Crotonaldehyde1

(E)

[123-73-9]  · C4H6O  · Crotonaldehyde  · (MW 70.09) (Z)

[15798-64-8]

(key electrophilic component in a wide variety of reactions1)

Alternate Names: 2-butenal; crotonic aldehyde.

Physical Data: (E) isomer: mp -76.5 °C; bp 104.0 °C d 0.846 g cm-3.

Solubility: sol H2O (19.2 g/100 mL); sol alcohol, ether, and most organic solvents.

Form Supplied in: commercial crotonaldehyde is predominately the (E) isomer containing 4-6% of the (Z) isomer; also available as a 90% solution stabilized with 8-10% water.

Preparative Methods: pure (E) isomer and highly enriched (Z) isomer have been prepared by oxidation of (E)- and (Z)-crotyl alcohols.2 Pure (Z) isomer has been prepared via a retro-Diels-Alder reaction at high temperature.3

Purification: fractionally distilled through a short Vigreux column.

Handling, Storage, and Precautions: to prevent polymerization and autooxidation, store under nitrogen atmosphere and refrigerate. Crotonaldehyde is readily absorbed through the skin and should be handled with gloves and protective clothing in a well ventilated fume hood. Toxicity: oral-rat LD50: 300 mg kg-1. Incompatible with strong acids, strong bases, oxidizing and reducing agents. Decomposes on prolonged exposure to air.

1,2-Additions.

Crotonaldehyde serves as an electrophilic target for a vast array of nucleophilic reagents. Grignard and organolithium reagents react to afford, after hydrolysis, good yields of secondary allyl alcohols.1,4 1,3-Dienes can be prepared by elimination of the resulting secondary allyl alcohols,5 or via Wittig6 and Wittig-type reactions.7 Allyl8 and alkynyl9 organometallic reagents afford good yields of the allyl alcohols from crotonaldehyde, some with a good stereocontrol.8c,d Allylation in aqueous solvent is also possible.10 Reformatsky reaction of difluorochloromethyl ketones utilizing a copper(I) or silver(I) catalyst with crotonaldehyde generates a,a-difluoro-b-hydroxy ketones in high yields,11 while the corresponding dichlorofluoroacetates afford the (Z)-a-fluoro-a,b-unsaturated carboxylates.12 Substituted lactones and butenolides are produced from 1,2-additions with nucleophilic reagents that possess latent carboxylate functionalities.13 1,3-Asymmetric induction has been achieved on addition of 2-lithio-2-(1-methyl-2-alkenyl)-1,3-dithianes to crotonaldehyde to produce predominately 1,3-syn adducts (eq 1).14 Enantioselective 1,2-addition has been demonstrated using chiral allenic boranes to produce the propargyl carbinol in 97-98% ee.15 The silylated cyanohydrin of crotonaldehyde is conveniently prepared using Sodium Cyanide impregnated on Amberlite XAD resin in the presence of Chlorotrimethylsilane.16 The enzyme mandelonitrile lyase catalyzes the enantioselective cyanohydrin formation from crotonaldehyde in as high as 95% ee.17

1,4-Additions.

In comparison, nucleophilic agents that preferentially add to the alkenic terminus of crotonaldehyde are few in number. Thiols,1 sodium nitrite,18 or imides,1 malonate esters,19 and nitromalonic or nitroacetic esters1 in the presence of base generally add with good 1,4-selectivity. Methanetricarboxylic esters under phase transfer catalysis afford a 90% yield of the two-carbon elongated Michael adduct.20 Surprisingly, the lithium dienolate of a chiral dioxinone adds in a Michael addition to give the four-carbon chain extended aldehyde with high diastereoselectivity (eq 2).21 Cyclopropylacylsilanes are formed from initial Michael addition of an acylsilylsulfur ylide.22 Examples of ring formation from crotonaldehyde involve an initial Michael addition followed by closure on the aldehyde carbonyl.23 The Skraup synthesis of 2-methylquinolines utilizes this mode of cyclization.24 Cyclization of crotonaldehyde on certain anthraquinones occurs through a Michael reaction followed by an intramolecular Marschalk reaction.25 Organocopper reagents react predominately with 1,4-addition to produce the substituted aldehydes.26

Acetal Formation.

Crotonaldehyde reacts with a variety of alcohols or orthoformates, usually under acid catalysis, to form acetals.1,27 Chiral C2-symmetric acetals, for use as chiral auxiliaries, have been prepared (eq 3).28 Cyclic dithioacetals of crotonaldehyde can easily be prepared from the dithiol using SiO2-SOCl2 as catalyst.29

Reduction.

Crotonaldehyde can be selectively reduced at either the carbonyl or the double bond to afford good yields of crotyl alcohol or butyraldehyde. Hydride transfer reagents, Meerwein-Pondorf-Verley reduction, or catalytic hydrogenation using Os on charcoal, all give crotyl alcohol.30 Hydrogenation over Pd catalysts gives varying amounts of butyraldehyde.1,30 Nickel catalysts at elevated temperatures fully hydrogenate crotonaldehyde to butanol.1,30

Aldol Condensations.

Crotonaldehyde readily participates in a wide variety of aldol condensations. Classic Knoevenagel condensation as well as CoII-catalyzed Knoevenagel condensations lead to dienone products.31 Dienones and dienoates may also be produced by reaction with the lithium enolates of ketones and esters in the presence of TMSCl at low temperature.32 Stereoselective aldol additions to crotonaldehyde have been numerous. Many highly anti-33 and syn-selective34 additions to crotonaldehyde have been demonstrated, one a catalytic asymmetric syn-selective aldol (eq 4).35 An asymmetric aldol between crotonaldehyde and p-Tolylsulfonylmethyl Isocyanide catalyzed by a chiral silver(I) catalyst affords the trans-4-tosyl-2-oxazoline in 85% ee.36 Diastereoselective aldols can also be achieved using chiral (h6-arene)chromium complexes.37

Pericyclic Reactions.

Crotonaldehyde is a versatile participant in pericyclic reactions. In Diels-Alder reactions it may either function as a diene or dienophile. As a diene, crotonaldehyde reacts at elevated temperatures with alkenes to afford a wide variety of substituted dihydropyrans.1,38 The addition of a lanthanide catalyst allows the cyclization to occur at significantly lower temperature.39 Additionally, enolized forms of crotonaldehyde also function as dienes.40 The double bond of crotonaldehyde acts as dienophile towards an array of 1,3-dienes.1 The temperature required for these cyclizations may be reduced by the addition of Lewis acid catalysts.41 Asymmetric catalysts have been developed for the reaction of crotonaldehyde with cyclopentadiene.42 The endo isomer predominates and ee's range from 2-96%. An asymmetric catalyst that promotes the hetero-Diels-Alder reaction of crotonaldehyde with Danishefsky diene, affording product dihydropyrone in 92% ee (eq 5), has also been described.43 Lewis-acid complexes of crotonaldehyde are normally unreactive towards ordinary alkenes in ene processes. However, a Lewis acid assisted ene-reaction of crotonaldehyde with achiral44 and chiral45 2-(alkylthio)allyl silyl ethers has been reported. The achiral ene-reaction is highly trans selective and the chiral ene-reaction occurs with almost complete chirality transfer.


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Abbott Laboratories, Abbott Park, IL, USA



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