Synthesis of Substituted α,β-Unsaturated Ketones, Pyrazoles, Isoxazoles and 2,4,6-Triarylpyrylium Chlorophosphates via β-Lithiation of Benzotriazolyl­vinyl Ethyl Ether

Abstract

Quenching the b-lithiated benzotriazolylvinyl ethyl ether 2 with aldehydes, acid chlorides and chalcones provided the corresponding b-hydroxyalkyl derivatives 4a-f, b-keto vinyl ethers 7a,b, and Michael adducts 8a,b, respectively. The alkylated product 4 was converted into a,b-unsaturated ketones 5a-f upon treatment with bromine. b-Keto vinyl ethers 7a,b cyclocondensed with hydrazines to afford pyrazoles 9a-d, and with hydroxylamine hydrochloride to give isoxazoles 10a,b. Treatment of 8 with phosphorus pentachloride resulted in the formation of 2,4,6-triarylpyrylium chlorophosphates 12.Heteroatom-assisted metalations are important tool for the functionalization of carbocyclic-aromatic and heteroaromatic compounds, and regioselective ortho-lithiation at an sp 2 -hybridized ring carbon directed by heteroatom bearing substituent. 1 Recently, the generation and reaction of sp 2 carbanionic centers in the proximity of heterocyclic nitrogen atom have been reported. 2 The metalation without the assistance of an activating group is often difficult to achieve due to charge repulsion of the heteroatom lone pair, and low acidity of the hydrogen to be abstracted. Repulsion between the lone pair of nitrogen atom and negative charge considerably reduces the thermodynamic stability.Regioselective metalation of vinyl ethers has received considerable attention. McDougal and Rico reported the b-lithiation by sec-butyllithium of methoxymethyl vinyl ether, which was then reacted with a variety of electrophiles. 3,4 cis-2-Ethoxyvinyl lithium has been synthesized by transmetalation from the corresponding tin derivative. 5,6 Lithiation of vinyl ethers is known to proceed smoothly at the a-position upon treatment with organolithium compounds at low temperature, 7,8 and the pressure of additional directing groups such as halogens or thioaryl groups generally assist and stabilize the lithiation product by intramolecular interaction.Benzotriazole is a good activating group for a-lithiations, 9-12 serving as both a strong electron-withdrawing and coordinative group during the lithiation. These two properties can facilitate metalation. We report herein the b-lithiation of benzotriazolylvinyl ethyl ether 2 and the subsequent reactions with various electrophiles provide a method of producing substituted derivatives (e.g. a,b-unsaturated ketones, pyrazoles, and isoxazoles) and 2,4,6-triarylpyrylium chlorophosphates (Schemes 1 and 2). Scheme 1a-Benzotriazolyl-substituted ketones have been used as a precursor for the synthesis of various useful organic compounds. 13-15 Thus, simply mixing benzotriazol-1-ylacetophenone (1) with diethyl sulfate in dimethyl sulfoxide in the presence of t-BuOK at room temperature afforded aphenyl-b-benzotriazolylvinyl ethyl ether (2) in excellent yield (Scheme 1). The 1 H NMR spectrum showed a characteristic signal at approximately 7.10 ppm, which was assigned to the proton attached to the double bond. The cis orientation of the ethoxy group and the vinylic proton was established by NOE: irradiation of the vinylic pr...

Five‐Membered Heterocycles: 1,2‐Azoles. Part 1. Pyrazoles

“…Alkylation of pyrazolines 128 at the 4-position of the pyrazoline ring is a versatile route to unsymmetrical 1,3,4,5-tetrasubstituted pyrazolines 130 and -pyrazoles 131 [159]. The a-benzotriazolyl-b-ethoxy-a,b-unsaturated ketones 132 react with hydrazines to afford directly the corresponding 4-benzotriazolylpyrazoles 133 [160].…”