We wish to report the discovery of a novel skeletal rearrangement of α-aminoketones. An example of this rearrangement is the conversion of 2-ethyl-2-methylaminobutyrophenone (Ia) to 3-methylamino-3-phenyl-4-hexanone (IIa) in 35% yield at 240°C. Similarly, Ib could be rearranged to IIb in 32% yield. The scope of the reaction was shown to include aliphatic aminoketones by the 32% conversion of a-methylaminocyclopentyl methyl ketone (V) to 2-methyl-2-methylamino-cyclohexanone (VI), which rearrangement involved ring enlargement.
A mechanism for this rearrangement is proposed which involves two carbon skeleton migrations. In the rearrangement of Ia, for example, the iminoalcohol III is considered to be an intermediate resulting from the migration of an ethyl group.
Further rearrangement of III with migration of a phenyl group would result in formation of the product, IIa. The hydroxyimine III or a mixture of the corresponding hydroxyketone and methylamine, when placed under the conditions of the original rearrangement reaction, gave the product in comparable yield. The isomeric iminoalcohol IV was eliminated as an intermediate, since it gave significantly lower yields (7%) of product IIa when subjected to comparable reaction conditions.
In the aliphatic series the isomeric iminoalcohols, although not considered as intermediates in the rearrangement, nevertheless can be used as starting materials for the synthesis of α-aminoketones which would otherwise be difficult to prepare. For example, the α-hydroxyketone VII in the presence of methylamine gave a 22% yield of the α-aminocyclohexanone VI.
The proposed mechanism predicts that an α-tertiary aminoketone would be much more difficult, if not impossible, to rearrange, since the first rearrangement product would involve a zwitterion. The validity of this prediction was demonstrated in an attempted rearrangement of the tertiary aminoketone 2-ethyl-2-dimethylaminobutyrophenone at 265°C. The absence of unconjugated carbonyl in the infrared spectrum and the recovery of the starting aminoketone in 70% yield indicated that no rearrangement had occurred.
The generality of the rearrangement of hydroxyimines was further demonstrated by the similar conversions of 3-hydroxy-3-phenyl-2-butanone and 1,1-diphenyl-1-hydroxy-2-propanone to 3-methylamino-3-phenyl-2-butanone (39%) and 2-methylamino-2-phenylpropiophenone (36%), respectively.
2-Ethyl-2-methylaminobutyrophenone (Ia) had b.p. 74-6°C(0.12 mm.), n25D 1.5227; Ia HCl salt, m.p. 204.5-205°C. The structure of Ia was established by sodium borohydride reduction to 1-(1-ethyl-1-methylaminopropyl)-benzyl alcohol (HCl salt, m.p. 259°C) with subsequent N-methylation according to the Eschweiler-Clark procedure to give 1-(1-dimethylamino-1-ethylpropyl)-benzyl alcohol (m.p. 81-82°C; HCl salt, m.p. 233°C dec). The dimethylamino alcohol was synthesized independently.
The rearranged product from Ia, namely, 3-methylamino-3-phenyl-4-hexanone, IIa, had b.p. 60-65°C(0.03 mm.), n28.5D 1.5135, d25 0.9972; HCl salt, m.p. 210.5-211°C.
The structure of IIa was established by sodium borohydride reduction to 3-methylamino-3-phenyl-4-hexanol (m.p. 120-121°C), then periodate cleavage of the amino alcohol and isolation of propiophenone as its 2,4-dinitrophenylhydrazone derivative.
When 2-methyl-2-methylaminobutyrophenone, Ib [b.p. 79°C(0.4 mm.), n25D 1.5243], was heated in a sealed tube at 200°C for ten hours, 2-methylamino-2-phenyl-3-pentanone, IIb, could be isolated (HCl salt m.p. 192-193°C). Sodium borohydride reduction of IIb gave diastereoisomeric 2-methylamino-2-phenyl-3-pentanols (m.p. 115-116°C and m.p. 75-76°C) which, upon periodate cleavage, gave acetophenone and propionaldehyde, both isolated as their 2,4-dinitrophenylhydrazone derivatives.
The structure of the starting aliphatic aminoketone, α-methylaminocyclopentyl methyl ketone, V [b.p. 49-50°C (1.5 mm.), n25D 1.4642; HCl salt, m.p. 118-120°C] was established by sodium borohydride reduction to 1-(1-methylaminocyclopentyl)-ethanol (HCl salt, m.p. 113-114°C), then periodate cleavage and isolation of cyclopentanone as its 2,4-dinitrophenylhydrazone derivative. The structure of the rearranged product, 2-methyl-2-methylaminocyclohexanone, VI [b.p. 55-57°C(2mm.), n25D 1.4710; HCl salt, m.p. 191-192°C] was established by its independent synthesis from 2-bromo-2-methylcyclohexanone and methylamine.
The structure of the product (3-methylamino-3-phenyl-2-butanone; HCl salt, m.p. 213°C) obtained from the reaction of 3-hydroxy-3-phenyl-2-butanone with methylamine was established by ultraviolet and infrared spectra.
The structure proof used for the product (2-methylamino-2-phenyl-propiophenone; HCl salt, m.p. 215.5-216°) obtained from the reaction of 1,1-diphenyl-1-hydroxy-2-propanone with methylamine comprised sodium borohydride reduction of the aminoketone to diastereoisomeric 1-(1-methylamino-1-phenyl-ethyl)-benzyl alcohols (m.p. 122°C and m.p. 91°C) and then periodate cleavage and isolation of acetophenone as its 2,4-dinitrophenylhydrazone derivative.
The structure of 1,1-diphenyl-1-methylamino-2-propanone (HCl salt, m.p. 214-215°C) was established by infrared analysis as well as by sodium borohydride reduction to 1,1-Biphenyl-1-methylamino-2-propanol (m.p. 76-76.5°C), with periodate cleavage to give benzophenone and acetaldehyde, both isolated as their respective 2,4-dinitrophenylhydrazone derivatives.