Remarkable Effects of Additives to Facilitate Aza-Mannich Type Reaction: A Rapid Access to β-Amino Ketone O-Alkyl Oximes

Abstract

Aza-Mannich-type reaction proceeded between imines and the aza-enolates formed from α-iodomethyl ketone O-alkyl oximes with titanium tetraiodide to give β-amino ketone O-alkyl oximes in good to excellent yields. Remarkable effects of added ­silica gel or molecular sieves (4 Å) were observed to promote the addition reactions.

aza-Mannich-type reaction - titanium tetraiodide - iodo­acetone O-benzyl oxime - β-amino ketone O-alkyl oximes

References and Notes

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4

To a solution of O-benzylhydroxylamine hydrochloride (2.07 g, 13.0 mmol) in H₂O (30.0 mL) was added chloroacetone (0.79 mL, 10.0 mmol) and NaHCO₃ (0.84 g, 10.0 mmol) at ambient temperature for 5.0 h. Then, the mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were dried over anhyd Na₂SO₄ and concentrated in vacuo to give chloroacetone O-benzyl oxime (2.08 g, quant., E/Z-mixture) as a colorless oil. Under an argon atmosphere, to a solution of chloroacetone O-benzyl oxime (2.00 g, 10.1 mmol) in acetone (30.0 mL) was added a NaI (2.11 g, 14.1 mmol) at ambient temperature for 14.5 h. The mixture was filtered through a Celite^® pad, and extracted with Et₂O (3 × 10 mL). The organic phase was washed with 10% aq NaHSO₃, dried over anhyd Na₂SO₄, and concentrated in vacuo. Purification by silica gel column chromatography (n-hexane-EtOAc = 30:1) gave iodoacetone O-benzyl oxime (2, 1.90 g, 65%, E:Z = 23:77, E-isomer: R _f = 0.23; Z-isomer: R _f = 0.29) as a pale brown oil. E-Isomer: ¹H NMR (500 MHz, CDCl₃): δ = 2.03 (s, 3 H), 3.87 (s, 2 H), 5.15 (s, 2 H), 7.28-7.38 (m, 5 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 6.0, 13.9, 76.0, 127.9, 128.0, 128.4, 137.6, 154.6. Z-Isomer: ¹H NMR (500 MHz, CDCl₃): δ = 2.34 (s, 3 H), 3.91 (s, 2 H), 5.10 (s, 2 H), 7.26-7.40 (m, 5 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = -7.2, 18.5, 76.0, 127.8, 127.9, 128.3, 137.7, 153.5.

5

To a solution of TiI₄ (69.4 mg, 0.125 mmol) and titanium tetraisopropoxide (0.125 mL, 0.125 mmol, 1.0 M in CH₂Cl₂) in THF (1.0 mL) was added a solution of (Z)-iodoacetone O-benzyl oxime (2, 72.2 mg, 0.250 mmol) in THF (1.0 mL) at 0 °C under an argon atmosphere. After 30 min stirring, to the resulting solution was added a THF (1.0 mL) solution of N-benzylidene-4-methoxyphenylamine (1a, 21.1 mg, 0.100 mmol) and silica gel (dried, 300 mg/mmol) at -78 °C. The mixture was allowed to warm to ambient temperature with stirring for 12.0 h. The reaction was quenched with sat. aq NaHCO₃, and EtOAc and 10% aq NaHSO₃ were added successively. The mixture was filtered through a Celite^® pad, and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over anhyd Na₂SO₄ and concentrated in vacuo. Purification on preparative silica gel TLC (n-hexane-EtOAc = 4:1 as an eluent) gave 4-[N-(4-methoxyphenyl)amino]-4-phenyl-2-butanone-O-benzyl oxime (3a, 35.4 mg, 94%) as a pale brown oil. ¹H NMR (270 MHz, CDCl₃): δ = 1.70 (s, 3 H), 2.41 (dd, J = 5.3, 13.1 Hz, 1 H), 3.20 (dd, J = 8.9, 13.1 Hz, 1H), 3.66 (s, 3 H), 4.30 (br s, 1 H), 4.51 (dd, J = 5.3, 8.9 Hz, 1 H), 5.11 (d, J = 12.2 Hz, 1 H), 5.17 (d, J = 12.2 Hz, 1 H), 6.26-6.30 (m, 2 H), 6.57-6.62 (m, 2 H), 7.22-7.46 (m, 10 H). ¹³C NMR (67.8 MHz, CDCl₃): δ = 20.7, 38.8, 55.7, 56.6, 75.8, 114.2, 114.6, 126.2, 127.3, 128.0, 128.4, 128.5, 128.7, 137.7, 141.3, 143.4, 151.7, 156.0.

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Scheme 4

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