One-Pot Synthesis of Isoindolo[2,1-a]quinolin-11-ones by Cyclocondensation of 3-Hydroxy-2-arylisoindol-1-ones with 1,3-Dicarbonyls

Abstract

Isoindolo[2,1-a]quinolin-11-ones have been synthesized by one-pot reaction of 3-hydroxy-2-arylisoindol-1-ones with 1,3-dicarbonyls via coupling of N-acyliminium ion intermediates with 1,3-dicarbonyls and subsequent intramolecular Friedel-Crafts reactions catalyzed by H₃PO₄-P₂O₅ or H₃PO₄-H₂SO₄.

2,3-dihydro-3-hydroxy-2-arylisoindol-1-one - 1,3-dicarbonyls - 6a,11-dihydroisoindolo[2,1-a]quinolin-11-ones - N-acyl-iminium ions - Friedel-Crafts reaction

References and Notes

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<A NAME="RW14608ST-1B">1b</A> Sui Z. Altom J. Nguyen VN. Fernandez J. Bernstein JI. Hiliard JJ. Barrett JF. Podlogar BL. Ohemeng KA. Bioorg. Med. Chem.  1998,  6:  735 

<A NAME="RW14608ST-1C">1c</A> Goto G, and Ishihara Y. inventors; JP  02042078.  ; Application: JP 88-193656 19880802

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<A NAME="RW14608ST-2B">2b</A> Zubkov FI. Boltukhina EV. Turchin KF. Borisov RS. Varlamov AV. Tetrahedron  2005,  61:  4099 

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<A NAME="RW14608ST-8">8</A>

Typical Experimental ProcedureMethod A
To a stirred mixture of 3-hydroxy-2-phenylisoindol-1-one (1a, 1.0 mmol), ethyl acetoacetate (2b, 1.2 mmol) and H₃PO₄ (2 mL), P₂O₅ (2 g) was added at one portion at r.t. After the solid was dissolved completely the mixture was stirred at r.t. or heated at 60 ˚C for 6-24 h (TLC control). The reaction was quenched by crashed ice and the solution was extracted with CH₂Cl₂ (2 × 10 mL).The organic phase was washed with sat. aq NaHCO₃ (10 mL) and H₂O, respectively and dried with anhyd Na₂SO₄, concentrated at reduced pressure to furnish the crude products 3a which was purified by silica gel column chromatography using EtOAc-hexane (1:9) as eluents and further purified by recrystallization from EtOH.
Method B
The procedure is similar to method A, only P₂O₅ was replaced by H₂SO₄ (2 mL, 98%) which was added dropwise into the mixture of 1a (1.0 mmol), 2a (1.2 mmol), and H₃PO₄ (2 mL).
Selected Spectroscopic Data
Compound 3a: colorless needles; mp 124-126 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.33 (t, 3 H, J = 7.5 Hz, CH₃), 2.21 (s, 3 H, CH₃), 4.35 (q, 2 H, J = 7.5 Hz, OCH₂), 5.92 (s, 1 H, H-6a), 7.23 (t, 1 H, J = 7 8 Hz), 7.42-7.60 (m, 5 H), 7.96 (d, 1 H, J = 7.2 Hz H-10), 8.05 (d, 1 H, J = 7 8 Hz H-1). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.2 (CH₃), 15.6 (CH₃), 58.7 (OCH₂), 61.0 (C-6a), 122.0 (CH), 123.7 (CH), 124.3 (CH), 125.0 (CH), 125.2 (CH), 126.8 (C), 127.5 (C), 128.9 (CH), 129.7(CH), 132.0 (C), 132.5 (CH), 133.7 (C), 134.7 (C), 140.7 (C), 166.5 (CO), 166.9 (CO). MS (EI): m/z (%) = 319 (18) [M⁺], 304 (8), 290 (30), 274 (4), 262 (6), 246 (99), 86 (100). Anal. Calcd (%) for C₂₀H₁₇NO₃: C, 75.22; H, 5.37; N 4.39 Found: C, 75.13; H, 5.45; N 4.25.
Compound 3c: colorless needles; mp 151-153 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.33 (t, 3 H, J = 7.2 Hz, CH₃), 2.17 (s, 3 H, CH₃), 4.35 (q, 2 H, J = 7.5 Hz, OCH₂), 5.90 (s, 1 H, H-6a), 7.39 (dd, 1 H, J = 7.5, 1.5 Hz), 7.42 (d, 1 H, J = 1.5 Hz, H-4), 7.52-7.60 (m, 3 H), 7.94 (d, 1 H, J = 7.5 Hz, H-1), 8.00 (d, 1 H, J = 8.1 Hz, H-10). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.2 (CH₃), 15.6 (CH₃), 58.5 (OCH₂), 61.2 (C-6a), 123.1 (CH), 123.7 (CH), 124.4 (CH), 125.2 (CH), 128.0 (C), 129.0 (CH), 129.4 (CH), 130.4 (C), 131.7 (C), 132.5 (C), 132.7 (CH), 133.1 (C), 140.5 (C), 166.5 (CO), 166.7 (CO). MS (EI): m/z (%) = 355 (8) [M + 2⁺], 353 (25 [M⁺], 340 (20), 338 (62), 326 (31), 324 (87), 310 (28), 296 (5), 282 (29), 280 (100). Anal. Calcd (%) for C₂₀H₁₈ClNO₃: C, 67.90; H, 4.56; N, 3.96 Found: C, 67.83; H, 4.63; N, 4.07.
Compound 3f: colorless needles; 141-143 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.09 (s, 3 H, CH₃), 2.16 (s, 3 H, CH₃), 2.39 (s, 3 H, CH ₃), 5.80 (s, 1 H, H-6a), 7.23 (s, 1 H, H-4), 7.26 (t, 1 H, J = 6.0 Hz), 7.41 (d, 1 H, J = 7.2 Hz, H-2), 7.50-7.59 (m, 3 H), 7.95 (d, 2 H, J = 8.7 Hz, H-1, H-10). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.6 (CH₃), 21.2 (CH₃), 32.8 (CH₃), 58.5 (C-6a), 121.5 (CH), 123.7 (CH), 124.3 (CH), 125.2 (CH), 127.2 (C), 128.9 (CH), 129.1 (C), 130.1 (CH), 132.1 (C), 132.2 (C), 132.4 (CH), 134.5 (C), 134.8 (C), 140.1 (C), 166.1 (CO), 204.6 (CO). MS (EI): m/z (%) = 303 (16) [M⁺], 302 (10), 288 (36), 260 (62), 246 (18), 230 (5), 217 (13), 43 (100). Anal. Calcd (%) for C₂₀H₁₇NO₂: C, 79.18; H, 5.65; N, 4.62 Found: C, 79.12; H, 5.74; N, 4.55.
Compound 3g: colorless needles; 156-158 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.94 (s, 3 H, CH₃), 6.06 (s, 1 H, H-6a), 7.22-7.54 (m, 9 H), 7.80 (d, 2 H, J = 7.8 Hz, H-2¢), 7.90 (d, 1 H, J = 6.9 Hz, H-10), 8. 16 (d, 1 H, J = 7.5 Hz, H-1). ^¹³C NMR (75 MHz, CDCl₃): δ = 16.4 (CH₃), 59.2 (C-6a), 121.7 (CH), 124.0 (2 CH), 124.8 (CH), 125.0 (CH), 127.6 (C), 128.7 (CH), 128.9 (2 CH), 129.2 (2 CH), 129.6 (CH), 131.3 (C), 131.7 (C), 131.9 (C), 132.3 (CH), 134.1 (CH), 134.7 (C), 136.8 (C), 140.1 (C), 166.5 (CO), 196.9 (CO). MS: m/z (%) = 351 (37) [M⁺], 350 (14), 336 (25), 246 (79), 105 (100), 77 (89). Anal. Calcd (%) for C₂₄H₁₇NO₂: C, 82.03; H, 4.88; N, 3.99 Found: C, 81.94; H, 4.84; N, 4.07.
Compound 3j: colorless needles; 131-132 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.49-1.75 (m, 2 H), 1.81-1.85 (m, 2 H), 2.16-2.31 (m, 2 H), 2.54-2.62 (m, 2 H), 5.40 (s, 1 H, NCH), 7.22 (t, 1 H, J = 8.7 Hz), 7.30-7.35 (m, 2 H), 7.49-7.61 (m, 2 H), 7.67 (d, 1 H, J = 7.8 Hz), 7.95 (d, 1 H, J = 6.5 Hz), 8.05 (d, 1 H, J = 6.9 Hz). ^¹³C NMR (75 MHz CDCl₃): δ = 22.0 (CH₂), 22.2 (CH₂), 22.4 (CH₂), 27.5 (CH₂), 60.8 (NCH), 121.3 (CH), 122.7 (CH), 124.0 (CH), 124.7 (CH), 127.3 (CH), 127.6 (C), 128.4 (CH), 129.2 (C), 130.4 (C), 131.5 (CH), 132.4 (C), 133.6 (C), 141.2 (C), 165.6 (NCO). MS (EI): m/z (%) = 287 (86) [M⁺], 286 (67), 270 (4), 258 (100), 232 (10), 216 (11). Anal. Calcd (%) for C₂₀H₁₇NO: C, 83.60; H, 5.96; N, 4.87 Found: C, 83.67; H, 6.02; N, 4.74.
Compound 5: colorless needles; 172-174 ˚C. ^¹H NMR (300 MHz CDCl₃): δ = 2.20 (s, 3 H, CH₃), 2.73 (dd, 1 H, J = 18.6, 9.6 Hz, CHH), 3.15 (dd, 1 H, J = 18.0, 2.4 Hz, CHH), 5.83 (dd, 1 H, J = 9.6, 2.4 Hz CH), 7.49 (d, 1 H, J = 7.5 Hz, C-5), 7.64 (t, 1 H, J = 7.2 Hz, ArH), 7.55 (t, 1 H, J = 7.2 Hz, ArH), 7.88 (d, 2 H, J = 8.7 Hz, H-2′), 7.92 (d, 1 H, J = 7.8 Hz, H-7), 8.30 (d, 2 H, J = 9.0 Hz, H-3′). ^¹³C NMR (75 MHz, CDCl₃): δ = 30.7 (CH₃), 46.2 (CH₂), 55.7 (C-3), 121.2 (2 C), 122.8 (CH), 124.5 (CH), 124.9 (2 C), 129.1 (CH), 130.1 (C), 133.3 (CH), 142.6 (C), 143.8 (C), 144.8 (C), 167.1 (NCO), 205.6 (CO). MS (EI): m/z (%) = 310 (11) [M⁺], 293 (10), 281 (7), 267 (27), 253 (44), 234 (18), 43 (100). Anal. Calcd (%) for C₁₇H₁₄N₂O₄: C, 65.80; H, 4.55; N, 9.03 Found: C, 65.75; H, 4.62; N, 9.02.
Compound 6b: mixture of cis- and trans-isomers (30:70). ^¹H NMR (300 MHz, CDCl₃): δ (trans-isomer) = 1.48 (d, 3 H, J = 7.8 Hz, CH₃), 1.78 (dt, 1 H, J = 9.3, 3.3 Hz, CHH), 2.30 (dd, 1 H, J = 12.9, 1.2 Hz, CHH), 2.33 (s, 3 H, CH₃), 3.18 (t, 1 H, J = 6.6 Hz, CH), 4.78 (d, 1 H, J = 12.3, Hz NCH), 7.06 (s, 1 H, H-4), 7.11 (d, 1 H, J = 8.4 Hz, H-2), 7.48-7.51 (m, 2 H), 7.57 (d, 1 H, J = 7.5 Hz), 7.92 (d, 1 H, J = 8.4 Hz), 8.46 (d 1 H, J = 8.1 Hz); δ (cis-isomer) = 1.42 (d 3 H, J = 6.9 Hz, CH₃), 2.35 (s 3 H, CH₃), 2.60 (dt 1 H, J = 13 5, 1 2 Hz, CHH), 3 21 (t 3 H, J = 6 9 Hz, CH₃), 4 70 (dd 1 H, J = 12 3, 2.4 Hz, NCH), 7.11 (d, 1 H, J = 8.4 Hz, H-2), 7.18 (s, 1 H, H-4), 7.48-7.51 (m, 2 H), 7.59 (d, 1 H, J = 6.9 Hz), 7.92 (d, 1 H, J = 8.4 Hz), 8.44 (d, 1 H, J = 7.8 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ (trans-isomer) = 21.0, 24.5, 30.8, 34.8, 54.2 (NCH), 120.1 (CH), 121.7 (CH), 124.1 (CH), 127.6 (CH), 128.3 (CH), 129.6 (CH), 131.0 (C), 131.8 (CH), 132.8 (C), 133.4 (C), 144.6 (C), 165.9 (NCO); δ (cis-isomer) = 20.9, 21.1, 31.4, 37.5, 58.7, 120.0 (CH), 121.7 (CH), 124.1 (CH), 127.6 (CH), 128.4 (CH), 129.6 (CH), 131.0 (C), 131.8 (CH), 132.9 (C), 133.4 (C), 144.6 (C), 165.9 (NCO). MS (EI): m/z = 263 (87) [M⁺], 248 (100), 232 (16), 220 (17), 115 (25), 77 (38).

<A NAME="RW14608ST-9">9</A>

(9) Crystal Data for Compound 3c
Formula: C₂₀H₁₆ClNO₃; Mr = 353.79 monoclinic; a = 9.3133(17) Å, b = 7.3351(14) Å, c = 24.716(5) Å, β = 96.800(3)˚; space group P2(1)/n; V = 1676.6(5) Å^³; colorless plates ρ = 1.402 g cm^-³, T = 296(2) K, space group P2(1)/c Z = 4, µ(Mo Ka) = 0.71073 mm^-¹, c _max = 25.82˚, 3217 reflections collected 2045 unique (R _int = 0.1585) which was used in all calculations. Final wR (F2) = 0.0830 (all data); CCDC No: 695063