Print version ISSN 0370-5943
Rev. latinoam. quím vol.38 no.2 Naucalpan de Juárez Aug. 2010
Amino compounds and benzimidazoles derived from trifluralin and flumetralin
P. S. M. Alvaresª, F. Vandresenª, I. T. A. Schuquelª, C.M.A. Oliveirab, C. C. Silvaª*
ª Departamento de Química, Universidade Estadual de Maringá, Av. Colombo 5790, 87020900. Maringá, PR, Brazil.
b Instituto de Química, Universidade Federal de Goiás Campus II, 74091970. Goiânia, GO, Brazil. * Corresponding author: firstname.lastname@example.org
Received March 2010.
Accepted July 2010.
In this work, we describe the synthesis of the amino compounds (5a) and (5b), and the benzimidazoles (6a), (6b) and (6c). These amino compounds and the benzimidazoles were obtained by catalytic hydrogenation of two widely used pesticides flumetralin (4a) and trifluralin (4b). The reactions described are simple to perform, and generate no chemical wastes. The structures of the compounds were determined through MS and NMR data.
Keywords: Trifluralin, flumetralin, benzimidazoles, catalytic hydrogenation.
En este trabajo se describe la síntesis de los compuestos amino (5a) y (5b), y los benzimidazoles (6a), (6b) y (6c). Estos compuestos fueron obtenidos por hidrogenación catalítica de dos plaguicidas ampliamente utilizados flumetralin (4a) y trifluralina (4b). Las reacciones descritas son simples de realizar, y no generan desechos químicos. Las estructuras de los compuestos se determinaron através de MS y los datos de RMN.
Amino compounds account for a substantial fraction of the world market of pharmaceuticals and pesticides. Commercially important pesticides that are amino compounds include chloramben, dicloran, and fluroxypyr (Feuer, 1970; Schach et al., 1996). Benzimidazoles are recognised as a most interesting class of heterocyclic compounds. Their applications include their widespread use as anthelmentic drugs in human and veterinary medicine. Examples include fenbendazole, thiabendazole, albendazole, and oxibendazole (Balizs, 1999; Ruyck et al., 2000).
The importance of amino compounds in the world market for chemicals, in particular pesticides and pharmaceuticals, is driving the constant search for better means to their production, where 'better' must now take account of environmental concerns. Benzimidazoles frequently show biological activity, and the synthesis of new members of this class may lead to the development of commercial products.
Various methods exist for the production of amino compounds from the corresponding nitro compounds; these include selective reduction by sulphite (Nickson, 1986), sodium borohydridetransition metal salt system (Satoh et al., 1969), activated metal catalysis (Pyo et al., 1995) and catalytic hydrogenation (Downing et al., 1997). The latter has attracted the attention of industry, because the transformation can be performed without the generation of wastes, and a number of patents have been issued for the reduction of aromatic nitro compounds (Nason, 1970; Boudakian, 1986; Baasner et al., 1986).
Benzimidazoles can also be obtained starting from nitro compounds. Andersch and Sickler have reported the synthesis of benzimidazoles containing hydrophilic chiral chains, which possess anthelmintic activity (Andersch and Sickler, 1999). In their method, catalytic hydrogenation was followed by treatment with acid, which lead to the undesirable accumulation of acidic wastes.
In the present work, we report the synthesis ofthe amino compounds N2(2chloro6fluorobenzyl)N2ethyl5(trifluoromethyl)benzene1,2,3triamine (5a) and N2, N2dipropyl5(trifluoromethyl)benzene 1,2,3triamine (5b), and the benzimidazoles 2(2chloro6fluorophenyl)1ethyl5(trifluoromethyl)1Hbenzimidazol7amine (6a), 1(2chloro6fluorobenzyl)2methyl5(trifluoromethyl)1Hbenzimidazole7amine (6b) and 2ethyl 1propyl5(trifluoromethyl)1Hbenzimidazol7amine (6c). Syntheses of these compounds have not previously been reported in the literature. The structures of the synthesised compounds were determined on the basis of their MS, IR and NMR (1H and 13C) spectral data.
MATERIALS AND METHODS
The melting points were determined on equipment Microquímica, model MQAPF301. 1H and 13C NMR spectra were recorded using a Varian Gemini 2000 spectrometer (operating at 300.06 MHz for 1H and 75.45 MHz for 13C). Low resolution mass spectra were obtained with a HP 5972 MSD mass spectrometer, with electron impact (70 eV) ionisation. Samples could be introduced directly into the source, or via a gas chromatograph. The GC instrument was a HP 5890, equipped with a HP 1 capillary column. The carrier gas was helium, with a flow rate of 1 mL/min. Injected volumes were of the order of 0.1 mL, with a split ratio of 100:1. The column programme was: 50°C (4 min) followed by a 30°C/min ramp to a maximum temperature of230°C, which was then held for 45 min. The temperatures of the injector and of the detector were 240°C and 280°C, respectively. The high resolution mass spectra were obtained with a VG Autospec spectrometer, with 70 eV electron impact ionisation. Separations by column chromatography were performed using type 60 G silica gel (0.063 0.200 mm).
Nitration and amination reactions were carried out in a jacketed 500 mL glass reactor (FGG). The reactor was equipped with a temperature sensor, together with facilities for heating, cooling, and mechanical shaking and stirring. The catalytic hydrogenations were performed in a jacketed 500 mL stainless steel reactor (Buchi type 316 L). This reactor was fitted with temperature and pressure monitors. It was equipped with facilities for heating and mechanical shaking, together with an antiexplosion system.
A mixture of concentrated nitric acid (95.5 g, 1.5 mol) and concentrated sulphuric acid (100.0 g, 1.0 mol) was slowly added to 1chloro4(trifluoromethyl)benzene (1) (182.3 g, 1.0 mol), with constant stirring and maintaining a temperature of 80°C. Once addition of the reagents was completed, constant stirring of the reaction mixture was continued and the temperature was held at 80°C for a period of 90 minutes. At the end of this period, the temperature was decreased to 60°C, water (41.4 g, 2.3 mol) was then added to the reaction mixture, and the reaction vessel and contents were allowed to stand, while the mixture separated into an organic phase and an acid phase. The organic phase was concentrated with a rotary evaporator. Yellow oil. Yield: 91.3%. 1H NMR (CDCl3): δ 7.76 (d, H6, 1H, J=8.4 Hz), 7.83 (dd, 1H, 5H, J=8.4 and 1.8 Hz), 8.16 (d, 1H, H3, J=1.8 Hz); 13C NMR (CDCl3): δ 122.8 (q, CF3, J=272.7 Hz), 123.3 (q, C3, J=3.4 Hz), 130.1 (q, C5, J=3.4 Hz), 130.8 (q, C4, J=35.5 Hz), 131.5 (s, C1), 133.4 (s, C6), 148.4 (s, C2). MS (70 eV, electron impact): m/z 225 (molecular ion).
2chloro1,3dinitro5(trifluormethyl) benzene (3).
A mixture of concentrated nitric acid (76.4 g, 1.2 mol) and concentrated sulphuric acid containing 23% SO3 (264.9g, 2.0 mol) was added slowly to 1chloro2nitro4(trifluoromethyl)benzene (2) (227.8 g, 1.0 mol), with constant stirring and maintaining a temperature of 70°C. Over a period of 6 hours the temperature was gradually raised to 140°C, with constant stirring. The reaction mixture was then maintained at 140°C, with constant stirring, for 2 hours. The temperature of the reaction mixture was lowered to 80°C, and it was then allowed to stand and separate into an organic phase and an acid phase. The organic phase was concentrated with a rotary evaporator. Yellow solid. Yield: 82.2%. 1H NMR (CDCl3): δ 8.26 (s, 2H, H4/H6); 13C NMR (CDCl3): δ 121.5 (q, CF3, J=274.1 Hz), 124.8 (s, C2), 125.0 (s, C4/C6), 131.3 (q, C5, J=36.7 Hz), 150.0 (s, C1/C3). MS (70 eV, electron impact): m/z 270 (molecular ion).
N2ethyl2chloro6fluorobenzylamine (60.6 g, 0.32 mol) and 50% sodium hydroxide (21.4 g, 0.32 mol) were added simultaneously, with constant stirring, to 2chloro1,3dintro5(trifluoromethyl)benzene (3) (72.3 g, 0.26 mol). Following the addition of the reagents, the temperature was adjusted to 115°C. The reaction mixture was maintained at this temperature, with stirring, for a period of 2 hours and 30 minutes. At the end of this period water (50 mL) was added, the mixture was allowed to stand and separate into an organic phase and an aqueous phase. Yellow solid. Yield: 78.9%. 1H NMR (CDCl3): δ 1.28 (t, 3H, H2'', J=6.9 Hz), 2.97 (q, 2H, H1'', J=6.9 Hz), 4.34 (d, 2H, H7', J=1.2 Hz), 7.02 (qd, 1H, H5', J=9.3 and 0.9 Hz), 7.19 (dd, 1H, H3', J=8.1 and 0.9 Hz), 7.27 (td, 1H, H4', J=8.1 and 5.7 Hz), 8.16 (s, 2H, H3/H5). 13C NMR (CDCl3): δ 12.9 (s, C2''), 46.7 (s, C1"), 46.8 (d, C7, J=2.3 Hz), 114.2 (d, C5', J=22.9 Hz), 121.4 (d, C1', J=18.3 Hz), 122.3 (q, CF3, J=272.5 Hz), 123.0 (q, C4, J=35.4 Hz), 125.7 (d, C3', J=3.5 Hz), 127.0 (q, C3/C5, J=4.6 Hz), 130.4 (d, C4', J=10.2 Hz), 136.3 (d, C2', J=5.7 Hz), 141.8 (s, C1), 146.1 (s, C2/C6), 162.3 (d, C6', J=250.7 Hz). MS (70 eV, electron impact): m/z 421 (molecular ion).
N2[2,6dinitro4(trifluoromethyl)phenyl]N2, N2dipropylamine (4b)
Dipropylamine (34.2 g, 0.34 mol) and 20% sodium hydroxide (46.2 mL, 0.25 mol) were added simultaneously, with constant stirring, to 2chloro1,3dinitro5(trifluoromethyl)benzene (3) (77.6 g, 0.28 mol). Following the addition of the reagents, the temperature was adjusted to 60°C. The reaction mixture was maintained at this temperature, with stirring, for a period of 2 hours and 30 minutes. At the end of this period water (180 mL) was added, the mixture was allowed to stand and separate into an organic phase and an aqueous phase. Maintaining the temperature at 60°C, the organic phase was diluted with ethanol (250.0 mL). Red solid. Yield: 74.6%. 1H NMR (CDCl3): δ 0.88 (t, 6H, H3', J=7.5 Hz), 1.62 (m, 4H, H2'), 2.98 (t, 4H, H1', J=7.5 Hz), 8.07 (s, 2H, H3/H5). 13C NMR (CDCl3): δ 11.0 (s, C3'), 20.6 (s, C2'), 54.0 (s, C1'), 118.7 (q, CF3, J=272.5 Hz), 121.4 (q, C4, J=36.7 Hz), 126.9 (q, C3/C5, J=3.5 Hz), 141.4 (s, C1), 145.4 (s, C2/C6). MS (70 eV, electron impact): m/z 335 (molecular ion).
N2(2chloro6'fluorobenzyl)N2ethyl5(trifluoromethyl)benzene1,2,3triamine (5a), 1(2chloro6fluorobenzyl)2methyl5(trifluoromethyl) 1Hbenzimidazol7amine (6a) and 2(2chloro6fluorophenyl)1 ethyl5(trifluoromethyl) 1Hbenzimidazol7amine (6b).
Methanol (200 mL) and 10% platinum on charcoal (9.75 g, 0.5 mmol) were added to (4a) (43.9 g, 0.10 mol). The system was purged with nitrogen gas, and the temperature was raised to 80°C. The reaction vessel was pressurised with hydrogen (5 bar), and reaction was allowed to occur for 5 hours at 80°C under a constant pressure of 5 bar of hydrogen, with constant shaking. Following depressurisation, the catalyst was recovered by filtration, and the solvent was evaporated. A portion (2.91 g) of the raw products from the reaction was chromatographed with gradient elution (hexane/ethyl acetate mixture, increasing polarity) on a silica gel column.
The amino compound (5a) (410.1 mg, 58.3%) was obtained as a red solid upon eluting the column with hexane/ethyl acetate 20%, m.p. = 120.0121.9 ºC. MS (70 eV, electron impact, high resolution): m/z 361.08978 (molecular ion, 30.1 %), 332.04680 (19.5 %), 218.08351 (100 %). 1H and 13C NMR, see Table 1.
Benzimidazole (6a) (46.3 mg, 6.5%) was obtained as a red solid upon eluting the column with hexane/ethyl acetate 30%, m.p. = 179.1182.2. MS (70 eV, electron impact, high resolution): m/z 357.07162 (molecular ion, 100 %), 214.05179 (35.9 %), 143.00045 (81.0 %). NMR, see Table 2 (1H) and Table 3 (13C).
Benzimidazole (6b) (116.1 mg, 16.3%) was obtained as a red solid upon eluting the column with hexane/ethyl acetate 25%, m.p = 80.381.6. MS (70 eV, electron impact, high resolution): m/z 357.05463 (molecular ion, 100 %), 342.0461 (33.6 %). NMR, see Table 2 (1H) and Table 3 (13C).
N ,Ndipropyl5(trifluoromethyl)benzene1,2,3triamine (5b) and 2ethyl1propyl5(trifluoromethyl)1Hbenzimidazol7amine (6c).
Methanol (200 mL) and 10% platinum on charcoal (0.98 g, 0.05 mmol) were added to (4b) (33.8 g, 0.10 mol). The system was purged with nitrogen gas, and the temperature was raised to 80°C. The reaction vessel was pressurised with hydrogen (3 bar), and reaction was allowed to occur for 8 hours at 80°C under a constant pressure of 3 bar of hydrogen, with constant shaking. Following depressurisation, the catalyst was recovered by filtration, and the solvent was evaporated. A portion (2.12 g) of the raw products from the reaction was chromatographed with gradient elution (hexane/ethyl acetate mixture, increasing polarity) on a silica gel column.
The amino compound (5b) (575.3 mg, 66.3%) was obtained as a red solid upon elution of the column with hexane/ethyl acetate 35%, m.p. = 60.161.0. MS (70 eV, electron impact, high resolution): m/z 275.13711 (molecular ion, 37.0 %), 246.09874 (100 %), 202 (22.2 %). 1H and 13C NMR, see Table 1.
Benzimidazole (6c) (256.0 mg, 29.1%) was obtained as a red solid upon elution of the column with hexane/ethyl acetate 40%. m.p.= 159.5160.8. MS (70 eV, electron impact): m/z 271 (molecular ion, 89.9 % ), 242 (100 %), 229 (75.3 %). NMR, see Table 2 (1H) and Table 3 (13C).
RESULTS AND DISCUSSION
In this work the amino compounds 5a and 5b and the benzimidazoles 6a6c were prepared from the corresponding nitro compounds 4a and 4b through hydrogenation using a supported platinum catalyst, as shown in Figure 1. Flumetralin (4a) and trifluralin (4b) were obtained through amination reactions of 3 (Kwiatkowski, et al. 1998; Kwiatkowski, et al. 2000) which was itself prepared by stepwise nitration of compound 1. The nitration of compound 2 required the use of a mixture of concentrated nitric and sulphuric acids, to which SO3 was added.
The mass spectra of the amino compounds 5a and 5b showed the expected molecular ion peaks (M+•). The formation of these compounds was confirmed through the !H and 13C NMR spectra. The presence of an aromatic ring bearing two NH2 groups, a trifluoromethyl group and an amine group was revealed by the characteristic shielding of hydrogens H4/H6, and of carbons C4/C6 and C2. Assignments were assisted by comparisons of the NMR spectra of 5a and 5b with those of nitro compounds 4a and 4b, which contain NO2 groups in place of the two NH2 groups. The NMR spectra of 5a showed signals characteristic of a second aromatic ring bearing both a chlorine and a fluorine atom, while the spectra of 5b demonstrated the presence of two npropyl groups. For both molecules splittings of signals arising from 13C19F coupling through one, two, three and four bonds were identified, and found to be consistent with the structures. Through an analysis of the 1H and 13C NMR spectra of 5a and 5b, it was possible to assign chemical shifts to each of the hydrogens and carbons in these molecules. The assignments are summarised in Table 1.
The mass spectra of the benzimidazoles 6a6c showed the expected molecular ion peaks (M+*). Comparisons of the NMR spectra of 6a and 6b with 5a, and of 6c with 5b assisted in demonstrating the presence of the benzimidazole system in 6a6c. A key structural difference between the amines and the benzimidazoles is the formal conversion of a CH2 group attached to N in the amine to a C bearing no H atoms in the benzimidazole (carbon 2). Compared to the 13C NMR spectra of 5a and 5b, the spectra of each of the benzimidazoles showed the anticipated loss of a single CH2 signal and the appearance of a signal due to a carbon atom which did not bear hydrogen atoms; these new signals with δc 154.4, 146.9 and 159.6 were attributed to carbon C2 in 6a, 6b and 6c, respectively. The loss of the hydrogen atoms from the carbon which is incorporated into the heterocyclic ring of the benzimidazole was evident in the 1H NMR spectra. There were characteristic changes in the shielding observed for carbons 3a and 7a, which are located at the junction of the two rings, compared to the shielding of the related carbons in 5a and 5b. The !H NMR spectra demonstrated the inequivalence of protons H4 and H6 in the compounds 6a, 6b and 6c, indicating that in these molecules the C6 aromatic ring bearing the trifluoromethyl group is no longer symmetric. Other features of the structures of 6a, 6b, and 6c which were readily confirmed by the identification of characteristic signals in the !H and 13C NMR spectra were: an amino group and a trifluoromethyl group on the C6 ring of the benzimidazole system (common to 6a, 6b, and 6c), a C6 aromatic ring bearing one chlorine and one fluorine atom (6a and 6b), and alkyl chains (6a, 6b, and 6c). The observation of coupling to F atoms extending over one, two, three and four bonds allowed the bond connectivities proposed in the structures for 6a, 6b, and 6c to be confirmed. Detailed assignments of the 1H and 13C NMR spectra, giving the chemical shifts for each hydrogen and carbon atom are given in Tables 2 and 3.
The hypothesis that can explain the formation of benzimidazoles 6a6c is based on a degradation process, with oxidation of methylene group (NCH2) in 5a and 5b via radical mechanism catalyzed by platinum, leading to the closure of the ring with subsequent aromatization.
Concluded, based on the data presented in this paper that the synthetic methodology of amino compounds and benzimidazoles by catalytic hydrogenation of pesticides trifluralin and flumetralin have high efficiency, demonstrating that this methodology is interesting to obtain the cited products.
Paulo S. M. Alvares pleases Marcos Souza Lobo and Paulo Sérgio Berg the encouragement, friendship and made available to perform the tests in their departments.
Andersch, J., Sicker, D. (1999) Reductive cyclization of carbohydrate 2nitrophenylhydrazones to chiral functionalized 1,2,4benzotriazines and benzimidazoles. Journal of Heterocyclic Chemistry 36: 589594. [ Links ]
Baasner, B., Ziemann, H., Klauke, E., (1986) Process for the preparation of partially hydrogenated derivatives of 2nitro1,1,1trifluoroalkanes. US Patent 4,622,427. [ Links ]
Balizs, G (1999) Determination of benzimidazole residues using liquid chromatography and tandem mass spectrometry Journal of Chromatography B 727: 167177. [ Links ]
Boudakian, M.M. (1986) Process for producing metaaminobenzotrifluoride. US Patent 4,582,935. [ Links ]
Downing, R.S., Kunkeler, P.J., van Bekkum, H. (1997) Catalytic syntheses of aromatic amines. Catalysis Today 37: 121136 [ Links ]
Feuer, H.E., (1970) Chemistry of nitro and nitroso groups. Part2. New York; Ed. Interscience. [ Links ]
Kwiatkowski, S., Mobley, S.G., Pupek, K., Golinski, M.J., Smith, P.D. (2000) Method of manufacturing flumetralin. US Patent 6,137,009. [ Links ]
Kwiatkowski, S., Pupek, K., Golinski, M.J., Smith, P.D., Lawrence. L.J. (1998) Process for preparing trifluralin. US Patent 5,728,881. [ Links ]
Nason, B.R. (1970) Hydrogenation of dinitrotoluene to tolylene diamine. US Patent 3,517,063. [ Links ]
Nickson, T.E. (1986) A unique application of the sulfide reducction useful for the preparation of isomerically pure aromatic nitro compounds and anilines. Journal of Organic Chemistry 51: 39033904 . [ Links ]
Pyo, S.H., Han, B.H. (1995) Reduction of nitroarenes by activated metals. Bulletin of the Korean Chemical Society 16: 181183. [ Links ]
Ruyck, H., Renterghem, R., Redder, H., Bradander, D. (2000) Determination of anthelmintic residues in milk by high performance liquid chromatography. Food Control 11 : 165173. [ Links ]
Satoh, T., Suzuki, S., Suzuki, Y., Miyaji, Y., Imai, Z. (1969) Reduction of organic compounds with sodium borohydridetransition metal salt systems: Reduction of organic nitrile, nitro and amide compounds to prymary amines. Tetrahedron Letters 10: 45554558. [ Links ]
Schach, T., Papenfuhs, T., (1996) Process for preparing fluoroanilines. US Patent 5,498,794. [ Links ]