Iridium-Catalyzed Direct Cyclization of Aromatic Amines with Diols

Abstract

We developed an environmentally friendly iridium-catalyzed direct cyclization of aromatic amines with diols that generates the corresponding N-heterocyclic compounds with water as the sole by-product. Thus, under conditions of 165 °C for 18 hours, the direct cyclization of N-methylanilines with 1,3-propanediol by using an IrCl₃ catalyst with rac-BINAP as a ligand in mesitylene afforded the corresponding tetrahydroquinoline derivatives with yields ranging from 73 to 83%. ­Under similar reaction conditions, direct cyclization of anilines with 1,3-propanediol produced the corresponding tetrahydrobenzoquinolizine derivatives with yields ranging from 26 to 76%.

Key words

iridium catalyst - aromatic amines - diols - cyclization - N-heterocycles

• References and Notes

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• 8 In entry 11, 2a was not detected in ¹H NMR analysis (conversion: 100%). The main product seems to be N,N'-diphenyl-1,3-propanediamine (45% NMR yield).
• 9 In entry 2, N-methyl-N-propylaniline was also detected.^4e The ratio of 3a to N-methyl-N-propylaniline was 18:1 (¹H NMR analysis). A similar ratio of 3a to N-methyl-N-propylaniline was observed in entries 3 and 4.
• 10a The reaction of N-ethylaniline (1g) with 1,3-propanediol (2a) gave 1-ethyl-1,2,3,4-tetrahydroquinoline (3g) in 40% yield. The reaction of N-propylamine (1h) with 1,3 -propanediol (2a) gave 1-isopropyl-1,2,3,4-tetrahydroquinoline (3h) in <3% yield. Both reactions included the corresponding diamine compound (like 7) (3g/7g = 1:1 and 3h/7h = 1:39). Compound 3g:^{10a 1}H NMR (CDCl₃, 400 MHz): δ = 1.13 (t, J = 7.0 Hz, 3 H), 1.92–1.98 (m, 2 H), 2.74 (t, J = 6.2 Hz, 2 H), 3.26 (t, J = 5.8 Hz, 2 H), 3.34 (q, J = 7.1 Hz, 2 H), 6.54 (tt, J = 0.93 Hz, 7.3 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 6.93 (dd, J = 1.2 Hz, 7.2 Hz, 1 H), 7.02–7.06 (m, 1 H) ppm. HRMS: m/z calcd for C₁₁H₁₅N [M]⁺: 161.1204; found: 161.1197. Compound 3h:^{10a 1}H NMR (CDCl₃, 600 MHz): δ = 1.17 (d, J = 6.6 Hz, 6 H), 1.88–1.92 (m, 2 H), 2.73 (t, J = 6.6 Hz, 2 H), 3.14 (t, J = 6.0 Hz, 2 H), 4.10 (sept, J = 6.7 Hz, 1 H), 6.52–6.56 (m, 1 H), 6.68 (d, J = 7.8 Hz, 1 H), 6.94 (d, J = 6.6 Hz, 1 H), 7.03–7.06 (m, 1 H) ppm. HRMS: m/z calcd for C₁₂H₁₇N [M]⁺: 175.1361; found: 175.1359.
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• 12 General Procedure and Characterization Data: Ir-catalyzed direct cyclization of 3-fluoro-aniline (4e) with 1,3-propanediol (2a) (Table 3, entry 5): To a vial was added 3-fluoroaniline (111.1 mg, 1.0 mmol), IrCl₃·3H₃O (11.5 mg, 5.0 mol%), and rac-BINAP (30.4 mg, 7.5 mol%) under air. Furthermore, mesitylene (0.5 mL) and then 1,3-propanediol (98.9 mg, 1.3 mmol) were added and the reaction mixture was stirred at 165 °C for 18 h. After the reaction, the resulting mixture was diluted with hexane. Then, the reaction mixture was filtrated with a filter paper and concentrated in vacuo. The resulting residue was purified by flash column chromatography on SiO₂ ( ^t BuOMe/hexane 1:15) to yield 2,3,6,7-tetrahydro-8-fluoro-1H,5H-benzo[ij]quinolizine (5e) in 59% yield (73.2 mg) as a pale yellow solution. ¹H NMR (500 MHz, CDCl₃): δ = 1.92−1.98 (m, 4 H), 2.68−2.72 (m, 4 H), 3.09−3.12 (m, 4 H), 6.24 (t, J _HF = 8.8 Hz, 1 H), 6.70 (t, J _HF = 7.5 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.3 (d, ³ J _CF = 5.9 Hz), 21.3, 22.2, 27.3, 49.6, 50.0, 102.0 (d, ² J _CF = 22.9 Hz), 108.5 (d, ² J _CF = 21.7 Hz), 116.8 (d, ⁴ J _CF = 2.4 Hz), 126.8 (d, ³ J _CF = 10.8 Hz), 144.1, (d, ³ J _CF = 8.4 Hz), 159.7 (d, ¹ J _CF = 241.3 Hz) ppm. ¹⁹F-NMR (470 MHz, CDCl₃): δ = −124.2 ppm. HRMS: m/z calcd for C₁₂H₁₄FN [M]⁺: 191.1110; found: 191.1110.
• 13 the reaction 4a with 2d−g, the desired products 3ad−ag were not detected (Scheme 7) by ¹H NMR analysis
• 14 The reaction of 4a with 1,4-butanediol (2c) resulted in a double N-alkylation to afford 1-phenylpyrrolidine in 76% yield (see Supporting Information).
• 15 Compound 5g was unstable and gradually decomposed under chromatographic conditions.
• 16 Under similar reaction conditions with 4 Å molecular sieves, the reaction of aniline (4a) with 1,3-propanediol (2a) gave quinoline in 7% yield and no tetrahydrobenzoquinolizine 5a.
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• 18 For example: LD 490 (Coumarin 6H) [CAS: 58336-35-9].