964, 2925, 1452, 1374, 1165, 1129, 1088, 742, 698. MS m/z (%): 193(5), 178(15), 134(83), 106(28), 91(100). 1H NMR syn-1b d: 1.12(d, J 6.3 Hz, 3H), 1.17(d, J 8.1 Hz, 3H), 1.20-1.55(m, 2H), 2.92(dqd, J 2.7, 6.3, 10.6 Hz, 1H), 3.71(d, J 13.0 Hz, 1H), 3.90(s, large, 1H), 3.93(d, J 13.0 Hz, 1H), 3.94(dqd, J 2.3, 5.8, 17.0 Hz, 1H), 7.20-7.36(m, 5H). 13C NMR syn-1b d: 139.24, 128.72, 128.49, 127.48, 68.94, 54.08, 50.64, 44.91, 23.87, 20.82. 1H NMR anti-1b d: 1.15(d, J 8.1 Hz, 3H), 1.21(d, J 6.6 Hz, 3H), 1.43(ddd, J 2.7, 5.1, 14.4 Hz, 1H), 1.70(ddd, J 3.3, 9.0, 14.4 Hz, 1H), 3.12(dqd, J 3.2, 3.9, 6.6 Hz, 1H), 3.50(s, large, 2H), 3.74(d, J 12.6 Hz, 1H), 3.86(d, J 12.6 Hz, 1H), 4.15(dqd, J 3.0, 6.2, 9.0 Hz, 1H), 7.20-7.37(m, 5H). 13C NMR anti-1b d: 139.51, 128.73, 128.43, 127.45, 65.03, 51.48, 51.97, 45.06, 23.56, 19.76. Anal. Calc. for C12H19NO: C, 74.55; H, 9.91; N, 7.25%. Found: C, 74.48; H, 10.17; N, 7.31%.

4-(N-isopropylamino)-pentan-2-ol, (1c). IR (neat) nmax/cm-1: 3340, 3274, 2965, 2927, 1560, 1461, 1382, 1163, 1133, 1084. MS m/z (%): 145(0.2), 130(15), 86(65), 45(25). 1H NMR syn-1c d: 1.08(d, J 6.0 Hz, 3H), 1.10(d, J 5.6 Hz, 3H), 1.11(d, J 6.2 Hz, 3H), 1.14(d, J 6.2 Hz, 3H), 1.20-1.40(m, 1H), 1.53(ddd, J 2.2, 2.8, 14.0 Hz, 1H), 3.00(hept, J 6.4 Hz, 1H), 3.05(m, 1H), 3.97(dqd, J 1.8, 6.2, 10.7 Hz, 1H), 4.30(s, large, 2H). 13C NMR syn-1c d: 69.07, 51.68, 45.35, 45.03, 24.23, 24.01, 21.72, 21.13. 1H NMR anti-1c d: 1.10(d, J 6.2 Hz, 3H), 1.13(d, J 6.3 Hz, 3H), 1.18(d, J 6.3 Hz, 3H), 1.20(d, J 6.6 Hz, 3H), 1.20-1.40(m, 1H), 1.65(ddd, J 3.3, 8.1, 13.0 Hz, 1H), 3.00(hept, J 6.4 Hz, 1H), 3.26(dqd, J 3.8, 6.3, 6.7 Hz, 1H), 4.16(dqd, J 3.2, 5.9, 8.4 Hz, 1H), 4.30(s, large, 2H). 13C NMR anti-1c d: 65.03, 48.25, 45.77, 41.23, 23.51, 22.70, 22.05, 19.51.

1-Phenyl-3-(N-isopropylamino)-butan-1-ol, (1d). IR (neat) nmax/cm-1: 3270, 3200, 3040, 3020, 2980, 2880, 1470, 1380, 1330, 1100, 1070, 750, 700. MS m/z (%): 207(4.6), 192(2), 107(4.6), 105(6.9), 86(100), 77(20), 70(37). 1H NMR syn-1d d: 1.30-1.35(3d, 9H), 1.67(td, J 10.7, 14.5 Hz, 1H), 1.92(td, J 2.5, 14.5 Hz, 1H), 3.21(hept, J 6.2 Hz, 1H), 3.18-3.35(dqd, J 2.6, 5.8, 7.0 Hz, 1H), 4.47(s, large, 2H), 5.07(dd, J 1.5, 10.6 Hz, 1H), 7.37-7.60(m, 5H). 13C NMR syn-1d d: 145.55, 128.11, 126.79, 125.53, 75.08, 51.63, 46.38, 45.30, 24.39, 21.93, 21.83. 1H NMR anti-1d d: 1.00(d, J 6.3 Hz, 3H), 1.03(d, J 6.3 Hz, 3H), 1.07(d, J 6.3 Hz, 3H), 1.65(ABMX, J 3.9, 7.0, 14.0 Hz, 1H), 1.74(ABMX, J 3.6, 6.0, 15.0 Hz, 1H), 2.82(hept, J 6.3 Hz, 1H), 2.90(m, 1H), 3.82(s, large, 2H), 4.88(dd, J 3.7, 6.7 Hz, 1H), 7.06-7.30(m, 5H). 13C NMR anti-1d d: 150.09, 131.91, 130.34, 129.71, 75.19, 51.93, 49.63, 47.58, 27.83, 26.82, 24.70. Anal. Calc. for C13H21NO: C, 75.32; H, 10.21; N, 6.75%. Found: C, 75.10; H, 10.22; N, 6.26%.

4-(N-Pyrrolidinyl)-pentan-2-ol, (1e). IR (neat) nmax/cm-1: 3400, 2980, 2940, 2880, 2830, 1455, 1160, 1150. MS m/z (%): 157(4.2), 142(9), 96(100), 70(24), 56(20), 45(24). 1H NMR syn-1e d: 0.97(d, J 6.6 Hz, 3H), 1.13(d, J 6.2 Hz, 3H), 1.34(ddd, J 1.8, 3.6, 14.5 Hz, 1H), 1.52(td, J 10.9, 14.0 Hz, 1H), 1.70-1.80(AA'B2, 4H), 2.57-2.80(AA'B2, 4H), 3.17(dqd, J 3.3, 6.9, 10.5 Hz, 1H), 3.96(dqd, J 2.0, 6.2, 10.3 Hz, 1H), 6.24(s, large, 1H). 13C NMR syn-1e d: 69.08, 55.56, 46.70, 41.94, 23.67, 23.23, 12.43. 1H NMR anti-1e d: 1.21(d, J 6.2 Hz, 3H), 1.25(d, J 6.6 Hz, 3H), 1.55(ddd, J 2.6, 7.0, 14.0 Hz, 1H), 1.83(ddd, J 6.1, 10.6, 14.0 Hz, 1H), 1.94-2.20(m, 4H), 3.09(t, J 6.5 Hz, 4H), 3.50(sext, J 6.6 Hz, 1H), 3.90(dqd, J 1.8, 5.6, 11.0 Hz, 1H), 5.20(s, large, 1H). 13C NMR anti-1e d: 64.43, 57.62, 51.48, 41.05, 23.52, 23.28, 17.28.

General procedure to obtain tetrahydro-1,3-oxazines, (3). To a solution of g-amino alcohol (1, 1mmol) in diethyl ether (1 mL), was added a solution of 40% formaldehyde (0.1 mL). The reaction was stirred for 16-20 hours at room temperature. After this time, diethyl ether (approximatelly 5 mL) was added, and the solution was dried over MgSO4, filtered and concentrated in vacuo. The yield was quantitative.

3-Phenyl-4,6-dimethyl-tetrahydro-1,3-oxazine, (3a). IR (neat) nmax/cm-1: 2960, 2920, 1600, 1485, 1370, 1250, 1240, 1175, 1100, 1000, 700. MS m/z (%): 192(7), 191(50), 190(11), 176(58), 132(83), 120(50), 119(83), 118(22), 106(33), 105(83), 104(91), 91(14), 77(100). 1H NMR syn-3a d: 1.02(d, J 6.3 Hz, 3H), 1.26(d, J 6.3 Hz, 3H), 1.42(dt, J 11.1, 13.0 Hz, 1H), 1.57(dt, J 2.7, 13.5 Hz, 1H), 3.73(ddq, J 3.3, 6.3, 11.1 Hz, 1H), 3.68(ddq, J 2.7, 6.3, 12.3 Hz, 1H), 4.39(d, J 9.3 Hz, 1H), 4.73(d, J 9.3 Hz, 1H), 7.06-7.33(m, 5H). 13C NMR syn-3a d: 147.57, 129.02, 126.32, 124.83, 85.76, 73.43, 53.90, 40.03, 21.70, 20.04. 1H NMR anti-3a d: 1.16(d, J 6.3 Hz, 3H), 1.25(dt, J 2.0, 13.0 Hz, 1H), 1.41(d, J 6.9 Hz, 3H), 1.75(ddd, J 5.4, 12.0, 13.8 Hz, 1H), 3.95(m, 2H), 4.83(d, J 11.1 Hz, 1H), 4.98(d, J 11.4 Hz, 1H), 6.85(t, J 8.4 Hz, 1H), 7.03(d, J 7.8 Hz, 2H), 7.22(dd, J 7.2, 8.7 Hz, 2H). 13C NMR anti-3a d: 150.88, 129.35, 120.65, 119.08, 74.85, 68.14, 52.79, 35.76, 22.07, 17.07. Anal. Calc. for C12H17NO: C, 75.35; H, 8.96; N, 7.32%. Found: C, 74.80; H, 8.80; N, 7.37%.

3-Benzyl-4,6-dimethyl-tetrahydro-1,3-oxazine, (3b). IR (neat) nmax/cm-1: 2980, 2940, 1450, 1370, 1200, 1050, 740, 700. MS m/z (%): 206(3), 205(17), 204(8), 190(38), 146(14), 92(42), 91(100). 1H NMR syn-3b d: 1.13(d, J 6.0 Hz, 6H), 1.20-1.40(m, 2H), 2.95(m, 1H), 3.47(d, J 13.5 Hz, 1H), 3.47(m, 1H), 3.79(d, J 13.5 Hz, 1H), 3.92(d, J 10.2 Hz, 1H), 4.21(d, J 10.2 Hz, 1H), 7.20-7.40(AA'BBC, 5H). 13C NMR syn-3b d: 139.43, 128.39, 127.74, 126.32, 83.00, 72.79, 55.29, 48.92, 37.29, 21.74, 20.16. 1H NMR anti-3b d: 1.17(d, J 6.0 Hz, 3H), 1.25(d, J 6.0 Hz, 3H), 1.10-1.20(AXYZ, 1H), 1.88(AXYZ, 1H), 2.98(q, J 6.0 Hz, 1H), 3.81(dqd, 1H), 3.96(AA', 2H), 4.25(d, J 11.0 Hz, 1H), 4.65(d, J 11.0 Hz, 1H), 7.40-7.20(m, 5H). 13C NMR anti-3b d: 139.67, 128.50, 128.23, 126.89, 78.47, 67.80, 56.92, 49.28, 32.58, 22.20, 18.10. Anal. Calc. for C13H19NO: C, 76.06; H, 9.33; N, 6.82%. Found: C, 76.58; H, 9.23; N, 6.60%.

3-Isopropyl-4,6-dimethyl-tetrahydro-1,3-oxazine, (3c). MS m/z (%): 157(20), 142(100), 114(9), 100(14), 98(45), 56(81). 1H NMR syn-3c d: 0.92(d, J 6.6 Hz, 3H), 1.09(d, J 6.6 Hz, 6H), 1.15(d, J 6.9 Hz, 3H), 1.03-1.24(m, 2H), 2.75(dqd, J 3.0, 12.0 Hz, 1H), 3.22(hept, J 6.0 Hz, 1H), 3.39(dqd, J 3.0, 6.0, 12.0 Hz, 1H), 3.82(d, J 8.7 Hz, 1H), 4.49(d, J 9.0 Hz, 1H). 13C NMR syn-3c d: 78.47, 72.65, 52.55, 45.03, 41.38, 21.98, 21.68, 19.63, 17.18. 1H NMR anti-3c d: 1.02-1.24(m, 1H), 1.09(d, J 6.6 Hz, 6H), 1.27(d, J 6.3 Hz, 3H), 1.99(d, J 7.2 Hz, 3H), 1.62(m, 1H), 3.03(hept, J 6.0 Hz, 1H), 3.15(quint, J 6.0 Hz, 1H), 3.65(dqd, J 3.0, 6.0, 10.5 Hz, 1H), 4.36(AA', 2H). 13C NMR anti-3c d: 75.72, 67.20, 51.07, 46.92, 34.72, 22.81, 22.33, 21.82, 18.87.

6-Phenyl-3-isopropyl-4-methyl-tetrahydro-1,3-oxazine, (3d). IR (neat) nmax/cm-1: 2967, 2922, 2871, 1604, 1495, 1452, 1383, 1210, 1079. MS m/z (%): 220(4.3), 219(26.5), 205(10.6), 204(67.4), 174(5.6), 140(5.2). 1H NMR syn-3d d: 1.02(d, J 6.4 Hz, 3H), 1.20(d, J 6.5 Hz, 3H), 1.26(d, J 6.7 Hz, 3H), 1.69(AA'Y, 2H), 2.99(dqd, J 3.2, 6.4, 10.7 Hz, 1H), 3.36(hept, J 6.6 Hz, 1H), 4.45(dd, J 3.7, 10.6 Hz, 1H), 4.65(d, J 8.9 Hz, 1H), 4.84(d, J 8.9 Hz, 1H), 7.21-7.45(m, 5H). 13C NMR syn-3d d: 142.63, 128.42, 127.51, 125.96, 79.76, 79.68, 53.13, 45.67, 41.89, 21.96, 19.72, 16.93. 1H NMR anti-3d d: 1.14(d, J 6.4 Hz, 3H), 1.18(d, J 6.5 Hz, 3H), 1.34(d, J 7.2 Hz, 3H), 1.60(m, 1H), 1.93(ddd, J 6.0, 11.8, 13.4 Hz, 1H), 3.15(quint, J 6.6 Hz, 1H), 3.25(m, J 6.3 Hz, 1H), 4.59(AA', 2H), 4.60(dd, J 3.2, 9.7 Hz, 1H), 7.20(m, 5H). 13C NMR anti-3d d: 143.57, 127.91, 126.78, 125.38, 76.33, 73.57, 51.68, 47.31, 35.55, 22.86, 21.95, 18.80. Anal. Calc. for C14H21NO: C, 76.06; H, 9.33; N, 6.82%. Found: C, 76.58; H, 9.23; N, 6.60%.

3-Benzyl-4-methyl-6-terc-butyl-tetrahydro-1,3-oxazine, (3f). IR (neat) nmax/cm-1: 2956, 2869, 1188, 1105, 1027, 734, 698. MS m/z (%): 232(9), 190(12), 146(15), 118(4), 91(100). 1H NMR syn-3f d: 0.71(s, 9H), 1.02(d, J 6.6 Hz, 3H), 1.12(dt, J 2.8, 11.3 Hz, 1H), 1.29(AXYZ, 1H), 2.79(dqd, J 3.0, 6.6, 11.3 Hz, 1H), 2.87(dd, J 11.3, 2.6 Hz, 1H), 3.35(d, J 13.5 Hz, 1H), 3.65(d, J 13.5 Hz, 1H), 3.83(dd, J 0.9, 9.8 Hz, 1H), 4.20(d, J 9.8 Hz, 1H), 6.93-7.21(m, 5H). 13C NMR syn-3f d: 139.34, 128.74, 127.95, 126.56, 84.55, 83.34, 55.07, 48.26, 34.01, 29.41, 25.64, 20.44.

 

Acknowledgment

The authors thank the FINEP-Financiadora de Estudos e Projetos for financial support.

 

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15. Tramontini, M.; Synthesis 1982, 605.        [ Links ]

16. For a comprehensive review of uses of borohydrides in carboxylic acid media see: Gribble, G. W.; Nutaitis, C. F.; Org. Prep. Proc. Int. 1985, 17, 317;         [ Links ]Gribble, G. W.; Chem. Soc. Rev. 1998, 27, 395.        [ Links ]

17. Harris, M. I. N. C.; PhD. Thesis, Universidade Estadual de Campinas, Brazil, 1993; Braga, A. C. H.; Harris, M. I. N. C.; Br PI 9.502.467-0, 1995. (CA 128:243740).        [ Links ]

18. It is well known that the reaction of NaBH4 with neat carboxilic acids or solutions of carboxilic acids in nonprotic solvents leads to the formation of acyloxyborohydrides.16 In order to understand the real nature of the reducing agent, studies with sodium triacetoxyborohydride are in progress.

19. Barluenga, J.; Olano, B.; Fustero, S.; J. Org. Chem. 1985, 50, 4052.        [ Links ]

 

 

Received: March 9, 2004
Published on the web: September 28, 2004

 

 

* e-mail: herrera@iqm.unicamp.br
FAPESP helped in meeting the publication costs of this article.