Reactions of Oxabutadienes

A major breakthrough in the Diels-Alder reaction of oxabutadienes has been accomplished through the introduction of an electron-withdrawing group in the 3-position. In several papers we have demonstrated the usefulness of this concept which found broad acceptance after our discoveries. 

Predictions based on rigorous or simplified theoretical calculations support the formation of the predominant 2-substituted 3,4-dihydro-2//-pyran regioisomer and accommodate a preferred endo approach of the reactants in which the carbon-carbon bond formation is more advanced than carbon-oxygen bond formation, i.e., a concerted but nonsynchronous [4 + 2] cycloaddition.5 15-20 Notable exceptions to the predicted regioselectivity of the Diels-Alder reactions of oxabutadienes have been observed, and without exception the examples have involved the poorly matched reaction of electron-deficient a,/3-unsaturated carbonyl compounds (An-component) with electron-deficient dienophiles (2tt component), e.g., methyl crotonate or methacrolein.5 2122... 

Scheme 8.20. Diels-Alder reaction of oxabutadiene 78 with 61a.

In the course of these investigations Hoffmann and his group have also developed novel entries to f-butyl 2-methylene-3-oxoalkanoates 2-109a and 2-methylene-3-oxo-sulfones 2-109b by oxidation of 2-108a and 2-108b, respectively obtained by reaction of the aldehydes 2-106 and acrylate 2-107 a or phenyl vinyl sulfone 2-107 b. The cycloadditions of these oxabutadienes to enol ethers and alkenes proceeded in the expected way (Fig. 2-29) [133]. 

Reactions of unsymmetrical methylene 1,3-dicarbonyl compounds with enol ethers have been investigated by Yamauchi et al. [137]. As we have mentioned earlier, the a,/ -unsaturated ketone moiety in alkylidene-/ -ketoesters reacts exclusively as the oxabutadiene. However, high regioselectivity is also observed with mixed alkyl-phenyl-1,3-diketones with exclusive reaction of the aliphatic carbonyl group, whereas in alkylidene-1,3-dicarbonyl compounds bearing an aldehyde and a keto-moiety, the a,/J-unsaturated aldehyde reacts preferentially as oxabutadiene, but not exclusively [130a]. 

Comparable to the 1-oxabutadienes, the azabutadienes constitute a class of widely investigated heterodienes capable of productive 4tr participation in [4 + 2] cycloaddition reactions. TMs work has been the subject of several comprehensive reviews including recent accounts " that should be consulted for a thorough treatment of the mechanism, scope and applications of the [4 + 2] cycloaddition reactions of azabutadienes. Conjugated systems containing nitrogen characteristically are electron-deficient ir-systems (Table 8) and exhibit an expected diminished Diels-Alder reactivity toward representative electron-deficient dienophiles and a modest Diels-Alder reactivity toward electron-rich dienophiles. 

Tietze, L F, Schneider, C, Montenbiuck, A, Asymmetric 1,6-induction in hetero-Diels-Alder reactions of chiral oxabutadienes for a de novo synthesis of enantiomerically pure carbohydrates Lewis acid dependent reversal of facial selectivity, Angew. Chem. Int. Ed. Engl., 33,980-982, 1994. 

The [4 + 2] cycloaddition reactions of 1-oxabutadienes generally exhibit excellent, predictable regioselectivity, and 2-substituted 3,4-dihy-dro-2//-pyrans are formed nearly exclusively at the expense of the 3-substituted isomers [Eq. (I)].1... 

Since the thermal dimerizations of acrolein and methyl vinyl ketone were shown to provide the 3,4-dihydro-2//-pyrans l,12 an extensive range of related observations have been disclosed. This work has been the subject of several reviews.3 14 Only the work reported since the extensive Desimoni and Tacconi account5 of the Diels-Alder reaction of a,/3-unsatu-rated carbonyl compounds, 1-oxabutadienes bearing an oxygen atom at the diene terminus, has been detailed herein. The prior reviews should be consulted for an excellent discussion of the mechanism, scope, and application of the [4 + 2] cycloaddition reactions of a,/3-unsaturated carbonyl compounds as well as for extensive tabular compilations of the work through 1974.3-6... 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

An effective approach to promoting the 4ir participation of oxabutadiene systems in Diels-Alder reactions employs the intramolecular cycloaddition reactions of a,/3-unsaturated carbonyl compounds.27 If this intramolecular variant of the oxabutadiene [4 + 2] cycloaddition is combined with the use or generation of a,j8-unsaturated carbonyl compounds bearing an additional C-3 (a) electron-withdrawing group, exceptionally effective room temperature, regio-, diastereo-, and enantioselective [4 + 2] cycloadditions are observed.134-138 Table 7-II details the intramolecular [4 + 2] cycloadditions of a,j3-unsaturated carbonyl compounds.27,131-145... 

Reactions of Chiral Oxabutadienes with Achiral Vinylethers... 

Reactions of Achiral Oxabutadienes with Chiral Vinylethers... 

As the name implies, the first step of this domino process consists of a Knoevenagel condensation of an aldehyde or a ketone 2-742 with a 1,3-dicarbonyl compound 2-743 in the presence of catalytic amounts of a weak base such as ethylene diammonium diacetate (EDDA) or piperidinium acetate (Scheme 2.163). In the reaction, a 1,3-oxabutadiene 2-744 is formed as intermediate, which undergoes an inter- or an intramolecular hetero-Diels-Alder reaction either with an enol ether or an alkene to give a dihydropyran 2-745. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

This three-component reaction as the key step of this synthesis is called a domino-Knoevenagel-hetero-Diels-Alder reaction. Domino reactions are defined as processes of two or more bond forming reactions in which a subsequent transformation takes place by virtue of the functionalities introduced in a former transformation.2,16 The tetrahydrocarbolinaldehyde 11 first reacts in a Knoevenagel type condensation with Meldrum s acid 14 and ethyleneammonium diacetate 41 as the catalyst to oxabutadiene 44 which then undergoes a Diels-Alder reaction with enol ether 13. 

An extensive range of hetero 1-oxabutadiene systems containing nitrogen (Section 4.3.4) and sulfur (Section 4.3.3) have been investigated and found to function as 4ir components of Diels-Alder reactions. In general, the incorporation of an additional heteroatom into the 1-oxabutadiene system increases its electrophilic character and facilitates its 4tt participation in LUMOdiene-controlled Diels-Alder reactions with electron-rich dienophiles. Examples of such systems are presented in Figure 4. ... 

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