J. Chil. Chem. Soc., 50, N° 3 (2005), págs: 559-563

VLADÍMIR V. KOUZNETSOV,* JUAN MANUEL URBINA G., ELENA E. STASHENKO*

Laboratorio de Química Orgánica y Biomolecular, Laboratorio de Cromatografía, CIBIMOL, Escuela de Química, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia. Fax: (5776)- 45 67 37. E-mail: kouznet@uis.edu.co; elena@tucan.uis.edu.co

ABSTRACT

The easy N-functionalization of dihydrocarvone was achieved through the preparation of its imine derivatives. Secondary amines were obtained by the reduction and allylation of ketimines derived from dihydrocarvone. It was established that these amines represent mixtures of four stereoisomers which were analyzed by capillary gas chromatographic-mass spectrometry (GC-MS) (EI, 70 eV). Total energy and heat of formation for diastereoisomeric amines were calculated using AM1 and PM3 semi-empiric methods.

INTRODUCTION

Monoterpenoids from the menthane series occupy an important place in organic and natural product chemistry. They exhibit a broad range of biological effects and are also important as industrial raw materials. Dihydrocarvone and carvone are used widely as starting blocks in the synthesis of various natural products, for example, sesquiterpenes [1-3]. On the other hand, imine derivatives of monoterpenoids, aza-analogues of carbonyl compounds, exhibit diverse biological activities and are useful intermediates in organic synthesis. The imines derived from cyclic ketones are particularly important [4]. In the course of our research program aimed at the preparation of bioactive nitrogen-containing heterocycles [5-7], we addressed to the chemistry of 1-N-arylimino-5-isopropenyl-2-methylcyclohexanes, which are sources of secondary biological active aminocyclohexanes. This class possesses considerable biological potential [8,9]. In this article, we describe the preparation of new aminomonoterpene derivatives obtained by means of the reduction or allylation of C=N imine double bond and some stereochemical peculiarities.

EXPERIMENTAL

All reagents were purchased from Aldrich, commercial grade. The purity of the products and the composition of the reaction mixtures were monitored by thin layer chromatography over Alufol 60 and Silufol UV254 0.25 mm-thick chromatoplates. Product isolation and purification were performed by column chromatography over alumina (Brockmann activity grade II), using ethyl acetate-heptane mixtures as eluents. The IR spectra were measured with a Perkin Elmer 599B FT-IR spectrophotometer in KBr. The 1H NMR spectra were acquired on Jeol EX-90, Bruker AC-200, and Bruker Advance DPX-300 spectrometers using CDCl3 as a solvent and TMS as internal reference. The mass spectra were obtained on an HP 5890A series II gas chromatograph interfaced to an HP 5972 mass selective detector that used electron impact ionization (70 eV).

Data of GC-MS (70 eV) for commercial (+)-dihydrocarvone (Aldrich): trans isomer (77.962%) tR= 20.32 min., m/z: 152, 137, 123, 109, 95, 81, 67, 55, 41; cis isomer (22.038%) tR= 20.50 min., m/z: 152, 137, 123, 109, 95, 81, 67, 55, 41.

General method for the preparation of imines (2a-d)

(+)-Dihydrocarvone 1 (10.0 g, 66 mmol) and arylamines (64 mmol) were dissolved in 100 ml anhydrous toluene (benzene) which contained a catalytic amount of acetic acid. The mixture was refluxed (8-10 hours) in a Dean-Stark setup until the theoretically expected volume of water for a 100% yield was collected (1.1 ml). Toluene (benzene) was separated by simple distillation and the residue was distilled at reduced pressure.

Data for N-((5S)-5-isopropenyl-2-methylcyclohexyliden)-N-phenylamine (2a)

Bp 112-113°C/10-3 mm Hg, yield (58%). Anal. calcd. for C16H21N: N, 6.16. Found: N, 6.24. M+ 227. 1H NMR (200 MHz): d 7.27 (t, 2H, m-H-Ph), 7.05 (t, 1H, p-H-Ph), 6.75 (d, 2H, o-H-Ph), 4.75 (s, CH2=), 1.65 (s, CH3-C=), 1.44 (d, CH3-C). 13C NMR, (75.5 MHz): d 175.6, 151.2; 128.6, 122.6, 119.4; 109.1; 47.13, 41.2, 36.2, 35.8, 31.2, 20.3, 16.5. IR: 3077 (=CH2), 1658 (C=N), 892 (C=C) cm-1.

Data for N-benzyl-N-((5S)-5-isopropenyl-2-methylcyclohexyliden)amine (2b) Bp 164-166°C /9 mm Hg, yield (32%). Anal. calcd. for C17H23N: N, 5.80. Found: N, 6.05. M+ 241. IR: 3085 (=CH2), 1660 (C=N),

Data for N-(2-chlorobenzyl)-N-((5S)-5-isopropenyl-2-methylcyclohexyliden) amine (2c)

Bp 114-147°C /9 mm Hg, yield (42%). Anal. calcd. for C17H22ClN: N, 5.08. Found: N, 5.30. M+ 276. IR: 3070 (=CH2), 1662 (C=N), 892 (C=C) cm-1. After isolation, this compound was dissolved immediately in anhydrous methanol in order to perform the reduction step.

Data for N-(4-chlorobenzyl)-N-((5S)-5-isopropenyl-2-methylcyclohexyliden) amine (2d)

Bp 91-93°C /9 mm Hg, yield (51%). Anal. calcd. for C17H22NCl: N, 5.08. Found: N, 5.22. M+ 276. IR: 3082 (=CH2), 1661 (C=N), 892 (C=C) cm-1. After isolation, this compound was dissolved immediately in anhydrous methanol in order to perform the reduction step.

General method for the preparation of N-arylaminocyclohexanes (3a,b)

Sodium borohydride (6.9 g, 0.18 mol) was slowly added in several portions to a solution of 8.5 g (0.037 mol) of the imine 2a or 2b in 120 ml dry methanol. The yellowish reaction mixture was treated with a chlorohydric acid (15 ml). Methanol was evaporated, the reaction mixture was made basic with a sodium hydroxide 3N-solution (20 ml) and the organic products were extracted with dichloromethane (3 x 50 ml). The organic layer was dried on anhydrous sodium sulfate and was filtered. After evaporation of solvent, the residue was distilled at reduced pressure.

Data for N-((5S)-5-isopropenyl-2-methylcyclohexyl)-N-phenylamine (3a)

Bp 120-121°C/10-3 mm Hg, yield (91%). Anal. calcd. for C16H23N: C, 83.79; H, 10.11; N, 6.11. Found: C, 83.64; H, 9.80; N, 6.23. M+ 229. GC-MS: 4 isomers. 1H NMR (200 MHz): d 7.38-7.25 (m, 2H, m-H-Ph), 6.90-6.65 (m, 3H, o,p-H-Ph), 4.66 (s, CH2=), 1.67 (s, CH3-C=), 0.99 (d, 2-CH3). 13C NMR (75.5 MHz): d 149.7, 129.2, 116.8, 113.1, 108.4, 52.6, 38.9, 35.4, 31.7, 29.2, 21.2, 19.1, 11.4. IR: 3421 (NH), 3083 (=CH2), 1645 (C=C) cm-1.

Data for N-benzyl-N-((5S)-5-isopropenyl-2-methylcyclohexyl)amine (3b)

Oil, yield (79%). Anal. calcd. for C17H25N: C, 83.89; H, 10.35; N, 5.75. Found: C, 83.68; H, 10.11; N, 5.58. M+ 243. GC-MS: 4 isomers. 1H NMR (90 MHz): d 7.60-7.20 (m, 5H, Ph), 4.69 (s, CH2=), 3.78 (s, -CH2-Ph), 1.72 (s, CH3-C=), 0.96 (d, 2-CH3). IR: 3317 (NH), 3084 (=CH2), 1644 (C=C) cm-1.

General method for the preparation of 1-allyl-1-N-arylaminocyclohexanes (4a-d)

The cyclohexylidenamines 2a-d (0.012 mol) dissolved in 20 ml of anhydrous ether were added slowly to a magnetically stirred suspension of allyl magnesium bromide prepared from allyl bromide (4.61 g, 0.038 mol) and magnesium (1.85 g, 0.076 mol) in 100 ml of ether, at room temperature. The mixture was heated to 30-35C during 4 hours, cooled to 0C and treated with a concentrated ammonium hydroxide solution (pH 8-9). Two liquid-liquid extractions with ether (50 ml each) were performed. The organic layers were combined and dried over anhydrous magnesium sulfate. The residue from ether evaporation was purified by column chromatography over silica to give products 4a-d as oils.

Data for N-((5S)-1-allyl-5-isopropenyl-2-methylcyclohexyl)-N -phenylamine (4a)

Bp 74-77°C/9 mm Hg, yield (55%). Anal. calcd. for C19H27N: C, 84.70; H, 10.10; N, 5.20. Found: C, 84.53; H, 10.37; N 5.05. M+ 269. GC-MS: 4 isomers. 1H NMR (300 MHz): d 7.47 ­ 7.25 (m, Ph), 6.02 (m, allyl =CH), 5.15 (m, allyl CH2=), 4.67 (m, CH2=), 3.77 (m, allyl CH2), 1.68 (s, CH3-C=), 1.07 (d, 2-CH3). 13C NMR (75.5 MHz): d 152.2, 147.2, 139.1, 128.3, 126.5, 121.4, 117.0, 108.0, 56.3, 39.5, 38.1, 34.5, 31.8, 29.0, 21.0. IR: 3420 (NH), 3074 (=CH2), 1642 (C=C) cm-1.

Data for N-((5S)-1-allyl-5-isopropenyl-2-methylcyclohexyl)-N -benzylamine (4b)

Bp 160-162°C/10 mm Hg, yield (44%). Anal. calcd. for C20H29N: C, 84.75; H, 10.31; N 4.94. Found: C, 84.66; H, 10.57; N 4.68. M+ 283. GC-MS: 4 isomers. 1H NMR (300 MHz): d 7.47-7.10 (m, Ph), 5.91 (m, allyl =CH), 5.10 (m, allyl CH2=), 4.68 (s, CH2=), 3.69 (m, CH2-Ph and allyl CH2 ), 1.72 (s, CH3-C=), 0.92 (s, 2-CH3). 13C NMR (75.5 MHz): d 150.4, 141.1, 134.7, 128.3, 128.1, 126.6, 117.6, 108.1, 57.2, 41.3, 38.7, 36.6, 36.5, 31.4, 31.2, 21.1, 14.8. IR: 3328 (NH), 3068 (=CH2), 1644 (C=C) cm-1.

Data for N-((5S)-1-allyl-5-isopropenyl-2-methylcyclohexyl)-N -(2-chlorobenzyl) amine (4c)

Bp 115-118°C/9 mm Hg, yield (42%). Anal. calcd. for C20H28ClN: C, 75.56; H, 8.88; N 4.41. Found: C, 75.30; H, 9.04; N 4.11. M+ 317. GC-MS: 4 isomers. 1H NMR (300 MHz): d 7.53-7.10 (m, Ph), 5.92 (m, allyl =CH), 5.08 (m, allyl CH2=), 4.68 (s, CH2=), 3.77 (m, CH2-Ph), 1.72 (s, CH3-C=), 0.91 (d, 2-CH3). 13C NMR (75.5 MHz): d 150.3, 139.2, 134.6, 133.6, 130.0, 129.2, 127.8, 126.8, 117.7, 108.1, 57.4, 42.4, 41.3, 38.5, 36.7, 36.5, 31.3, 31.2, 21.0, 14.8. IR: 3326 (NH), 3072 (=CH2), 1642 (C=C) cm-1.

Data for N-((5S)-1-allyl-5-isopropenyl-2-methylcyclohexyl)-N -(4-chlorobenzyl) amine (4e)

Bp 100-102°C/9 mm Hg, yield (38%). Anal. calcd. for C20H28ClN: C, 75.56; H, 8.88; N 4.41. Found: C, 75.23; H, 4.68; N 4.17. M+ 317. GC-MS: 4 isomers. 1H NMR (300 MHz): d 7.32-7.17 (m, 4H, Ph), 5.89 (m, allyl =CH), 5.09 (m, allyl CH2=), 4.68 (s, CH2=), 3.66 (m, CH2-Ph), 1.72 (s, CH3-C=), 0.91 (d, 2-CH3). 13C NMR (75.5 MHz): d 150.3, 140.4, 134.6, 132.2, 129.4, 128.3, 117.7, 108.1, 57.2, 44.3, 41.2, 38.7, 36.7, 36.5, 31.3, 31.1, 21.0, 14.7. IR: 3326 (NH), 3074 (=CH2), 1641 (C=C) cm-1.

RESULTS AND DISCUSSION

The N-functionalization of dihydrocarvone 1 was achieved through its condensation with aniline and different benzylamines in toluene or benzene. Ketimines 2a-d were obtained in 32-58% yields (Scheme 1). The IR spectra of the imines exhibit an intense absorption at 1658-1660 cm-1 that corresponds to C=N stretching. No absorptions related to the starting materials were observed in these spectra. The 13C NMR spectrum of imine 2a shows a resonance at 175.6 ppm, which we assigned to the imine carbon. The commercial S-(+)-dihydrocarvone used as starting material was a mixture of the cis and trans isomers in which the trans-ee isomer was predominant. Therefore, the imines were obtained as mixtures of their geometric isomers, as evidenced by 1H and 13C NMR spectra.

Scheme 1

The reduction of the imine bond used sodium borohydride in anhydrous methanol at room temperature was made following a known procedure [10,11]. Amines 3a,b were isolated by vacuum distillation in 79-91% yields. The nucleophilic addition of organometallic compounds to the C=N bond of the imines is well known method to form the new C-C bond [12]. This interaction between allylmagnesium bromide and ketimines 2a-d conducted to the corresponding gem-allyl-arylaminocyclohexanes 4a-d, which were obtained in 38-50 % yields (Scheme 2).

Scheme 2

It is a well known fact, that the hydride anion or Grignard reagents attacks cyclic systems both from the axial and the equatorial directions, giving rise to two products via Felkin transition states for a nucleophile to a cyclohexanone derivatives [13,14]. Moreover, it was established that for cyclic ketimines derived from substituted cyclohexanone [15] and g-piperidone [16] equatorial attack of organometallic reagents was predominant which leads to axial amines. Recently, we demonstrated that the reduction of the imine C=N bond of ketimines based on 2-allylcyclohexanone leads to the exclusively equatorial amines [17]. With this background, we studied the obtained amines 3,4 by GC-MS method that indicates to the formation of axial and equatorial amines mixture. Since the imines were mixtures of two stereoisomers, we expected their reduction and allylation products to consist of a mixture of four geometric isomers with the following substituent disposition: "1e,2e,5e"-, "1a,2e,5e"-, "1a,2e,5e"-, "1e,2a,5e"-, and "1a,2a,5e"- (Scheme 3). This was in fact observed for amines 3 and 4 according to a gas chromatogram obtained using an HP-5MS (30 m) capillary column and a mass selective detector.

Scheme 3

The structure of the diastereomeric amines 3a,b and 4a-d was determined by spectroscopic and spectrometric methods. Their IR spectra exhibit an N-H stretching absorption in the region of 3326-3347 cm-1. In the 1H NMR spectra of aminocyclohexanes 3 the olefinic protons are responsible for signals between 4.6 and 4.7 ppm, the methyl group from the isopropenylic fragment gives rise to a singlet at 1.65-1.72 ppm, and the methyl group directly bonded to the cyclohexane ring originates a doublet at 0.99-1.05 ppm. The 1H nmr spectra of gem-allyl-arylaminocyclohexanes 4 displayed characteristic multiplets at 5.89 and 5.08 due to introduced allyl group in addition to other signals. Since these all samples corresponded to mixtures of four isomers, the remaining multiplet signals from the ring protons could not be assigned.

The mass spectra of amines 3 were qualitatively and quantitatively very similar (Table 1). This is probably due to an early aperture of the ring during the first step of the dissociative ionization. The formation of acyclic molecular ions M1+ and M2+, common to the four isomers from amine 3a explains the appearance of fragments f1 at m/z 172 and f2 at m/z 146 (Scheme 4), whose intensities are independent of the initial molecular conformation. The fragmentation pattern of gem-allyl-arylaminocyclohexanes 4 (Scheme 5) in the mass spectra is different to that of related aminocyclohexanes 3; the spectra contain a low intensity (<4%) peak of their molecular ions as it is shown in Table 1.

Table 1. Chromatographic and mass-spectroscopic parameters of amines 3a,b and 4a-d

Scheme 4

Scheme 5

According to the analyses by high resolution gas chromatography coupled to mass spectometry (HRGC-MS, EL 70 eV), amines 3a, b and 4a-d are mixtures of four geometric isomers. These isomers are easily separated on a column of intermediate polarity such as un HP-5MS (30 m), but their retention times are very close /Table1). The mass spactra of amine 3 and 4 were very similar, qualitatively and quantitatively, respectively. This did not permit a univocal distinction among the isomers based on the intensity of their characteristic ions. Since the various isomers were formed in different proportions were used semi-empirical quantum-mechanical methods (PM3 and AM1) to calculate the total energy and the heat of formation for each geometric isomer in order to have additional thermodynamic criteria to make the chromatographic peak assiggnments.

The results form both calculation method (AM1, PM3) showed the following thermodynamic stability order for animates 3a,b: 1a, 2a, 5e<1e, 2e, 5e1e, 2a, 5e<1e, 2e, 5e as it can be seen in Table 2.

Table 2. Molecular parameters calculated by semi-empirical methods (AM1, PM3) for isomeric amines 3 and 4

According to the calculations and the chromatographic data (Tables 1,2), we suppose that isomers 1e,2e,5e and 1a,2e,5e, which are obtained from trans-2e,5e-dihydrocarvone, are formed in the largest proportion: ~70% for amine 3a and ~60% for amine 3b, in 2:1 and 3:1 ratios respectively (Table 1). This is consistent with a dominant axial approach of the hydride ion to the C=N double bond [12]. Isomers 1e,2a,5e and 1a,2a,5e, genetically related to cis-2a,5e-dihydrocarvone, appear in 30 - 40% abundance in 3:1 and 3.5:1 ratios, which also confirms the preferential axial attack of this ion to the imine (Scheme 3).

The similar calculations for amines 4a,b allowed us to have a range of thermodynamic data (Table 2). According with the chromatographic data (Table 1) we can also suppose that during the allylation of ketimine 2a resulted the 1-allyl-1-N-phenylaminocyclohexane 4a which were produced via predominant equatorial attack of Grignard reagent to the C=N double bond giving axial amines (1a,2e,5e and 1a,2a,5e) as major components. The same allylation reaction of the ketimines 2b-d derived from benzylamine gave the 1-allyl-1-N-benzylaminocyclohexanes 4b-d whose major components were axial (1a,2e,5e) and ecuatorial (1e,2a,5e) amines, products of both equatorial and axial attacks of Grignard reagent to the C=N double bond, respectively.

CONCLUSIONS

The easy N-functionalization of dihydrocarvone was achieved by means of the preparation of their imine derivatives. A two-step facile synthetic route led to new N-substituted amines with potential bioactivity. Mixtures of diastereoisomeric amines were analyzed by high resolution gas chromatographic methods. Although early attempts to explain the predominant formation of the more stable isomeric product were criticized as a vague concept [13], we were able to make the chromatographic peak assignment in base of thermodynamic data by semi empirical methods. Total energy and heat of formation for each amine isomer were calculated that made possible to attempt the chromatographic peak assignments. In addition, some of them are considered versatile synthons for the construction of N-heterocycles.

ACKNOWLEDGMENTS

This work was carried out thanks to the financial support of the Colombian Institute for Science and Research (COLCIENCIAS, grant CENIVAM), which we gratefully thank.

REFERENCES

1. Veertegen-Haaksma A.A., Swarts H.J., Jansen B., de Groot A., Tetrahedron, 1994, 50, 10095.

2. Brito B.L.H., Mendez A.A., Liebigs Ann. Chem., 1994, 785.

3. Srikrishna A., Anebouselvy K., Jagadeeshwar Reddy T., Tetrahedron Lett, 2000, 41, 6643.

4. Kuznetsov V.V., Prostakov N.S., Khimia Geterotsikl Soedin., 1994, 3. Chem. Abstr., 1994, 121, 255518.

5. Vargas M.L.Y., Rozo W., Kouznetsov V., Heterocycles, 2000, 53, 785.

6. Palma A.R., Vargas M.L.Y., Silva J., Kouznetsov V., Heterocycl. Commun, 1998, 4, 455.

7. Kouznetsov V., Palma A.R., Aliev A.E., Anales de Química, Int. Ed., 1998, 94, 132.

8. Dayer P., Desmeules J., Collart L., Drugs, 1997, 53, 18.

9. Graudums I., Winter W., Frankus E., Strassburger W.W.A., Friderichs E.J., Eur Pat Appl EP 780369 (1997); Chem. Abstr., 1997, 127, 121560.

10. Billman J.H., Tai K.U., J. Org. Chem., 1957, 22, 1068.

11. Kuznetsov V.V., Gayvoronskaya L.A., Fomichov A.A., Romero R.M., Prostakov N.S., Khimia Geterotsikl. Soedin., 1987, 949; Chem. Abstr., 1988, 108, 150252.

12. Volkman R.A. in Comprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry, Trost B.M., ed., Pergamon Press, Oxford, 1991, Vol. 1, pp. 355-396.

13. Elliel E.L., Wilen S.H., Stereochemistry of Organic Compounds. John Wiley & Sons, New York, 1994, pp. 880-885.

14. Laube Th., J. Org. Chem., 1999, 64, 8177 and references cited therein

15. De Savignac M.A., Bon M., Mazarquil H., Lattes A., Bull. Soc. Chim. Fr., 1975, 6, 2057.

16. Kuznetsov V.V., Aliev A.E., Lantsetov S.V., Dvuzhilov A.S., Prostakov N.S., Khim Geterostikl. Soedin., 1991, 942; Chem. Abstr., 1992, 116, 106049.

17. Kouznetsov V., Palma A., Rozo W., Stashenko E., Bahsas A., Amaro-Luis J., Tetrahedron Lett., 2000, 41, 6985.

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