Unresolved mechanism and substrate scope of the $AlCl_3$-mediated modified Wichterle reaction: the $AlCl_3$/p-nitrophenol conversion of vinyl chlorides into ketones

The 1979 preliminary communication of Kobayashi, Fujiyama, Yoshioka and Matsumoto (Chemistry Letters 1979, 8, 837) reported that ketones bearing an alpha-(3-chloro-2-butenyl) or alpha-(2-chloroallyl) side chain — vinylic-chloride ('vinyl chloride') substrates accessible by ketone-enolate alkylation with 1,3-dichloro-2-butene — are converted by $AlCl_3$ in nitromethane into open-chain 1,5- and 1,4-diketones, and that one equivalent of p-nitrophenol markedly accelerates the reaction and improves isolated yields. The authors proposed only as a working hypothesis a mechanism involving coordination of the vinyl chloride to an $AlCl_3$/phenol complex and ionization to a carbocation stabilized by intramolecular participation of the substrate carbonyl. They left open the mechanistic role of p-nitrophenol (proton-transfer cocatalyst, ligand modifying the Lewis acidity of $AlCl_3$, or transient nucleophile), the reasons why other Lewis acids ($SnCl_4$, $TiCl_4$, $ZnCl_2$) divert the same substrates to bridged olefins or mixtures rather than diketones, the structural features that make some substrates unreactive or resinous, and the origin of small amounts of furan byproducts. No later study is known to have addressed these questions, and the reaction family has received no substantive follow-up since the early 1980s. The open problem is to establish the mechanism and predictive substrate scope of this $AlCl_3$-mediated modified Wichterle reaction.

Background

Name-reaction context. The Wichterle reaction, introduced by Otto Wichterle in 1947-1948, is the conversion of vinylic chlorides (alkenes with chlorine directly attached to a carbon of the carbon-carbon double bond) into ketones by treatment with concentrated sulfuric acid. Its most-used form transforms a gamma-chlorocrotyl (= 3-chloro-2-butenyl, $-CH_2-CH=C(Cl)-CH_3$) substituent into a 3-oxobutyl ($-CH_2-CH_2-CO-CH_3$) substituent. Because the newly formed ketone can then cyclize onto a nearby reactive center — by intramolecular aldol condensation if another carbonyl is present, or by intramolecular Friedel-Crafts reaction if an aromatic ring is present — the overall sequence builds a cyclohexenone ring onto a ketone and serves as an alternative to the Robinson annulation, in which methyl vinyl ketone is the annulating reagent; in the Wichterle variant, 1,3-dichloro-cis-2-butene plays the role of the methyl vinyl ketone surrogate. Classic applications include the synthesis of bicyclo[4.4.0]decanones and bridged bicyclo[3.3.1]nonanones (Marshall and Schaeffer, 1965). Under the classic strongly acidic conditions, 2-(3-chloro-2-butenyl)-2-methylcyclohexanone gives 2,5-dimethylbicyclo[3.3.1]non-2-en-9-one, a 'bridged olefin', as the main product. The required alpha-chloroalkenyl ketone substrates are prepared by alkylating a ketone enolate with 1,3-dichloro-2-butene.

Modifications of the reaction. Two lines of modification define the setting of the present problem. First, other groups had introduced milder methods for hydrolyzing vinyl halides to ketones (Mukaiyama, Imamoto and Kobayashi, 1973; Martin and Chou, 1978), which deliver the ketone without a strongly Brønsted-acidic medium. Second, Kobayashi and Matsumoto (Hokkaido University) developed from 1973 what they called the 'modifizierte Wichterle-Reaktion' (modified Wichterle reaction): replacing sulfuric acid by formic acid containing perchloric acid converts alpha-(3-chloro-2-butenyl)ketones into fused 2-cyclohexenones (octalones) and alpha-(2-haloallyl)ketones into 1,4-diketones, and was applied to the synthesis of 4-estrene-3,17-dione and the fragrance compound dihydrojasmone (Bull. Chem. Soc. Jpn. 1979, 52, 2978). Their 1979 papers then introduced a Lewis-acidic variant: in nitromethane ($CH_3NO_2$) solvent, $AlCl_3$ (a strong, water-sensitive Lewis acid, used in about four equivalents) converts alpha-(3-chloro-2-butenyl)ketones into open-chain 1,5-diketones (two ketone carbonyls separated by three carbon atoms) and partly into the fused-ring annelation products, while alpha-(2-chloroallyl)cyclohexanones give the corresponding 1,4-diketones (Chemistry Letters 1979, 8, 837; companion method paper: Tetrahedron Letters 1979, 20, 3489). One equivalent of p-nitrophenol accelerates the reactions and improves yields, phenol is less effective and harder to remove on workup, and methanol slows the reaction. Unlike the strong-acid versions, this variant diverts the substrates away from the bridged-olefin channel toward hydrolysis to the diketones.

What was left open. The 1979 Chemistry Letters communication is a preliminary account. It presents product distributions and a proposed mechanism — coordination of the vinyl chloride to an $AlCl_3$/phenol complex, followed by ionization to a carbocation that is stabilized by intramolecular participation of the substrate's own carbonyl group and then hydrolyzed to the ketone — explicitly as a working hypothesis, with no kinetic, spectroscopic, or trapping data. The effect of p-nitrophenol is documented quantitatively (for example, for the 2-chloroallyl series: 47% yield in 4 h with $AlCl_3$ alone versus 62% in 0.5 h with $AlCl_3$/p-nitrophenol; and 18% in 18 h versus 40% in 3 h for a methylated substrate) but its mechanistic role is not established. The comparative Lewis-acid data are empirical: $SnCl_4$ and $TiCl_4$ convert one alpha-(3-chloro-2-butenyl)cyclohexanone exclusively to the bridged olefin, $ZnCl_2$ (at reflux) gives a mixture of bridged olefin and diketone, while $AlCl_3$ (at room temperature) gives hydrolysis to the diketone. Two substrates fail outright (a bicyclic chloroketone is recovered unchanged; another chloroketone gives an intractable resin, rationalized only by the hypothesis of excessive carbocation stabilization by carbonyl participation), and small amounts of furan byproducts are detected (by chromatography and proton NMR) in the conversion of certain 2-chloroallyl cyclohexanones to 1,4-diketones — a connection that plausibly relates to the well-known cyclodehydration of 1,4-diketones to furans (cf. Nienhouse, Irwin and Finni, 1967, on substituted-furan synthesis). The structural features that predict which substrates convert cleanly were not delineated.

Problem Statement

Establish the mechanism and the predictive substrate scope of the $AlCl_3$-mediated modified Wichterle reaction — the conversion of vinyl chlorides into ketones reported by Kobayashi, Fujiyama, Yoshioka and Matsumoto (Chemistry Letters 1979, 8, 837) under the original protocol (about four equivalents of $AlCl_3$ in nitromethane at room temperature, with and without one equivalent of p-nitrophenol). The source communication left open four linked facets that jointly constitute this single objective:

(1) Intermediate and activation-mode validation: determine whether the conversion proceeds through the postulated carbocationic intermediate — formed upon coordination of the vinylic C-Cl bond to an $AlCl_3$/phenol complex and stabilized by intramolecular participation of the substrate carbonyl — or through some other pathway.

(2) Mechanistic role of p-nitrophenol: establish whether its rate- and yield-improving effect arises from proton-transfer cocatalysis, from ligand modification of the Lewis acidity of $AlCl_3$, or from transient nucleophilic participation (or a combination thereof).

(3) Lewis-acid channel control: establish why $SnCl_4$ and $TiCl_4$ convert alpha-(3-chloro-2-butenyl)ketones to bridged olefins (the classic Wichterle-type products) while $AlCl_3$ directs hydrolysis to the diketones and $ZnCl_2$ (at reflux, in the source comparison) gives a mixture of both channels — that is, which property of the Lewis acid (strength, halophilicity, coordination mode, temperature-dependent effects, or protic impurities) controls the channel.

(4) Scope and byproduct delineation: identify the structural features of the vinyl chloride ketone substrates that permit clean conversion to the diketones versus recovery of starting material or resin formation (including the reported failing substrates), and explain the origin of the small amounts of furan byproducts formed in the conversion of alpha-(2-chloroallyl)cyclohexanones to 1,4-diketones.

These facets are mutually dependent and share one scientific objective: a validated mechanistic model that predicts the reaction outcome (diketone, annelation product, bridged olefin, resin, or furan) for a given substrate, Lewis acid, and additive.

References

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