Alkylation of .alpha.-formamido ketone enolate anions. A versatile synthesis of .alpha.-alkyl .alpha.-amino ketones

Abstract

Parallel reaction conditions employing tetrabutylammonium iodide (19.4 g, 52.5 mmol, Aldrich) as the halide source for 16 h afforded the l-iodo-4-pentanol (3)5 in 32% yield after chromatography (silica gel, eluted with ether). Standard treatment of this alcohol (16 h, 21 °C) with acetic anhydride (15 mL) and pyridine (3 mL) with a catalytic amount of 4-(dimethylamino)pyridine (15 mg) afforded the acetate 4; 3.26 g (80%); IR (film) 1735 (0=0) cm'1; NMR (CDC13) 1.20 (d, 3 H, J = 6 Hz, CflgCHOAc), 1.35-2.05 (m, 4 H, CH2CH2), 2.05 (s, 3 H, CH3C=0), 3.21 (t, 2 H, J = 7 Hz, CH2I), 4.85 (m, 1 H, HCOAc).Reactioin of 2-methyltetrahydrofuran with anhydrous lithium bromide and boron trifluoride etherate in dichloromethane for 44 h gave 5 and 8 in approximately equal amounts on the basis of the integration of the methyl doublets at 1.29 and 1.40 in the NMR spectrum.1 -Acetoxy-4-bromopentane (9). Acetyl bromide (12.3 g, 100 mmol) in a pressure-equalizing dropping funnel was added dropwise over 20 min to a solution of 2-methyltetrahydrofuran (10.3 g, 120 mmol) containing zinc chloride (4 mg) maintained at 0 °C by an external ice bath. After addition was complete the ice bath was removed, the reaction stirred at 21 °C for 0.5 h and refluxed for 2.5 h. The reaction mixture was cooled, diluted with ether (130 mL), washed with 5% aqueous sodium bicarbonate solution, water, and brine, dried and the product purified by distillation to give 9: 19.6 g (93%); bp 65-68 °C (2.5 mm) [lit.12 bp 60 °C (0.01 mm)]; NMR (CDC13) 1.73 (d, 3 H, J = 6 Hz, CtfgCHBr), 1.7-1.9 (m, 4 H, CH2CH2), 2.00 (s, 3 H, CH3OC=0), 4.01 (m, 3 H, CHBr, CH2OAc). A weak doublet at 1.23 indicated the presence of ~10% of the positional isomer 6.

α-Azido ketones, Part 6. Reduction of acyclic and cyclic α-azido ketones into α-amino ketones: old problems and new solutions

“…The reaction could be performed in a "crossed" manner to synthesize complex pyrazines such as the naturally occurring cephalostatin 7, cephalostatin 12, and ritterazin K. 3 In some cases the catalytic reduction over Pd-charcoal, 4 Pd-calcium carbonate 5 or platinum oxide 6 was reported to give stable α-amino ketones but usually the products should be protected by their immediate transformation into a salt or an acylated / alkoxycarbonylated derivative to avoid the pyrazine formation. Hydrogen chloride or perchloric acid was added to the solution of the substrate prior to the hydrogenation [7][8][9][10][11] , or as an alternative, concentrated hydrochloric acid or dry hydrogen chloride was added to the reaction mixture just after filtering the catalyst off. 8,9 In situ derivatization of amino ketones was accomplished by adding acetic anhydride 12 or ditert-butyl dicarbonate 13 (Boc anhydride) to the solution of the substrate prior to the hydrogenation.…”

Alkylation of α-tert-butoxycarbonylamino ketone enolate anions. A useful synthesis of α-alkyl-α-amino ketones, 2-acylpyrrolidines, and 2-acylpiperidines

“…Phenacylamine hydrochloride (1, R1 = Ph) and 1-amino-4-phenyl-2-butanone hydrochloride (1, R' = PhCH2CH2) were synthesized by the method of Ackrell et al (9).…”

“…Numerous syntheses of these important starting materials have been devised (1) and new developments in this field continue apace (2)(3)(4)(5)(6)(7)(8). We recently demonstrated (9) that the monoanions of N-formylated a-amino ketones, like those of benzamidoacetone (lo), are regioselectively alkylated on the a-carbon atom and that acidic hydrolysis of these products provided access to a-alkyl-aamino ketones with satisfactory efficiency. A particular advantage of this process is that one substrate can serve as the progenitor of many new a-alkyl-a-amino ketones.…”

Synthesis and Cytotoxicity of Substituted Ethyl 2‐Phenacyl‐3‐phenylpyrrole‐4‐carboxylates

“…Chem. 2003, 336, 181-190 4 µg/mL were considered significant according to the NCI protocol [7].This was the concentration of test compound required to cause 50 % tumor cell death after 3 days incubation. All four compounds were active against the growth of human HL-60 leukemia, HuT-8 lymphoma, and suspended HeLa-S 3 uterine growth.Compounds 9 a and 9 d were active against Tmolt 4 T cell leukemia, and THP-1 acute monocytic leukemia growth but only compound 9 d was active against Tmolt 3 T cell leukemia growth.…”

“…Chem. 2003, 336, 181-190 Ethyl 2-Phenacyl-3-phenylpyrrole-4-carboxylates 185 an α-amino ketone (7) is conveniently prepared in two steps [7] by first forming an α-azidoketone (6) from the 2-bromoacetophenone (5) and NaN 3 in DMSO followed by a reduction carried out by Ph 3 P and pTSA (Figure 2). Finally, heating the β-chloroenal and the salt of the α-aminoketone in dry DMF forms the 2,3,4-trisubstituted pyrrole (9 a-9 d, Figure 3).…”