Syntheses of Amidines from Thioamides, Mediated by the N-Heterocyclic Carbene Indazol-3-ylidene

Abstract

On decarboxylation, 1,2-dimethylindazolium-3-carboxylate forms the N-heterocyclic carbene 1,2-dimethylindazol-3-ylidene in situ, which proved to be a suitable reagent for amidinations of the mono-thiolactams of succinimide and phthalimide.

Key Words

thiolactam - mesomeric betaine - decarboxylation

References and Notes

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Synthesis of 3-Methyl-2-(p-tolylimino)-pyrrolidin-1-one (13b); Typical Procedure: Samples of 2-methyl-3-thioxopyrrolidin-1-one (12; 77 mg, 0.60 mmol), p-toluidine (64 mg, 0.60 mmol) and 1,2-dimethylindazolium-3-carboxylate (1; 114 mg, 0.60 mmol) were suspended in toluene (3 mL) and heated for 3 h at reflux. The solvent was then distilled off, and the resulting residue was purified by chromatography on silica gel (petroleum ether-EtOAc, 4:1). The amidine 13b was obtained as a yellow solid (70 mg, 58%). ^¹H NMR (200 MHz, CDCl₃): δ = 7.10 (d, J = 8.0 Hz, 2 H, H-3′), 6.72 (d, J = 8.0 Hz, 2 H, H-2′), 3.12 (s, 3 H,
H-6), 2.60-2.53 (m, 4 H, H-4, H-5), 2.30 (s, 3 H, H-5′); ^¹³C NMR (50 MHz, CDCl₃): δ = 176.7, 160.8, 146.3, 133.1, 129.7, 120.5, 28.3, 26.0, 22.8, 21.0; IR (KBr): 2936, 1898, 1744, 1659, 1507, 1429, 1382, 1322, 1292, 1215, 1134, 946, 837, 745, 648, 563 cm^-¹; MS: m/z (%) = 202 (100) [M⁺], 173 (40) [M - 2CH₃], 159 (40) [M - 2CH₃ - O]; Anal. Calcd for C₁₂H₁₄N₂O: C, 71.26; H, 6.98; N, 13.85. Found: C, 70.60; H, 6.75; N, 13.61.

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3-(12-Methoxyphenylimino)isoindolin-1-one (15g); Typical Procedure: Samples of 3-thioxoisoindolinone (14a; 98 mg, 0.60 mmol), p -anisidine (74 mg, 0.60 mmol) and 1,2-dimethylindazolium-3-carboxylate (1; 114 mg, 0.60 mmol) were suspended in toluene (3 mL) and heated for 3 h at reflux. The solvent was then distilled off in vacuo, and the resulting residue was purified by chromatography (silica gel; petroleum ether-EtOAc, 4:1). The product was obtained as yellow needles (75 mg, 50% yield). mp 150 ˚C; ^¹H NMR (400 MHz, CDCl₃): δ (Z-isomer) = 8.02 (s, 1 H, NH), 8.01 (d, J = 7.4 Hz, 1 H, H-4), 7.85 (d, J = 7.4 Hz, 1 H, H-7), 7.73 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H, H-5), 7.66 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H, H-6), 7.00 (d, J = 8.5 Hz, 2 H, H-3′), 6.92 (d, J = 8.5 Hz, 2 H, H-2′), 3.81 (s, 3 H, H-5′); ^¹³C NMR (100 MHz, CDCl₃): δ (Z-isomer) = 168.6, 157.1, 148.7, 140.8, 136.2, 132.9, 132.2, 131.2, 123.5, 122.5, 122.5, 114.8, 55.6. ^¹H NMR (400 MHz, CDCl₃): δ (E-isomer) = 8.57 (br s, 1 H, NH), 7.82 (m, 1 H, H-7), 7.55 (m, 1 H, H-6), 7.35 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H, H-5), 6.94-6.90 (m, 4 H, H-2′,
H-3′), 6.75 (d, J = 7.7 Hz, 1 H, H-4), 3.85 (s, 3 H, H-5′); ^¹³C NMR (100 MHz, CDCl₃): δ (E-isomer) = 168.2, 156.9, 151.6, 141.2, 133.3, 133.3, 132.3, 130.0, 125.7, 123.7, 121.1, 114.6. IR (KBr): 2996, 2784, 1732, 1669, 1504, 1472, 1361, 1290, 1249, 1192, 1111, 1032, 837, 778, 702, 622

cm^-¹. MS: m/z (%) = 252 (100) [M⁺], 237 (75) [M - CH₃]; Anal. Calcd for C₁₅H₁₂N₂O₂: C, 71.41; H, 4.79; N, 11.11. Found: C, 70.41; H, 4.29; N, 11.19.

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X-ray structure analysis for 15d: Empirical formula: C₁₅H₁₂N₂O; M = 236.27 g/mol. A suitable single crystal of the title compound (grown in DMSO) was selected under a polarization microscope and mounted in a glass capillary (d = 0.3 mm). The crystal structure was determined by X-ray diffraction analysis using graphite monochromated Mo-K _α radiation [0.71073 Å; T = 223 (2) K], whereas the scattering intensities were collected with a single crystal diffractometer (STOE IPDS II). The crystal structure was solved by Direct Methods using SHELXS-97 and refined using alternating cycles of least squares refinements against F ^² (SHELXL-97). ^²5 All non-H atoms were located in Difference Fourier maps and were refined with anisotropic displacement parameters. The H positions were determined by a final Difference Fourier Synthesis. 15d crystallized in the space group P2₁/c(monoclinic), lattice parameters a = 5.489 (1) Å, b = 8.684 (1) Å, c = 24.851 (5) Å, β = 98.29 (2)˚, V = 1172.2 (3) Å^³, Z = 4, d (calcd.) = 1.339 g cm^-³, F(000) = 496 using 2066 independent reflections and 208 parameters. R1 = 0.0722, wR2 = 0.0983 [I >2σ(I)], goodness of fit on F ^²  = 1.104, residual electron density = 0.575 and -0.397 e Å^-³.

26

Details of the crystal structure investigations have been deposited with the Cambridge Crystallographic Data Center, CCDC 727259. Copies of this information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (Fax: [phone]; e-mail: [e-mail] or http://www.ccdc.cam.ac.uk)