2-Methoxy-1,3-butadiene

[3588-30-5]  · C5H8O  · 2-Methoxy-1,3-butadiene  · (MW 84.13)

(2p or 4p partner in cycloaddition reactions;1 regioselective cyclopropanation substrate;16 dihydrofuran precursor;18 d-hydroxy ketone synthon)

Physical Data: bp 75 °C; d 0.827 g cm-3.

Solubility: sol alcohol, ether, benzene, acetone.

Form Supplied in: colorless liquid; not commercially available, but its precursor, 1,3,3-trimethoxybutane, can be purchased.

Preparative Method: by slow addition of the acetal precursor to a preheated mixture (150 °C) of acetal and KHSO4 (1:1 w/w), and collection of the diene-containing distillate in a flask cooled to -78 °C. The distillate is poured into water, the organic and aqueous layers are separated, and the organic layer is dried with 4 Å molecular sieves. The resulting mixture is fractionally distilled in the presence of hydroquinone to afford the diene in modest yield.5

Handling, Storage, and Precautions: classified as a flammable liquid; reported to be toxic.

Reactivity.

2-Methoxy-1,3-butadiene (1) is a multifaceted diene that has seen application both as a masked cyclohexanone precursor in Diels-Alder cycloadditions and as an allylic vinylic ether. Polarization of the diene by the methoxy group dictates the regioselectivity of the reactions of (1);1 the dipole moment has been calculated using the Halverstadt-Kumler method.2 The regioselectivity observed is consistent with predictions obtained from frontier molecular orbital (FMO) theory using terminal and secondary orbital calculations,3 and by Hehre's reactive surface mapping technique.1,4

Cycloaddition Reactions.

2-Methoxy-1,3-butadiene (1) is commonly used as a 4p component in [p4s + p2s] cycloadditions to prepare masked cyclohexanone (cyclohexanone methyl enol ether) systems. (1) reacts readily with a variety of dienophiles to afford predominately the para-isomer (eq 1). The para/meta ratio of isomers is highly dependent upon the dienophile. Glyoxylate esters (eq 2),6 nitroso compounds (eq 3),7 and bicyclic dienophiles8 often afford regioisomeric mixtures, while quinones,9 acrylic acid derivatives,10 and cycloalkenes11 afford exclusively the para-isomer. The observed predominance for the para-isomer has allowed this reagent to be used in key steps for the synthesis of several natural products,12 most notably the anthracyclinone antibiotics (eq 4).13

In cycloaddition reactions with Fischer-type carbenes (eq 5) and other dienophiles, 2-methoxy-1,3-butadiene can be exposed to extreme temperatures (219 °C, sealed tube) without significant decomposition.12 However, (1) rapidly decomposes when exposed to Lewis acids (eq 6).14 Depending upon the dienophile and temperature, (1) also can act the 2p component in [4 + 2] cycloadditions. Cycloaddition of (1) with electron-deficient 5-methoxycarbonyl-2-pyranones (eq 7) at 25 °C affords the expected tetrahydrocoumarin, resulting from participation of (1) as the 4p reaction partner; warming the reaction mixture to 114 °C provides the 2-oxabicyclo[2.2.2]oct-5-en-3-one system, where the vinyl ether double bond reacts as the 2p component in this inverse electron-demand Diels-Alder reaction.15

(1) is also highly chemoselective with respect to the dienophile. In the synthesis of daunomycinone analogs, cycloaddition between (1) and an anthracene bisquinone affords the cycloadduct where the diene adds across the more electron-deficient tetrasubstituted double bond, rather than the more accessible, but less reactive, disubstituted double bond (eq 8).

Miscellaneous Reactions.

Predictable regioselectivity in the reactions of 2-methoxy-1,3-butadiene makes it an ideal cyclopropanation substrate. Reaction of (1) with the metallocarbenoid generated from Ethyl Diazoacetate occurs exclusively at the electron-rich 1,2-double bond to afford a 0.8 trans/cis isomeric mixture regardless of the cyclopropanation catalyst (eq 9).16 The best cyclopropanation catalyst is Dirhodium(II) Tetraacetate.

Transition metal-mediated transformation of these vinylcyclopropanes has been reported. Conversion of vinylcyclopropanes to dihydrofuran systems occurs with Copper Bronze (eq 10), whereas treatment with PdII and/or RhI or RhII affords ethyl 4-methoxy-2,4-hexadienoate (eq 11).17 The same vinylcyclopropane has been transformed to a dihydrofuran via an oxepin intermediate under acidic conditions in the presence of rhodium tetraacetate (eq 12).18

d-Hydroxy ketone systems have been prepared using (1). Alkylation of 2-methoxy-1,3-butadiene at the 4-position with an a-alkoxy iron carbene affords 6-ethoxy-6-phenylhex-3-en-2-one after acidic hydrolysis (eq 13).19 Electroreductive coupling of (1) with acetone followed by acid hydrolysis of the enol ether affords 6-hydroxy-6-methyl-2-heptanone in 78% yield (eq 14).20

The vinyl ether portion of (1) permits the rapid formation of unsymmetrical allylic acetals that can be converted via Claisen rearrangement to chroman systems in a one-pot reaction sequence (eq 15).21

Related Reagents.

1-Acetoxy-1,3-butadiene.


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Eugene B. Grant, J. Pierre Gittinger & Robert S. Coleman

University of South Carolina, Columbia, SC, USA



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