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Synlett 2006(11): 1687-1690  
DOI: 10.1055/s-2006-944220
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Makoto Shimizu*, Mitsue Tanaka, Tomohiro Itoh, Iwao Hachiya
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Fax: +81(59)2319413; e-Mail: mshimizu@chem.mie-u.ac.jp;
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Publication History

Received 14 March 2006
Publication Date:
04 July 2006 (online)

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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.

Key words

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

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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.

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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.