An efficient and short synthesis of 4-Aryl-3-methyltetrahydroquinolines from N -benzylanilines and propenylbenzenes through cationic imino diels-alder reactions

Synlett

Volumn , Issue 6, 2010, Pages 970-972

  Bohórquez, Arnold R Romero ^a   Kouznetsov, Vladimir V ^a  

^a UNIVERSIDAD INDUSTRIAL DE SANTANDER   (Colombia)

Author keywords

4 aryl 3 methyltetrahydroquinolines; Cationic imino Diels Alder reaction; N benzylanilines; Propenylbenzenes

Indexed keywords

4 ARYL 3 METHYLTETRAHYDROQUINOLINE; ANILINE DERIVATIVE; BENZENE DERIVATIVE; N BENZYLANILINE; PROPENYLBENZENE DERIVATIVE; QUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DIELS ALDER REACTION; DRUG STRUCTURE; DRUG SYNTHESIS; PROTON NUCLEAR MAGNETIC RESONANCE;

EID: 77949883312     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1219571     Document Type: Article

References (28)

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23. Synthesis of N-Benzyl-4-aryl-3-methyltetrahydroquinoline Derivatives 4; General Procedure: A mixture of N-benzylaniline 1 (1 mmol) and formaldehyde (37% in MeOH, 1.1 mmol) in MeCN (10 mL) was stirred at r.t. for 10 min. The system was cooled to 0 C and BF3OEt2 (154.27 mL, 1.1 mmol) was added dropwise into the mixture. After 30 min, dienophile reagent (trans-anethole 3a or trans-isoeugenol 3b; 1.1 mmol) was added over 5 min to the reaction mixture. The resulting mixture was stirred at 70 C for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was extracted with EtOAc (3 15 mL). The organic layer was separated and dried (Na2SO4), concentrated in vacuo and the crude product was purified by column chromatography using silica gel (60120 mesh; petroleum etherEtOAc) to afford pure tetrahydroquinoline 4ah. Selected spectral data for trans-N-benzyl-6-methoxy-4-(4-methoxyphenyl)-3-methyl-1,2,3,4- tetrahydroquinoline (4c): Beige solid. IR (KBr): 2949, 1657, 1608, 1506 cm1; 1H NMR (400 MHz, CDCl3, TMS): d = 0.92 (d, J = 6.7 Hz, 3 H, 3-CH3), 2.21 (m, 1 H, H- 3), 3.04 (dd, J = 11.3, 8.4 Hz, 1 H, H-2ax), 3.25 (dd, J = 11.3, 3.7 Hz, 1 H, H-2eq), 3.58 (s, 3 H, 6-OCH3), 3.62 (d, J = 8.3 Hz, 1 H, H-4), 3.79 (s, 3 H, 4-OCH3), 4.46 (s, 2 H, NCH2Ph), 6.29 (d, J = 2.8 Hz, 1 H, H-5), 6.51 (d, J = 8.9 Hz, 1 H, H-8), 6.59 (dd, J = 8.9, 2.9 Hz, 1 H, H-7), 6.84 (d, J = 8.6 Hz, 2 H, 2-ArH), 7.03 (d, J = 8.6 Hz, 2 H, 3-ArH), 7.237.34 (m, 5 H, PhH); 13C NMR (100 MHz, CDCl3, TMS): d = 158.0, 150.9, 140.2, 139.4, 137.4, 130.0, 128.5, 126.8, 126.7, 126.4, 116.6, 113.7, 112.6, 112.0, 56.1, 55.6, 55.2, 54.9, 51.1, 34.9, 18.2; MS (EI): m/z (%) = 373 (80) [M]+, 250 (12), 174 (82), 121 (27), 91 (100); Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C, 80.21; H, 7.44; N, 3.66. trans-N-Benzyl-6-chloro-4-(4-methoxyphenyl)- 3-methyl-1,2,3,4- tetrahydroquinoline (4d): White solid. IR (KBr): 2952, 1640, 1601, 1502 cm1; 1H NMR (400 MHz, CDCl3, TMS): d = 0.91 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.20 (m, 3 H, H-3), 3.10 (dd, J = 11.5, 8.1 Hz, 1 H, H-2ax), 3.30 (dd, J = 11.6, 3.7 Hz, 1 H, H-2eq), 3.60 (d, J = 8.0 Hz, 1 H, H-4), 3.81 (s, 3 H, 4-OCH3), 4.50 (s, 2 H, N-CH2Ph), 6.46 (d, J = 8.8 Hz, 1 H, H-8), 6.63 (br s, 1 H, H-5), 6.85 (d, J = 8.4 Hz, 2 H, 2-ArH), 6.91 (dd, J = 7.7, 2.1 Hz, 1 H, H- 7), 7.01 (d, J = 8.4 Hz, 2 H, 3-ArH), 7.247.35 (m, 5 H, PhH); 13C NMR (100 MHz, CDCl3, TMS): d = 158.2, 143.9, 138.4, 136.7, 129.9, 129.8, 128.7, 127.0, 127.0, 126.5, 126.2, 120.6, 113.9, 112.0, 55.4, 55.2, 54.6, 50.6, 34.3, 18.2; MS (EI): m/z (%) = 377 (60) [M]+, 254 (36), 178 (39), 121 (29), 91 (100). Anal. Calcd for C24H24ClNO: C, 76.28; H, 6.40; N, 3.71. Found: C, 76.43; H, 6.32; N, 3.89. trans-NBenzyl- 6-methoxy-4-(4-hydroxy-3-methoxyphenyl)-3- methyl-1,2,3,4-tetrahydroquinoline (4g): Beige solid. IR (KBr): 3542, 2936, 1638, 1603, 1511 cm1; 1H NMR (400 MHz, CDCl3, TMS): d = 0.92 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.22 (m, 1 H, H-3), 3.04 (dd, J = 11.2, 8.7 Hz, 1 H, H-2ax), 3.27 (dd, J = 11.4, 3.7 Hz, 1 H, H-2eq), 3.58 (s, 3 H, 6- OCH3), 3.59 (d, J = 8.5 Hz, 1 H, H-4), 3.80 (s, 3 H, 3- OCH3), 4.46 (d, J = 2.6 Hz, 2 H, N-CH2Ph), 5.55 (s, 1 H, 4- OH), 6.32 (d, J = 2.6 Hz, 1 H, H-5), 6.53 (d, J = 8.9 Hz, 1 H, H-8), 6.59 (m, 2 H, 2-ArH and 6-ArH), 6.63 (dd, J = 8.2, 1.3 Hz, 1 H, H-7), 6.84 (d, J = 8.0 Hz, 1 H, 5-ArH), 7.23 7.32 (m, 5 H, PhH); 13C NMR (100 MHz, CDCl3, TMS): d = 150.9, 146.5, 144.0, 140.1, 139.3, 137.1, 128.5, 126.8, 126.7, 126.3, 122.2, 116.6, 114.0, 112.6, 111.9, 111.1, 56.1, 55.9, 55.6, 55.1, 51.7, 34.8, 18.2. MS (EI): m/z (%) = 389 (66) [M]+, 250 (21), 174 (100), 131 (16), 91 (99). Anal. Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60. Found: C, 77.23; H, 7.17; N, 3.41. trans-N-Benzyl-6-chloro-4-(4- hydroxy-3-methoxyphenyl)-3-methyl-1,2,3,4 tetrahydroquinoline (4h): White solid. IR (KBr): 3539, 2944, 1641, 1594, 1510 cm1; 1H NMR (400 MHz, CDCl3, TMS): d = 0.91 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.20 (m, 1 H, H-3), 3.10 (dd, J = 11.5, 8.3 Hz, 1 H, H-2ax), 3.32 (dd, J = 11.6, 3.8 Hz, 1 H, H-2eq), 3.57 (d, J = 8.2 Hz, 1 H, H-4), 3.82 (s, 1 H, 3-OCH3), 4.50 (s, 2 H, N-CH2Ph), 5.57 (s, 1 H, 4-OH), 6.47 (d, J = 8.8 Hz, 1 H, H-8), 6.58 (br s, 1 H, H-5), 6.59 (dd, J = 8.2, 1.5 Hz, 1 H, 6-ArH), 6.65 (d, J = 2.2 Hz, 1 H, 2-ArH), 6.86 (d, J = 7.9 Hz, 1 H, 5-ArH), 6.91 (dd, J = 8.8, 2.4 Hz, 1 H, H-7), 7.227.34 (m, 5 H, PhH); 13C NMR (100 MHz, CDCl3, TMS): d = 146.6, 144.2, 143.8, 138.3, 136.4,129.8, 128.6, 127.1, 127.0, 126.5, 126.2, 122.1, 120.5, 114.2, 111.9, 110.9, 55.9, 55.4, 54.7, 51.1, 34.2, 18.1. MS (EI): m/z (%) = 393 (37) [M]+, 254 (30), 178 (40), 137 (20), 91 (100). Anal. Calcd for C24H24ClNO2: C, 73.18; H, 6.14; N, 3.56. Found: C, 72.93; H, 6.32; N, 3.31.
24. Kouznetsov V V., AstudilloSaavedra L, VargasMéndez L Y., CazarRamírez M E., J. Chil. Chem. Soc. 2004 49 319
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27. Synthesis of N-H-4-Aryl-3-methyltetrahydroquinoline Derivatives 5; General Procedure: A mixture of tetrahydroquinoline 4ah (1 mmol), wet 10% Pd/C (cat.) and MeOHCH2Cl2 (3:1, 20 mL) was stirred under H2 (1 atm) at r.t. for 1416 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo and extracted with CH2Cl2 (3 15 mL). The organic layer was separated and dried (Na2SO4), concentrated in vacuo and the resulting product was purified by flash column chromatography (silica gel; petroleum etherEtOAc) to afford the respective pure tetrahydroquinoline 5ah.Selected spectral data for trans-6-methoxy-4-(4-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (5c): Reddish oil. IR (KBr): 3387, 1604, 1509 cm1; 1H NMR (400 MHz, CDCl3, TMS): d = 0.91 (d, J = 6.7 Hz, 3 H, 3-CH3), 2.10 (m, 1 H, H-3), 2.98 (dd, J = 11.1, 8.9 Hz, 1 H, H-2ax), 3.25 (dd, J = 11.2, 3.4 Hz, 1 H, H-2eq), 3.57 (d, J = 9.0 Hz, 1 H, H-4), 3.59 (s, 3 H, 6-OCH3), 3.78 (s, 3 H, 4-OCH3), 6.24 (d, J = 2.7 Hz, 1 H, H-5), 6.51 (d, J = 8.6 Hz, 1 H, H-8), 6.61 (dd, J = 8.6, 2.8 Hz, 1 H, H- 7), 6.83 (d, J = 8.6 Hz, 2 H, 2-ArH), 7.04 (d, J = 8.6 Hz, 2 H, 3-ArH); 13C NMR (100 MHz, CDCl3, TMS): d = 158.0, 151.9, 138.8, 137.6, 130.0, 125.9, 116.0, 115.2, 113.6, 113.1, 55.6, 55.2, 50.7, 47.6, 35.4, 17.9; MS (EI): m/z (%) = 283 (100) [M]+, 268 (51), 240 (25), 174 (24), 160 (60); Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.02; H, 7.63; N, 4.78. trans-6-Methoxy-4- (4-hydroxy-3- methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline (5g): Beige solid. IR (KBr): 3302, 1603, 1506 cm1; 1H NMR (400 MHz, CDCl3, TMS): d = 0.91 (d, J = 6.6 Hz, 3 H, 3-CH3), 2.10 (m, 1 H, H-3), 2.99 (dd, J = 10.9, 9.4 Hz, 1 H, H-2ax), 3.27 (dd, J = 11.1, 3.3 Hz, 1 H, H-2eq), 3.54 (d, J = 9.0 Hz, 1 H, H-4), 3.59 (s, 3 H, 6-OCH3), 3.81 (s, 3 H, 3-OCH3), 6.26 (d, J = 2.4 Hz, 1 H, H-5), 6.52 (d, J = 8.6 Hz, 1 H, H-8), 6.59 (br s, 1 H, 2-ArH), 6.61 (dd, J = 8.8, 2.7 Hz, 2 H, 6- ArH), 6.65 (dd, J = 8.2, 1.3 Hz, 1 H, H-7), 6.84 (d, J = 8.0 Hz, 1 H, 5-ArH); 13C NMR (100 MHz, CDCl3, TMS): d = 152.0, 146.6, 144.1, 138.6, 137.2, 126.1, 122.4, 116.0, 115.3, 113.8, 113.3, 111.0, 55.9, 55.7, 51.5, 48.0, 35.4, 18.0; MS (EI): m/z (%) = 299 (100) [M]+, 284 (28), 270 (15), 256 (18), 174 (35), 160 (68). Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 75.65; H, 7.31; N, 5.13.
28. trans-Anethole is the main component of the anise essential oil, which is extracted from the seeds of the star anise (Illicium verum Hook fillius). trans-Isoeugenol could be easily prepared from eugenol, which is the main component of the clove fruit essential oil, and can be extracted from the flower buds of clove trees (fam. Myrtaceae). Therefore, both reagents can be considered to be renewable materials.