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

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.

Key words

pyrrolo[3,2-c]quinoline - Sonogashira reaction - nucleophilic substitution reaction - dihaloquinolines - 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.