Cycloaddition of acrolein

By using unactivated K-10 montmorillonite in the absence of solvent, the endo-exo selectivity of the cycloadditions of acrolein and methyl vinyl ketone with cyclopentadiene and cyclohexadiene is low [8] (Table 4.2, entry 3), while highly reactive dienophiles such as 1,4-benzoquinone and N-phenyl... 

Hersh et al. found that the cationic complex [CpFe(CO)2(THF)]BF4 (23) can accelerate the [4 + 2] cycloaddition of acrolein and cyclopentadiene [32]. However, the catalytic activity was higher than expected from rate constants determined in stoichiometric experiments, indicating that a Brpnsted or Lewis acid impurity might accelerate this process and generating doubts about the role of 23. 

For the preparation of cephems from a protected t-butyl ce-methoxygly-cinate thioamide and an orthoamide, an azathiadiene was formed which afforded the 1,3-thiazine derivative after cycloaddition of acrolein (Scheme 42) (89JOC2889). 

Remarkably, the cycloaddition of acrolein at the intermediate cobaltacycle selectively occurs at the carbonyl-, rather than at the C,C double bond, to give a vinylpyrane. In this cycloaddition, methyl acetate stabilizes the cpCo complex (87MI6) [Eq.(37)]. 

Another hint toward understanding reaction dynamics on a bifurcating surface was supplied by Singleton in his study of the Diels-Alder cycloaddition of acrolein with methyl vinyl ketone (Reaction 8.12). Recognizing the interconversion of 87 and 88 through a Cope rearrangement along with careful kinetic analysis led to an estimate of the ratio of the rate of formation of 87 88 as 2.5 1. 

Cationic ansa metallocenes can be utilized as chiral catalysts in Diels-Alder reactions. For example, in the presence of the cationic zirconocene complex [(ebthi)Zr(Ot-Bu) thf]+, the [4 + 2] cycloaddition of acrolein and cyclopentadiene proceeds efficiently to afford endo and exo cycloadducts (equation 71). In reactions in which methyl acrylate is used as the dienophile, cycloadditions occur with lower levels of enan-tioselection (23% ee), but with significantly higher degrees of diastereoselectivity (17 1 endo, exo). In these processes, recent studies demonstrated the great influence of chiral metallocene structure and the dramatic solvent effect. ... 

The resulting heterocycles in the complex may be further reduced or desilylated (either in the complex or after demetallation). Further synthetic potential exists in the use of the primary products, obtained by cobalt-mediated cycloadditions, as synthons in organic chemistry. For example, indole derivatives have been co-cyclized at the j/ -Cp-cobalt catalyst to give 4a,9a-dihydro-9//-carbazoles or, after oxidation, precursors for strychnine [50]. Remarkably, the cycloaddition of acrolein in the presence of a small amount of methyl acetate occurs at the carbonyl, rather than at the C=C double bond, to give vinylpyran selectively (eq. (19)) [48]. 

Chiral secondary amines such as nonracemic imidazolidin-4-ones have been found to be effective asymmetric organocatalysts in the Diels-Alder cyclization of cyclopentadiene and a,p-unsaturated aldehydes [60]. A tyrosine-derived imidazoli-din-4-one was immobilized on PEG to provide a soluble, polymer-supported catalyst 110. In the presence of 110, Diels-Alder cycloaddition of acrolein 112 to 1,3-cyclohexadiene 111 proceeded smoothly to afford the corresponding cycloadduct 113 with high endo selectivity and enantioselectivity up to 92% ee (Scheme 3.31) [61]. 

A strategy for synthesis of iboga alkaloids evolves from the acrolein cycloaddition (9,11). Focusing on the simplest conceptual approach to iboga alkaloids via Diels-Alder chemistry, a double bond must be introduced into the existing cyclohexyl ring. Such a retrosynthetic analysis, represented in equation 4, rapidly dissects the problem to the cycloaddition of acrolein to a 1-acyloxy-l,3-hexadiene. Scheme 2 summarizes the synthesis to... 

The Diels-Alder cycloaddition of acrolein with the (ft)-diene reported in reaction A affords a 4.5 1 ratio of the indicated diastereoisomers. When an enantiomerically pure (R)-dienophile is reacted with an achiral equivalent of the previous diene (Fig. 6 reaction B), two diastereoisomers are obtained in a 8 1 ratio. As the two major isomers of reactions A and B have the same configuration at the newly formed stereocenters, it can be anticipated that when the two enantiomerically pure (R)-partners are combined, the intrinsic stereoselection of each reactant is exalted to give a very stereoselective process. 

Retinoids. In a new synthesis of vitamin A [retinol (77)] the ring is constructed by acid-catalysed direct cyclocondensation and cycloaddition of acrolein and ethyl isopropyl ketone to give 2,6,6-trimethylcyclohex-2-enone (78) in 62% yield. Base-catalysed addition of the enyne HC=C—CMe=CH2 gives the intermediate (79) and thence, after further chain-lengthening steps, vitamin... 

The simplest of all Diels-Alder reactions, cycloaddition of ethylene to 1,3-butadiene, does not proceed readily. It has a high activation energy and a low reaction rate. However, the cycloaddition of acrolein (H2C=CHCH=0) to 1,3-butadiene occurs readily to give a high yield of the Diels-Alder adduct at a modest temperature. 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

In an investigation by Yamabe et al. [9] of the fine tuning of the [4-1-2] and [2-1-4] cycloaddition reaction of acrolein with butadiene catalyzed by BF3 and AICI3 using a larger basis set and more sophisticated calculations, the different reaction paths were also studied. The activation energy for the uncatalyzed reaction were calculated to be 17.52 and 16.80 kcal mol for the exo and endo transition states, respectively, and is close to the experimental values for s-trans-acrolein. For the BF3-catalyzed reaction the transition-state energies were calculated to be 10.87 and 6.09 kcal mol , for the exo- and endo-reaction paths, respectively [9]. The calculated transition-state structures for this reaction are very asynchronous and similar to those obtained by Houk et al. The endo-reaction path for the BF3-catalyzed reaction indicates that an inverse electron-demand C3-0 bond formation (2.635 A... 

Supported Lewis acids are an interesting class of catalysts because of their operational simplicity, filterability and reusability. The polymer-bound iron Lewis-acid 53 (Figure 3.8) has been found [52] to be active in the cycloadditions of a, S-unsaturated aldehydes with several dienes. It has been prepared from (ri -vinylcyclopentadienyl)dicarbonylmethyliron which was copolymerized with divinylbenzene and then treated with trimethylsilyltriflate followed by THF. Some results of the Diels-Alder reactions of acrolein and crotonaldehyde with isoprene (2) and 2,3-dimethylbutadiene (4) are summarized in Equation 3.13. 

Indium trichloride [30] and methylrhenium trioxide [31] catalyze the aqueous Diels-Alder reaction of acrolein and acrylates with cyclic and open-chain dienes. Some examples of the cycloaddition of methyl vinyl ketone with 1,3-cyclohexadiene are reported in Scheme 6.18. MeReOs does not give satisfactory yields for acroleins and methyl vinyl ketones with substituents at the jS-position and favors the self-Diels-Alder reaction of diene. 

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

Grieco utilized an aqueous intermolecular Diels-Alder reaction as the key step in forming the AB ring system of the potent cytotoxic sesquiterpene vernolepin. 87 Cycloaddition of sodium ( >3,5-hexa-dienoate with an a-substituted acrolein in water followed by direct reduction of the intermediate Diels-Alder adduct gave the desired product in 91% overall yield (Eq. 12.28). 

Table 2.22 Asymmetric 1,3-dipolar cycloadditions of nitrones with acrolein"...

Two other applications of catalyst 364, i.e. in cycloaddition reactions of a-substituted acroleins with dienes 374 and 376, have been depicted in equations 110 and 111237. Cycloadducts 375 and 377 have been used as precursors in the syntheses of cassiol and gibberellic acid, respectively. The use of catalysts 364 and 369b in cycloadditions with acrolein resulted in low enantioselectivities with opposite face selectivities. 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

Hong and co-workers have described a formal [3-t-3] cycloaddition of a,P-unsaturated aldehydes using L-proline as the catalyst (Scheme 72) [225], Although the precise mechanism of this reaction is unclear a plausible explanation involves both iminium ion and enamine activation of the substrates and was exploited in the asymmetric synthesis of (-)-isopulegol hydrate 180 and (-)-cubebaol 181. This strategy has also been extended to the trimerisation of acrolein in the synthesis of montiporyne F [226],... 

An interesting clue is given by the study of regioselectivity in cycloadditions The cyclodimerization of acrolein gives a single product resulting from the head-to-head orientation ... 

Chiral alkenes derived from ot,p-unsaturated aldehydes have also been applied in asymmetric 1,3-dipolar cycloadditions (142). Soucy et al. (142) used (—)-8-(benzylamino)menthol (94) and acrolein for the exclusive formation of 95 having an equatorial C(2) vinyl group (Scheme 12.31). The 1,3-dipolar cycloaddition of acetonitrile oxide with 95 gave 96 with a selectivity of > 90% de. 

Reaction of 1,2-dimethylcyclohexene with the ethylene glycol acetal of acrolein in methylene chloride in the presence of 25 mol % of BF3.0Et2 at -78 to -10°C for 2 hours gives a 70% yield of the cycloadduct 1 in a formal 2k + 2% intermolecular cycloaddition. All of the evidence for this and related reactions, however, indicates a stepwise mechanism for the formation of 1. 

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