Aminoalkylation of cyclic and acyclic alkyl vinyl ethers

Abstract

The aminoalkylation of carbonyl compounds with ternary iminium salts is of general interest [1 -9]. Recently, we have disclosed that the aminoalkylation of ketones, enamines, imines (derivatives of aldehydes, cyclic or acyclic ketones) and aromatic compounds provides the corresponding Mannich bases in excellent yields and diastereoselectivities [1, 2, 8 -11]. By contrast, only a few other types of nucleophiles have been treated with ternary iminium salts containing alkyl, aryl and carboxylate groups, presumably because of the difficult preparation and handling of these compounds [12 -14]. Aminoalkylation of Cyclic and Acyclic Alkyl Vinyl EthersBeatrix Merla and Nikolaus Risch* Paderborn, Universität-GH, Fachbereich für Chemie und Chemietechnik Received March, 8th, 1999, respectively May 4th, 1999 Keywords: Mannich bases, Synthetic methods, Aminoalkylation, Vinyl ethers, Iminium salts Böhme and Wagner have already described the aminomethylation of the acyclic alkyl vinyl ethers (1a,b) with preformed methylene iminium salts (2a) (R = H and X = Cl) [15]. Only in those cases where the dehydrohalogenation is impossible (e.g. 1b : R 1 = H, R 2 = Me), were they able to isolate the α-halogenated ether 3 (Scheme 1).Katritzky et al. reported that the ethyl vinyl ether 1a can be aminoalkylated by 1-(α-aminoalkyl)benzotriazoles 5 (R = H, Ph) by heating (120 °C) to give quantitatively a mixture of the benzotriazol-1-yl (6) and -2-yl (7) adducts (R = Ph, NR' 2 = morpholine: 6 : 7 = 1 : 1, syn-6 : anti -6 = 1 : 1, syn-7 : anti-7 = 1 : 1) [16] (Scheme 2). These compounds are easily converted into the 1,3-amino ethers by treatment with alkyl magnesium bromide or lithium aluminium hydride [16].Abstract. The aminoalkylation of cyclic and acyclic alkyl vinyl ethers from inexpensive starting materials yields Mannich bases 4 and 10. Preformed and in situ generated iminium salts are used under mild reaction conditions. In some cases it is possible to isolate the α-halogenated 1,3-amino ethers 3 which have so far only ever been assumed to exist. Furthermore, the preparation of the already known 1-benzotriazolyl-3-aminoalkyl ethers 6 and 9 using this methodology is also successful.

Capture of benzotriazole-based Mannich electrophiles by CH-acidic compounds

“…A significant diversification is exemplified by the development of mild benzotriazole-mediated aminoalkylations and related reactions. [12][13][14][15] Benzotriazole-based aminoalkylating reagents have been readily utilized with various nucleophiles, including: enolates, 16 imidazolidine derivatives, 17 isonitriles, 18 enol ethers, [19][20][21][22] enamines, 20,22,23 and enamides. 22,23 Many active pharmaceutical ingredients (APIs) are obtained through a key Mannich step or display the typical core of a Mannich base.…”