Iron(II)-Catalyzed Chlorolactamization of γ,δ-Unsaturated Carboxylic Acids

Abstract

A one-pot chlorolactamization of γ,δ-unsaturated carboxylic acids is presented. Substrates like carboxylic acid 1 were transformed into the acyl azides which upon treatment with FeCl₂ and TMSCl in i-PrOH cyclized to yield lactams such as 2 (75% yield). The reaction yielded exclusively the syn-addition product as proven by the crystal structure of chlorolactam 2. The acyclic alkenoic acids 3-6 reacted equally well to the products 7-10 (57-81% yield). The reaction proceeded not stereospecifically but yielded a mixture of erythro- and threo-products.

Key words

aminations - homogenous catalysis - iron - lactams - radical reactions

References

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• 12a

  Crystal structure analysis of lactam threo-7: C₁₁H₁₂ClNO, M _r = 209.67, colorless prism (0.10 × 0.23 × 0.58 mm³), orthorhombic, Pbca (No.: 61), a = 6.7261 (1), b = 11.9007 (1), c = 25.5914 (3) Å, V = 2048.47 (4) ų, Z = 8, d_calc = 1.360 gcm^-3, F₀₀₀ = 880, µ = 0.337 mm^-1. Preliminary examination and data collection were carried out on a kappa-CCD device (NONIUS MACH3) at the window of a rotating anode (NONIUS FR591) with graphite monochromated Mo-K_α radiation (λ = 0.71073 Å). Data collection were performed at T = 123 K within the Θ range of 3.18°<Θ< 25.37°. A total of 29038 reflections were integrated and corrected for Lorentz and polarization effects. A correction for absorption effects and/or decay was applied during the scaling procedure. After merging (R _int = 0.041), 1874 [1656: I _o>2σ(I _o)] independent reflections remained and all were used to refine 176 parameters. The structure was solved by a combination of direct methods and difference-Fourier syntheses. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were found and refined freely. Full-matrix least-squares refinements were carried out by minimizing Σw(F _o ²-F _c ²) [2] and converged with R1 = 0.0335 [I _o>2σ(I _o)], wR2 = 0.0830 [all data], GOF = 1.075, and shift/error <0.001. The final difference-Fourier map shows no striking features (Δe _min/max = +0.21/-0.19 eÅ^-3). A correction for extinction was applied ε = 0.0034 (9). Crystallographic data (excluding structure factors) for the structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-234 588 (threo-7). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]].

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9

General Procedure for the One-Pot Chloro-lactamization: To 141 mg (1.0 mmol) of 2-(cyclohex-2-enyl)acetic acid (1) [8] dissolved in 5 mL CH₂Cl₂ were added 94 µL (1.1 mmol) of oxalyl chloride and one drop of DMF. The reaction mixture was stirred at r.t. for 20 min. CH₂Cl₂ and the excess oxalyl chloride were removed in vacuum. The remaining acyl chloride was dissolved in 5 mL of acetone and a solution of 130 mg NaN₃ (2.0 mmol) in 300 µL H₂O was added at -15 °C. The reaction mixture was stirred for 1.5 h at -15 °C and the solvent was removed at this temperature in vacuum. The acyl azide was dissolved in 10 mL i-PrOH. A solution of 25.3 mg (0.2 mmol) FeCl₂ and 252 µL (2.0 mmol) TMSCl in 5 mL i-PrOH was added. The reaction mixture was stirred for 5 h at -15 °C and for 8 h at r.t.. After evaporation of the solvent in vacuo 40 mL of EtOAc were added. The organic layer was washed with H₂O (3 × 20 mL) and brine (2 × 20 mL) and dried over MgSO₄. After filtration the solvent was evaporated and the crude product was purified by flash chromatography. (silica 60, pentane-CH₂Cl₂-MeOH-NH_{3 ( aq)} = 65:30:5:0.25) to give 130 mg (75%) of lactam 2. ¹H NMR (500 MHz, CDCl₃): δ = 1.23-1.36 (m, 2 H, CH₂CHHCH₂CHCl, CHHCH₂CH₂CHCl), 1.60-1.70 (m, 1 H, CHHCH₂CH₂CHCl), 1.73-1.85 (m, 2 H, CH₂CH₂CHHCHCl, CH₂CHHCH₂CHCl), 1.93-2.01 (m, 1 H, CH₂CH₂CHHCHCl), 2.05 (d, J = 16.3 Hz, 1 H, CHCHHCO), 2.35-2.45 (m, 1 H, CHCH₂CO), 2.45 (dd, J = 16.3 Hz, J = 6.5 Hz, 2 H, CHCHHCO), 3.98-4.07 (m, 2 H, CH₂CH₂CH₂CHCl, CHClCHNH), 5.91 (br s, 1 H, NH). ¹³C NMR (90.6 MHz, CDCl₃): δ = 23.9 (CH₂ CH₂CH₂CHCl), 26.6 (CH₂CH₂ CH₂CHCl), 30.1 (CH₂CH₂CH₂CHCl), 35.9 (CHCH₂CO), 40.3 (CHCH₂CO), 58.2 (CH₂CH₂CH₂ CHCl), 59.7 (CHClCHNH), 177.2 (CO). Anal. Calcd for C₈H₁₂ClNO (173.64): C, 55.34; H, 6.97; N, 8.07. Found: C, 55.31; H, 6.92; N, 7.98.

10

Crystal structure analysis of lactam 2: C₈H₁₂ClNO, M _r = 173.64, colorless prism (0.56 × 0.64 × 0.97 mm³), monoclinic, P2₁/c (No.: 14), a = 10.1739 (1), b = 6.5823 (1), c = 12.4662 (2) Å, β = 94.0723 (5)°, V = 832.72 (2) ų, Z = 4, d_calc = 1.385 gcm^-3, F₀₀₀ = 368, µ = 0.398 mm^-1. Preliminary examination and data collection were carried out on a kappa-CCD device (NONIUS MACH3) at the window of a rotating anode (NONIUS FR591) with graphite monochromated Mo-K_α radiation (λ = 0.71073 Å). Data collection were performed at T = 173 K within the Θ range of 2.01°<Θ<25.36°. A total of 19024 reflections were integrated and corrected for Lorentz and polarization effects. A correction for absorption effects and/or decay was applied during the scaling procedure. After merging (R _int = 0.035), 1525 [1462: I _o>2σ(I _o)] independent reflections remained and all were used to refine 149 parameters. The structure was solved by a combination of direct methods and difference-Fourier syntheses. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were found and refined freely. Full-matrix least-squares refinements were carried out by minimizing Σw(F _o ²-F _c ²) [2] and converged with R1 = 0.0248 [I _o>2σ(I _o)], wR2 = 0.0609 [all data], GOF = 1.087, and shift/error <0.001. The final difference-Fourier map shows no striking features (Δe _min/max = +0.25/-0.19 eÅ^-3). A correction for extinction was applied ε = 0.066 (3). Crystallographic data (excluding structure factors) for the structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-234 589. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone]; e-mail: [e-mail]]. For references see ref. 12b-g.