Three-Component, Diastereoselective Synthesis of Highly Functionalized Indane Derivatives Based on an Anionic Domino Sequence from α-Nitroketones

Abstract

The reaction between seven- or eight-membered cyclic α-nitroketones and aromatic 1,2-dialdehydes in the presence of DBU, with tetrahydrofuran containing some water as solvent, afforded 2-nitroindane-1,2-diols with three contiguous stereocenters, one of which is quaternary, in a one-pot, diastereoselective fashion.

Key words

carbocycles - domino reactions - nitroketones - carbanions - nitroaldol reactions

References and Notes

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12

Representative Procedure
To a solution of the starting α-nitroketone (1 mmol) in THF (5 mL) was added DBU (1.5 mmol). The resulting solution was stirred at r.t. for 5 min, under an argon atmosphere. A solution of the requisite dialdehyde (2 mmol) in THF (5 mL) was then added, and stirring at r.t. was maintained for 24 h. The reaction mixture was neutralized with 2 M HCl and most of the THF was evaporated under reduced pressure. A further amount of 2 M HCl was added until pH 5, and the solution was then extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried over anhyd Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient from petroleum ether (PE) to CH₂Cl₂ or EtOAc. Characterization data for two representative compounds are given below.
(±)-(1′ S *,2′ s *,3′ R *)-6-(1′,3′-Dihydroxy-2′-nitroindan-2′-yl)hexanoic Acid (3a)
The initial 4:1 mixture of diastereomers was obtained in 81% yield. Chromatography on silica gel, eluting with a gradient from PE to CH₂Cl₂, followed by EtOAc, afforded the pure compound 3a in 56% isolated yield as a white solid.
Data for Compound 3a
Mp 102-103 ˚C. IR (NaCl): ν_max = 3397 (OH), 1702 (CO), 1534 and 1353 (NO₂) cm^-¹. ^¹H NMR (250 MHz, acetone-d ₆): δ = 7.44-7.34 (m, 4 H, HAr), 5.69 (s, 2 H, H-1′,3′), 5.50 (br s, 2 H, OH), 2.17-2.25 (m, 4 H, H-2,6), 1.44-1.56 (m, 2 H, H-3), 1.14-1.33 (m, 4 H, H-4,5) ppm. ^¹³C NMR (63 MHz, acetone-d ₆): δ = 174.2 (C-1), 140.9 (C-3′a,7′a), 129.0 (C-5′,6′), 123.8 (C-4′,7′), 105.8 (C-2′), 77.1 (C-1′,3′), 33.5 (C-6), 29.8 (C-2), 29.4 (C-5), 24.7 (C-3), 24.3 (C-4) ppm. Anal. Calcd for C₁₅H₁₉N0₆: C, 63.16; H, 6,66; N, 4.91. Found: C, 63.00; H, 6.58; N, 4.85.
Data for the Minor Diastereomer (Obtained from the Initial Mixture)
^¹H NMR (250 MHz, acetone-d ₆): δ = 7.50-7.20 (m, 4 H, HAr), 5.94 and 5.00 (2 s, 2 H, H-1′,3′), 5.27 (s, 2 H, 2 OH), 2.30-1.80 (m, 4 H, H-2,6), 1.60-1.30 (m, 6 H, H-3,4,5) ppm. ^¹³C NMR (63 MHz, acetone-d ₆): δ = 178.8 (C-1), 140.8 (C-3a′), 137.4 (C-7a′), 130.2 (C-5′), 129.4 (C-6′), 125.2 (C-4′), 124.3 (C-7′), 35.4 (C-2), 32.3 (C-6), 29.6 (C-5), 24.1 and 23.9 (C-3,4) ppm.
(±)-(1′ S *,2′ s *,3′ R *)-7-(1′,3′-Dihydroxy-2′-nitro-2′,3′-dihydro-1 H -cyclopenta[ b ]naphth-2′-yl)heptanoic Acid (3i)
The initial 3:1 mixture of diastereomers was obtained in 66% yield. Chromatography on silica gel, eluting with a gradient from PE to EtOAc, afforded the pure compound 3i in 42% isolated yield, as a pale yellow oil.
Data for Compound 3i
IR (NaCl): ν_max = 3415 (OH), 1722, 1711 (CO), 1536 and 1357 (NO₂) cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 7.92 (dd, 2 H, J = 6.6, 3.3 Hz, H-Ar), 7.85 (s, 2 H, HAr), 7.49 (dd, 2 H, J = 6.2, 3.2 Hz, HAr), 5.78 (s, 2 H, H-1′,3′), 2.25-2.12 (m, 4 H, H-2, 7), 1.54-1.48 (m, 2 H, H-3), 1.31-1.23 (m, 6 H, H-4,5,6) ppm. ^¹³C NMR (63 MHz, CDCl₃): δ = 175.4 (C-1), 137.5 (C-3a′,9a′), 133.2 (C-4a′,8a′), 126.8 (C-6′,7′), 124.7 (C-5′,8′), 120.9 (C-4′,9′), 103.9 (C-2′), 75.3 (C-1′,3′), 32.5 (C-7), 28.7 (C-2), 27.6 (C-5), 27.5 (C-4), 23.6 (C-3); 23.0 (C-6) ppm. Anal. Calcd for C₂₀H₂₃NO₆: C, 64.33; H, 6.21; N, 3.75. Found: C, 64.30; H, 6.20; N, 3.62.
Data for the Minor Diastereomer (Obtained from the Initial Mixture)
^¹H NMR (250 MHz, CDCl₃): δ = 8.10-7.80 (m, 4 H, HAr), 7.75-7.60 (m, 2 H, HAr), 6.20 (s, 2 H, C1′,3′), 5.60 (s, 2 H, OH), 2.40-2.30 (m, 4 H, H-2,7), 2.30-2.10 (m, 2 H, H-3), 1.80-1.50 and 1.40-1.20 (2 m, 6 H, H-4,5,6) ppm.