Elsevier

Tetrahedron

Volume 56, Issue 27, 30 June 2000, Pages 4725-4731
Tetrahedron

Reexamination of Products and the Reaction Mechanism of the Chalcogeno-Baylis–Hillman Reaction: Chalcogenide–TiCl4-mediated Reactions of Electron-Deficient Alkenes with Aldehydes

https://doi.org/10.1016/S0040-4020(00)00396-3Get rights and content

Abstract

Reactions of p-nitrobenzaldehyde (4) with methyl vinyl ketone (5) were conducted in the presence of TiCl4 and dimethyl sulfide (3) or selenopyranone 6. When the raw product was purified by column chromatography on silica gel, α-chloromethyl aldol 8 was obtained as a mixture of diastereoisomers 8a and 8b. In contrast, purification of the raw product by preparative TLC on silica gel gave α-methylene aldol 7. The mechanism for the formation of α-chloromethyl aldol 8 and diasteroselection for the syn-isomer 8a and anti-isomer 8b are discussed.

Introduction

We recently devised a new reaction, the chalcogeno-Baylis–Hillman reaction, in which a chalcogenide and TiCl4 are used instead of a tertiary amine as a catalyst of the Baylis–Hillman reaction.1 An advantage of this reaction is that it proceeds smoothly under mild conditions and is finished within an hour, thus overcoming the drawback of the slow rate of the Baylis–Hillman reaction.2 The chalcogeno-Baylis–Hillman reaction has been applied to the reactions of α,β-unsaturated ketones, nitriles, carboxylic acid esters, and thioesters.3., 4. Enantioselective synthesis utilizing this methodology has also been studied.5., 6. A hydrogen-chloride adduct 2 was detected in the raw product from the chalcogeno-Baylis–Hillman reaction of acrylic acid thioesters by 1H NMR spectroscopy4 (Scheme 1).

On the other hand, reactions of enones with aldehydes mediated by a combination of titanium (IV) halides (TiX4) and (n-Bu)4NI7 or TiX4 alone8 have been studied and found to be useful for preparation of α-halomethyl aldols or α-halomethyl enones. The outcome of these studies implied that the hydrogen-chloride adducts of the Baylis–Hillman products (α-chloromethyl aldols) would also be formed from the chalcogenide–TiCl4-mediated reaction of other active alkenes. We had not isolated the hydrogen-chloride adduct, but very recently were able to obtain it from the reaction of p-nitrobenzaldehyde (4) with methyl vinyl ketone (5) catalyzed by TiCl4 and 2,6-diphenylselenopyran-4-one (6). Experiments were undertaken to examine the difference between the previous reactions3., 9. and the present ones. In this report we describe the formation of an α-chloromethyl aldol (a hydrogen-chloride adduct of the Baylis–Hillman product) and its formation mechanism.

Section snippets

Results and Discussion

In the course of our study on the chalcogenide–TiCl4-mediated reaction using chalcogenopyrones, the raw product, obtained from the reaction of p-nitrobenzaldehyde (4) and methyl vinyl ketone (5), was purified by column chromatography instead of preparative TLC, and an unexpected product, 3-chloromethyl-4-hydroxy-4-(p-nitrophenyl)butan-2-one (8), was afforded as a mixture of two diastereoisomers, with a ratio of 8a:8b=3:1 in 95% yield. The isomer ratio did not vary with reaction times of 15 min, 1

General methods

Melting points were obtained with a Yanagimoto micro-melting-point apparatus and are uncorrected. IR spectra of solids (KBr) and liquids (NaCl) were recorded on a JASCO IRA-100 spectrophotometer. 1H NMR spectra were recorded on a JEOL GX-270 (270 MHz) or a JEOL EX-400 (400 MHz) spectrometer with tetramethylsilane as an internal standard. 13C NMR spectra were obtained on a JEOL EX-400 spectrometer. Mass spectra were recorded on a JEOL JMS-SX102A spectrometer with a direct-insertion probe at 70 eV.

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (Nos. 10133244 and 11120247) from the Ministry of Education, Science, Sports and Culture, Japan.

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