Synlett 2011(20): 2955-2958  
DOI: 10.1055/s-0031-1289909
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

4-Chloro-3-iodoquinoline as a Synthon in the Development of New Syntheses of 1,2-Disubstituted 1H-Pyrrolo[3,2-c]quinolines

Andreia I. S. Almeida, Artur M. S. Silva*, José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: [email protected];
Further Information

Publication History

Received 26 September 2011
Publication Date:
28 November 2011 (online)

Abstract

New syntheses of novel 1,2-pyrrolo[3,2-c]quinolines were established using 4-chloro-3-iodoquinoline as a synthon. The approach involved a palladium-catalyzed Sonogashira reaction of 4-chloro-3-iodoquinoline with appropriate arylacetylenes, followed by nucleophilic displacement of chlorine and cyclization. Studies on the reaction of 4-chloroquinoline derivatives with sodium azide led to the unexpected 4-aminoquinolines.

    References and Notes

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17

4-Chloro-3-iodoquinoline (2): Mp 91-92 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.63 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H, H-6), 7.79 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, H-7), 8.10 (d, J = 8.0 Hz, 1 H, H-8), 8.27 (dd, J = 8.0, 1.1 Hz, 1 H, H-5), 9.16 (s, 1 H, H-2); ¹³C NMR (75 MHz, CDCl3): δ = 95.0 (C-3), 124.9 (C-5), 127.6 (C-4a), 128.5 (C-6), 129.8 (C-8), 130.6 (C-7), 146.0 (C-4), 147.6 (C-8a), 156.5 (C-2). MS (ESI+):
m/z (%) = 289 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C9H5ClIN + H]+: 289.9233; found: 289.9235

19

Optimized procedure for the synthesis of 4-chloro-3-iodoquinoline (2): POCl3 (2.04 mL, 22.08 mmol) was added to a solution of 3-iodoquinolin-4 (1H)-one (1; 200 mg, 0.74 mmol) in anhyd DMF (4 mL), in an ice bath. After the addition, the reaction mixture was stirred at 80 ˚C, under an N2 atmosphere for 1.5 h. Then the reaction mixture was poured into H2O (50 mL) and ice (20 g) and neutralized with NaHCO3. The obtained solid was filtered, taken in EtOAc (50 mL) and washed with H2O (3 × 50 mL). The organic layer was dried with anhyd Na2SO4 and evaporated to dryness. The residue was recrystallized (CH2Cl2-light petroleum) to give 4-chloro-3-iodoquinoline (2; 137.1 mg, 67%) as a pale-yellow solid.

20

Optimized procedure for the synthesis of 3-(arylethynyl)-4-chloroquinolines 4a-c: [Pd(PPh3)4]
(21.2 mg, 0.018 mmol), CuI (3.3 mg, 0.014 mmol) and the appropriate alkyne 3a-c (0.67 mmol) were added to a solution of 4-chloro-3-iodoquinoline (2; 106 mg, 0.366 mmol) in a MeCN-Et3N (2:1) mixture. The reaction mixture was stirred at r.t. for 4 h (to obtain 4a) or 20 h (to obtain 4b/4c), under an N2 atmosphere. After that period, the mixture was poured into H2O (25 mL), neutralized with dilute aqueous solution of HCl, and the organic layer was extracted with EtOAc (3 × 50 mL), dried with anhyd Na2SO4, and concentrated. The crude product was purified by preparative thin layer chromatography (light petroleum-EtOAc, 56:4). 3-(Arylethynyl)-4-chloroquinolines 4a-c were obtained without recrystallization (4a: 82.0 mg, 85%; 4b: 80.6 mg, 75%; 4c: 64.4 mg, 57%) as yellow solids. In addition, 10 and 18% of starting material were recovered for derivatives 3b and 3c, respectively.

21

4-Chloro-3-[(4-methoxyphenyl)ethynyl]quinoline (4b). Mp 110-111 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 3.86 (s, 3 H, 4′′-OCH3), 6.93 (d, J = 8.9 Hz, 2 H, H-3′′,5′′), 7.59 (d, J = 8.9 Hz, 2 H, H-2′′,6′′), 7.68 (ddd, J = 7.9, 7.1, 0.5 Hz, 1 H, H-6), 7.76 (ddd, J = 8.0, 7.1, 1.1 Hz, 1 H, H-7), 8.11 (d, J = 8.0 Hz, 1 H, H-8), 8.27 (d, J = 7.9 Hz, 1 H, H-5), 8.95 (s, 1 H, H-2); ¹³C NMR (125 MHz, CDCl3): δ = 55.4 (4′′-OCH3), 83.2 (C-1′), 98.1 (C-2′), 114.4 (C-3′′,5′′), 114.7 (C-1′′), 117.9 (C-3), 124.3 (C-5), 126.0 (C-8a), 128.2 (C-6), 129.8 (C-4a), 130.4 (C-7), 133.8 (C-2′′,6′′), 142.7 (C-4), 147.2 (C-9), 151.9 (C-2), 160.3 (C-4′′). MS (ESI+): m/z (%) = 294 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C18H12ClNO + H]+: 294.0686; found: 294.0689.

22

Physical data of 4-[(2-phenylethyl)amino]-3-[(4-nitrophenyl)ethynyl]quinoline (6c). Mp (dp) 189-190 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 3.10 (t, J = 6.7 Hz, 2 H, H-2′′′), 4.40 (dt, J = 6.7, 6.5 Hz, 2 H, H-1′′′), 5.39 (br s, 1 H, NH), 7.25-7.33 (m, 5 H, 2′′′-Ph), 7.41-7.48 (m, 1 H, H-6), 7.49 (d, J = 8.8 Hz, 2 H, H-2′′,6′′), 7.63-7.69 (m, 1 H, H-7), 7.72 (d, J = 8.5 Hz, 1 H, H-5), 7.98 (d, J = 8.5 Hz, 1 H, H-8), 8.19 (d, J = 8.8 Hz, 2 H, H-3′′,5′′), 8.66 (s, 1 H, H-2); ¹³C NMR (75 MHz, CDCl3): δ = 36.7 (C-2′′′), 47.1 (C-1′′′), 93.1 (C-1′ or C-2′), 93.3 (C-1′ or C-2′), 96.7 (C-3), 118.7 (C-4a), 120.5 (C-5), 123.7 (C-3′′,5′′), 125.7 (C-6), 127.0 (C-4′′′′), 128.8 (C-2′′′′,6′′′′ or C-3′′′′,5′′′′), 128.9 (C-2′′′′,6′′′′ or C-3′′′′,5′′′′), 130.2 (C-8), 130.3 (C-7), 131.4 (C-2′′,6′′), 131.8 (C-1′′), 137.8 (C-1′′′′), 146.7 (C-4′′), 148.0 (C-8a), 151.1 (C-4), 154.4 (C-2). MS (ESI+): m/z (%) = 394 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C25H19N3O2 + H]+: 394.1556; found: 394.1540.

23

Optimized procedure for the synthesis of 3-(arylethynyl)-4-[(2-phenylethyl)amino]quinolines 6a-c: A mixture of 3-(arylethynyl)-4-chloroquinolines 4a-c (0.288 mmol) and 2-phenylethylamine (5; 2.9 mL, 2.88 mmol) was stirred at 60 ˚C for 24 h, under an N2 atmosphere. The mixture was poured into H2O (50 mL), neutralized with a dilute aqueous solution of HCl, and the organic layer was extracted with EtOAc (3 × 50 mL), dried with anhyd Na2SO4, and concentrated. The residue was purified by preparative thin layer chromatography (CH2Cl2-acetone, 36:04). 3-(Arylethynyl)-4-[(2-phenylethyl)amino]-quinolines 6a-c were obtained without recrystallization (6a: 67.0 mg, 67%; 6b: 70.8 mg, 65%; 6c: 73.7 mg, 60%) as yellow solids.

24

Optimized procedure for the synthesis of 2-aryl-1-(2-phenylethyl)-1 H -pyrrolo[3,2- c ]quinolines 7a-c:
A mixture of 3-(arylethynyl)-4-[(2-phenylethyl)amino]-quinolines 6a-c (0.138 mmol) and CuI (5.23 mg, 0.0276 mmol) in anhyd toluene (4 mL) was stirred at 120 ˚C, under an N2 atmosphere for 20 h (6a) or 24 h (6b). After that period, the solvent was evaporated and the residue was taken up in EtOAc and purified by preparative thin layer chromatography (CH2Cl2-acetone, 36:4). Recrystallization (light petroleum-CH2Cl2) gave 2-aryl-1-(2-phenylethyl)-1H-pyrrolo[3,2-c]quinolines 7a/7b as yellow solids (7a: 40.8 mg, 85%, 7b: 31.3 mg, 60%). In the case of 7c, anhyd 1,2,4-trichlorobenzene (3 mL) was used at 160 ˚C for 6 h, under an N2 atmosphere. The crude material was purified by silica gel column chromatography (light petroleum to remove the TCB, then CH2Cl2-acetone, 5:1) to give purified 7c (21.7 mg, 40%) as a brown oil.

25

Physical data of 1-(2-phenylethyl)-2-(4-methoxyphenyl)-1 H -pyrrolo[3,2- c ]quinoline (7b). Mp 143-144 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 3.10 (t, J = 7.4 Hz, 2 H, H-2′′), 3.90 (s, 3 H, 4′-OCH3), 4.76 (t, J = 7.4 Hz, 2 H, H-1′′), 6.65 (s, 1 H, H-3), 6.82-6.86 (m, 2 H, H-2′′′,6′′′), 6.97 (d, J = 8.8 Hz, 2 H, H-3′,5′), 7.17-7.23 (m, 3 H, H-3′′′,4′′′,5′′′), 7.19 (d, J = 8.8 Hz, 2 H, H-2′,6′), 7.64-7.69 (m, 2 H, H-7, H-8), 8.29-8.33 (m, 1 H, H-6), 8.43-8.46 (m, 1 H, H-9), 9.19 (s, 1 H, H-4); ¹³C NMR (75 MHz, CDCl3): δ = 36.3 (C-2′′), 47.7 (C-1′′), 55.4 (4′-OCH3), 103.0 (C-3), 113.8 (C-3′,5′), 118.8 (C-9a), 120.5 (C-9), 121.7 (C-3a), 124.4 (C-1′), 125.9 (C-7 and C-8), 126.8 (C-4′′′), 128.6 (C-2′′′,6′′′ and C-3′′′,5′′′), 130.9 (C-6), 131.4 (C-2′,6′), 133.7 (C-9b), 137.3 (C-1′′′), 141.8 (C-2), 144.7 (C-5a), 146.3 (C-4), 159.8 (C-4′). MS (ESI+): m/z (%) = 379 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C26H22N2O + H]+: 379.1810; found: 379.1806.

26

Physical data of 1-(4-methoxyphenyl)-2-phenyl-1 H -pyrrolo[3,2- c ]quinoline (12a). Mp 171-171 ˚C. ¹H NMR (300 MHz, CD3OD): δ = 3.92 (s, 3 H, 4′′-OCH3), 7.09 (s, 1 H, H-3), 7.12 (d, J = 8.9 Hz, 2 H, H-3′′, 5′′), 7.25-7.31 (m, 5 H, H-8, H-9, H-4′, H-2′′,6′′), 7.35-7.39 (m, 4 H, H-2′,3′,5′,6′), 7.54-7.59 (m, 1 H, H-7), 8.10 (d, J = 8.4 Hz, 1 H, H-6), 9.15 (s, 1 H, H-4); ¹³C NMR (75 MHz, CD3OD): δ = 46.6 (4′′-OCH3), 95.0 (C-3), 106.5 (C-3′′, 5′′), 110.1 (C-9a), 112.5 (C-9), 112.9 (C-3a), 117.2 (C-8), 118.1 (C-7), 119.5 (C-4′), 119.7 (C-2′′, 6′′), 120.3 (C-6), 121.3 (C-3′, 5′), 122.3 (C-2′, 6′), 123.6 (C-1′ or C-1′′), 123.7 (C-1′ or C-1′′), 127.9 (C-9b), 134.5 (C-2), 135.7 (C-5a), 137.3 (C-4), 152.4 (C-4′′). MS (ESI+): m/z (%) = 251 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C24H18N2O + H]+: 251.1497; found: 251.1498.

27

Optimized procedure for the synthesis of 4-amino-3-(phenylethynyl)quinoline (13). NaN3 (61.8 mg, 0.95 mmol) was added to a solution of 4-chloro-3-(phenyl-ethynyl)quinoline (4a; 50 mg, 0.19 mmol) in anhyd DMF (2 mL) and the mixture was stirred at 120 ˚C, under an N2 atmosphere for 1.3 h. After that period, the mixture was added into H2O (50 mL) and ice (20 g), neutralized with dilute aqueous HCl solution, and the organic layer was extracted with EtOAc (3 × 50 mL), dried with anhyd Na2SO4, and concentrated. The residue was taken up in acetone and purified by preparative thin layer chromatography using CH2Cl2 as solvent. 4-Amino-3-(phenylethynyl)quinoline (13; 33.4 mg, 72%) was obtained after recrystallization (CH2Cl2-light petroleum) as an off-white solid.

28

Physical data of 4-amino-3-(phenylethynyl)quinoline (13). Mp 205-206 ˚C. ¹H NMR (300 MHz, acetone-d 6):
δ = 6.74 (s, 2 H, NH2), 7.41-7.47 (m, 3 H, H-3′′,4′′,5′′), 7.51 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, H-6), 7.64-7.72 (m, 3 H, H-7, H-2′′,6′′), 7.91 (d, J = 8.7 Hz, 1 H, H-8), 8.26 (d, J = 8.0 Hz, 1 H, H-5), 8.60 (s, 1 H, H-2); ¹³C NMR (75 MHz, acetone-d 6): δ = 85.2 (C-1′), 97.2 (C-2′), 98.1 (C-3), 118.2 (C-4a), 122.6 (C-5), 124.3 (C-1′′), 125.8 (C-6), 129.1 (C-4′′), 129.3 (C-3′′, 5′′), 130.4 (C-7), 130.5 (C-8), 132.2 (C-2′′, 6′′), 148.9 (C-8a), 152.7 (C-4), 152.9 (C-2). MS (ESI+): m/z (%) = 245 (100) [M + H]+. HRMS (ESI+): m/z calcd for [C17H12N2 + H]+: 245.1079; found: 245.1064.