Mendeleev Communications Electronic Version, Issue 1, 2002 1 Kinetic resolution of (±)-2-methyl-1,2,3,4-tetrahydroquinoline and (±)-2-methylindoline Victor P. Krasnov,* Galina L. Levit, Irina N. Andreeva, Alexander N. Grishakov, Valery N. Charushin and Oleg N. Chupakhin Institute of Organic Synthesis, Urals Branch of the Russian Academy of Sciences, 620219 Ekaterinburg, Russian Federation. Fax: +7 3432 74 1189; e-mail: ca@ios.uran.ru 10.1070/MC2002v012n01ABEH001545 The acylation of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline by (S)-naproxen acyl chloride resulted in their kinetic resolution with the predominant formation of (S,S)-diastereoisomeric amides (de 78–76%), recrystallisation of which followed by acid hydrolysis gave individual (S)-isomers of heterocyclic amines.The kinetic resolution of racemic compounds from various classes is an effective method for obtaining individual stereoisomers.1 We found previously that the kinetic resolution of 2,3-dihydro- 3-methyl-4H-1,4-benzoxazine derivatives by (S)-2-(6-methoxynaphthyl- 2)propionyl chloride [(S)-naproxen acyl chloride] gave (S)-2,3-dihydro-3-methyl-4H-1,4-benzoxazines of high optical purity.2 In this paper, we report on the use of the above resolving agent for the preparation of individual (S)-stereoisomers of 2-methyl-1,2,3,4-tetrahydroquinoline 1 and 2-methylindoline 2, close structural analogues of 2,3-dihydro-3-methyl-4H-1,4-benzoxazine.As the first step, the diastereomeric mixtures of amides 4a,b and 5a,b were obtained by the interaction of acyl chloride 3 with racemic amines 1 and 2 in the stoichiometric ratio in the presence of TEA (Scheme 1).† In both cases, the compositions of diastereoisomeric mixtures 4a,b (5a,b) were 1:1 according to the 1H NMR spectra‡ and HPLC data.§ When the molar ratio between starting amine 1 (or 2) and acyl chloride 3 was 2:1, without any tertiary amine present in the reaction mixture, the resulting products 4a,b (5a,b) were found to be significantly enriched with (S,S)-diastereoisomers 4a (5a).¶ In the case of amide 4a, de was 78%; in the case of 5a, de was 76%.The (S,S)-diastereoisomers 4a and 5a of high diastereoisomeric purity (de > 99%) were obtained after recrystallisation from hexane in yields about 75%.†† The (R)-isomers of amines 1 and 2 can be isolated from acidic solutions in ee 78 and 76%, respectively.‡‡ (S,S)-Amides 4a and 5a were hydrolysed on heating under reflux in a mixture of concentrated HCl and glacial acetic acid2 to give individual (S)-isomers of amines 1 and 2 (Scheme 2).§§ The yields of (S)-(–)-isomers of amines 1 and 2 were 30 and † To a stirred solution of amine 1 or 2 (1 mmol) and TEA (1 mmol) in dry benzene (5 ml) a solution of acyl chloride 3 (1 mmol) in dry benzene (5 ml) was added dropwise.The reaction mixture was stirred at room temperature for 24 h. Then, it was washed successively with 1 M HCl, water, 5% NaHCO3 and water and dried (MgSO4). The resulting solution was evaporated to dryness to give a yellow oily residue, which was treated with hexane to yield amides 4a,b (82%), 5a,b (86%) as yellow oil. 1+ ; 0H 20H &O 2 0H 7($ EHQ]HQH URRP WHPSHUDWXUH ; 1 2 0H 20H 0H DD ; 1 2 0H 20H 0H EE ; &+ ; &+ 6FKHPH ‡ 1H NMR spectra were recorded on a Bruker DRX 400 spectrometer, the spectra of amides 4a,b and 5a,b were measured in [2H6]DMSO at 100 °C; the spectra of amines S-1 and S-2 were measured in CDCl3 at ambient temperature.All signals are given in ppm (d) with TMS as an internal standard. 4a,b: 7.79–6.96 (m, 10H, arom.), 4.79 (m) and 4.66 (m) (1H, CH– quinoline), 4.42 (q) and 4.15 (q) (1H, CH–naproxen, J 6.9 Hz), 3.89 (s) and 3.84 (s) (3H, OMe), 2.63 (ddd) and 2.30 (ddd) (1H, C4–HA– quinoline, J 15.0, 5.3 and 5.2 Hz), 2.12 (dddd, 1H, C3–HA–quinoline, J 13.0, 7.6, 5.4 and 5.2 Hz), 1.79 (ddd) and ~1.29 (m) (1H, C4–HB– quinoline, J 15.0, 10.1 and 5.4 Hz), 1.47 (d) and 1.37 (d) (3H, Me– naproxen, J 6.9 Hz), ~1.29 (m) and 1.16 (dddd) (1H, C3–HB–quinoline, J 13.0, 10.1, 6.7 and 5.3 Hz), 1.04 (d) and 0.93 (d) (3H, Me–quinoline, J 6.6 Hz). 5a,b: 7.98–6.94 (m, 10H, arom.), 4.85 (dqd) and 4.66 (dqd) (1H, CH– indoline, J 8.8, 6.4 and 1.4 Hz), 4.35 (q) and 4.21 (q) (1H, CH–naproxen, J 6.8 Hz), 3.864 (s) and 3.858 (s) (3H, OMe), 3.38 (dd) and 3.12 (dd) (1H, C3–HA–indoline, J 15.9 and 8.7 Hz), 2.59 (dd) and 2.58 (dd) (1H, C3–HB–indoline, J 15.9 and 0.6 Hz), 1.53 (d) and 1.52 (d) (3H, Me– naproxen, J 6.8 Hz), 1.32 (d) and 0.97 (d) (3H, Me–indoline, J 6.5 Hz). § The de values of amides 4 and 5 were measured by HPLC on a Merck- Hitachi chromatograph with an L-4000A Intelligent Pump, an L-4000A UV Detector, and a D-2500A Chromato-Integrator [Hibar Pre-packed Column RT250-4, Lichrosorb Si-60]; mobile phase: hexane–PriOH, 200:1 (A), hexane–PriOH, 80:1 (B), flow rate of 1 cm3 min–1; UV detection at 230 nm; t4a 17.0 min, t4b 15.4 min (A); t5a 6.8 min, t5b 5.4 min (B).¶ To a stirred solution of amine 1 or 2 (1 mmol) in dry benzene (5 ml) a solution of acid chloride 3 (0.5 mmol) in dry benzene (3 mmol) was added.The reaction mixture was stirred for 24 h at room temperature; then, it was washed sequentially with 1 M HCl, water, 5% NaHCO3 and water and dried (MgSO4). The solution was evaporated to dryness to give (S,S)-diastereoisomer 4a (de 78%) in 90% yield or (S,S)-diastereoisomer 5a (de 76%) in 86% yield. †† 4a: mp 57–59 °C; [a]D +66.8° (c 1.3, CHCl3); de 99.0%.HPLC: tR 17.0 min (A). 1H NMR, d: 7.79–6.96 (m, 10H, arom.), 4.79 (ddq, 1H, CH–quinoline, J 7.6, 6.7 and 6.6 Hz), 4.42 (q, 1H, CH–naproxen, J 6.9 Hz), 3.84 (s, 3H, OMe), 2.30 (ddd, 1H, C4–HA–quinoline, J 15.0, 5.3 and 5.2 Hz), 2.12 (dddd, 1H, C3–HA–quinoline, J 13.0, 7.6, 5.4 and 5.2 Hz), 1.79 (ddd, 1H, C4–HB–quinoline, J 15.0, 10.1 and 5.4 Hz), 1.47 (d, 3H, Me–naproxen, J 6.9 Hz), 1.16 (dddd, 1H, C3–HB–quinoline, J 13.0, 10.1, 6.7 and 5.3 Hz), 0.93 (d, 3H, Me–quinoline, J 6.6 Hz). 5a: mp 106–107 °C; [a]D +82.8° (c 1.9, CHCl3); de 99.3%.HPLC: tR 6.8 min (B). 1H NMR, d: 7.98–6.94 (m, 10H, arom.), 4.85 (dqd, 1H, CH–indoline, J 8.7, 6.5 and 1.4 Hz), 4.35 (q, 1H, CH–naproxen, J 6.9 Hz), 3.864 (s, 3H, OMe), 3.38 (dd, 1H, C3–HA–indoline, J 15.9 and 8.7 Hz), 2.59 (dd, 1H, C3–HB–indoline, J 15.9 and 0.6 Hz), 1.53 (d, 3H, Me– naproxen, J 6.8 Hz), 0.97 (d, 3H, Me–indoline, J 6.5 Hz).‡‡The aqueous acid layers after preparing amide 4a or 5a were treated with NaOH up to pH 9–10 under ice cooling, extracted by chloroform, washed with brine, and dried (MgSO4). The solution was evaporated to dryness to give amines (R)-1 in 90% yield or (R)-2 in 86% yield as colourless oils.Optical purity was determined by HPLC with the pre-column derivatization of amines by acyl chloride 3.Mendeleev Communications Electronic Version, Issue 1, 2002 2 27%, respectively, relative to the starting racemic amines. The optical purity of the obtained stereoisomers was confirmed by HPLC after the derivatization of amines by acyl chloride 3.The stereochemical configuration of compound (S)-(.)-1 was determined by a comparison of the [a]D sign with published data3 for (R)-(+)-1. The absolute configuration of (S)-2 has not been determined before our study. Assignment of the absolute configuration for the 2-methylindoline fragment of amide 5a was performed by X-ray diffraction analysis, taking into account the known absolute configuration of the starting (S)-naproxen (Figure 1).In conclusion, note that the use of (S)-naproxen acyl chloride as a resolving agent in the kinetic resolution of racemic heterocyclic amines appears to be a good general procedure for obtaining individual stereoisomers of high optical purity. This work was supported by the Russian Foundation for Basic Research (grant nos. 00-03-32776, 01-03-96424 and 00-15-97390). References 1 R. Noyori, M. Tokunaga and M. Kitamuro, Bull. Chem. Soc. Jpn., 1995, 36. 2 V. N. Charushin, V. P. Krasnov, G. L. Levit, M. A. Korolyova, M. I. Kodess, O. N. Chupakhin, M. H. Kim, H. S. Lee, Y. J. Park and K.-Ch. Kim, Tetrahedron Asymmetry, 1999, 2691. 3 M. P. Paradisi and A.Romeo, J. Chem. Soc., Perkin Trans. 1, 1977, 596. ¡×¡×Amide 4a or 5a (1 mmol) was heated under reflux in a mixture of glacial acetic acid (5 ml) and conc. HCl (5 ml) for 15 h. The reaction mixture was evaporated to dryness. Water (10 ml) was added to the residue; the precipitate was filtered off and washed with water. The combined filtrates were made alkaline with 10 M NaOH to pH 10 at +5 ¡ÆC and extracted with CH2Cl2.The organic layer was washed with brine and dried (MgSO4). The solution was evaporated to dryness to give amines (S)-1 in 90% yield or (S)-2 in 85% yield as colourless oils. (S)-(.)-1: [a]D .85¡Æ (c 1.5, benzene). Lit.,3 (R)-1: [a]D +85¡Æ (c 2, benzene). 1H NMR, d: 6.96.6.92 (m, 2H, C5H, C7H), 6.58 (t, 1H, C6H, J 7.4 and 1.2 Hz), 6.44 (dd, 1H, C8H, J 8.3 and 1.2 Hz), 3.63 (br.s, 1H, NH), 3.38 (dqd, 1H, C2H, J 9.8, 6.3 and 2.8 Hz), 2.82 (ddd, 1H, C4.HA, J 16.4, 11.4 and 5.6 Hz), 2.71 (ddd, 1H, C4.HB, J 16.4, 5.4 and 3.7 Hz), 1.91 (dddd, 1H, C3.HA, J 12.8, 5.7, 3.5 and 2.9 Hz), 1.57 (dddd, 1H, C3.HB, J 12.8, 11.4, 9.9 and 5.4 Hz), 1.19 (d, 3H, Me, J 6.3 Hz). (S)-(.)-2: [a]D .12.2¡Æ (c 2.6, benzene). 1HNMR, d: 7.07 (dd, 1H, C4H, J 7.2 and 0.3 Hz), 7.00 (ddd, 1H, C5H, J 7.5, 7.4 and 0.4 Hz), 6.68 (ddd, 1H, C6H, J 7.5, 7.3 and 0.8 Hz), 6.59 (dd, 1H, C7H, J 7.8 and 0.3 Hz), 3.98 (ddq, 1H, C2H, J 8.5, 7.8 and 6.2 Hz), 3.62 (br. s, 1H, NH), 3.13 (dd, 1H, C3.HA, J 15.4 and 8.5 Hz), 2.62 (dd, 1H, C3.HB, J 15.4 and 7.8 Hz), 1.28 (d, 3H, Me, J 6.2 Hz). ; 1 2 0H 20H 0H DD 1+ ; 0H +&O $F2+ . ; &+ ; &+ 6FKHPH C(5) C(6) C(7) C(24) C(8) C(2) C(3) C(9) C(4) N(1) C(10) O(1) C(12) C(11) C(15) C(16) C(14) C(13) C(21) C(22) C(17) C(18) C(23) O(2) C(19) C(20) Figure 1 Crystal structure of (S,S)-amide 5a. Received: 25th December 2001; Com. 01/1871