Synthesis of Aminoindolizine and Quinoline Derivatives via Fe(acac)₃/TBAOH-Catalyzed Sequential Cross-Coupling-Cycloisomerization Reactions

Abstract

Fe(acac)₃/TBAOH-catalyzed three-component coupling-cycloisomerization reaction of aldehydes, terminal alkynes, and amines provides a diverse range of heterocyclic compounds such as aminoindolizines and quinoline derivatives.

aminoindolizines - quinoline derivatives - tetrabutylammonium hydroxide (TBAOH) - Fe(acac)₃ catalyst - cross-coupling - cycloisomerization

References and Notes

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General Procedure for the Synthesis of Aminoindolizine Derivatives To a solution of TBAOH (0.1 mmol) in DMSO (5 mL), pyridine-2-carboxaldehyde (1.0 mmol), phenyl acetylene (1.2 mmol), morpholine (1.2 mmol), and Fe(acac)₃ (0.05 mmol) were added successively. The resulting mixture was stirred at r.t. until the reaction was complete as indicated by TLC. The mixture was then diluted with EtOAc (5 mL), washed with H₂O (2 × 5 mL), and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with sat. aq NaCl, dried over anhyd Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on Al₂O₃ to afford the target product as a yellow oil.
4 - (Methoxyphenyl)-1-(piperidin-1-yl) indolizine ^4a (Table 2, Product 4b) Pale yellow liquid. ^¹H NMR (300 MHz, C₆D₆): δ = 1.40-1.48 (m, 2 H), 1.66-1.74 (m, 4 H), 3.01 (dd, J = 5.4 Hz, 4 H), 3.33 (s, 3 H), 6.04-6.09 (m, 1 H), 6.35 (dd, J = 9.0, 6.3 Hz, 1 H), 6.76 (s, 1 H), 6.78-6.83 (m, 2 H), 7.27-7.32 (m, 2 H), 7.58 (d, J = 9.3 Hz, 1 H), 7.91 (d, J = 7.5 Hz, 1 H). ^¹³C NMR (75 MHz, C₆D₆): δ = 24.8, 27.0, 54.8, 55.7, 106.0, 110.8, 114.0, 114.6, 118.4, 121.6, 122.5, 125.3, 125.6, 129.6, 131.7, 159.0. IR (neat): 2933, 1522, 1245, 1034, 835, 738 cm^-¹.

<A NAME="RD19911ST-17">17</A>

General Procedure for the Preparation of Quinoline Derivatives
A mixture of aldehyde (1 mmol) and aniline (1.4 mmol) was dissolved in DMSO (10 mL) and heated at 60 ˚C for 2 h. It was cooled to r.t., TBAOH (10 mol%), phenylacetylene (1.2 mmol), and Fe(acac)₃ were added, and the mixture stirred at r.t. overnight. The reaction mixture was poured into H₂O, and extracted with EtOAc (or CH₂Cl₂). The organic layer was washed with H₂O and dried over anhyd Na₂SO₄. The solvent was removed in vacuo. The product was purified by column chromatography on silica gel eluting with EtOAc-hexane (10:90).
4-(4-Methoxyphenyl)-2-(naphthalen-2-yl)quinoline (Table 3, Entry 5) Pale yellow solid, mp 265-269 ˚C (lit.^¹¹ 268-270 ˚C). ^¹H NMR (300 MHz, CDCl₃): δ = 3.93 (s, 3 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.26 (s, 1 H), 7.54 (m, 5 H), 7.75 (t, J = 8.1 Hz, 1 H), 7.96 (m, 4 H), 8.28 (d, J = 8.1 Hz, 1 H), 8.41 (d, J = 9 Hz, 1 H), 8.64 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 55.4. 114.0, 119.4, 125.0, 125.7, 126.6, 127.1, 127.7, 128.5, 128.8, 129.5, 130.0, 130.8, 131.3, 133.4, 136.2, 147.6, 149.8, 156.6, 164.2.