Diels-Alder reactions unsaturated ketones

Formation of a double bond between carbon and a heteroatom or between two heteroatoms can be accomplished by a hetero retro-Diels-Alder reaction. Aldehydes, ketones and carboxylic esters can be obtained by this retrodiene process. A series of ct,3-unsaturated aldehydes (152) was prepared by Funk using the facile bis-hetero retro-Diels-Alder reaction of 4-alky 1-4//-1,3-dioxins (151) as shown in equation (66). This retrodiene process involves exceptionally mild conditions, refluxing in toluene, in order to unmask the a,3-unsaturated aldehyde. The diversity of this process is illustrated by the partial list of reactions shown. The same mild conditions can be used to prepare a,3-unsaturated ketones by reflux-... 

Compared to the hetero-Diels-Alder reaction of carbonyl compounds and derivatives with dienes, where only a limited number of catalytic and enan-tioselective reactions have been reported, the number of asymmetric hetero-Diels-Alder reactions in which the ketone or imine functionality is part of a heterodiene is much higher. In contrast, there are only a few examples of using a,p-unsaturated aldehydes in inverse hetero-Diels-Alder reactions. In the case of the inverse electron demand hetero-Diels-Alder reaction, the ketone or imine functionality is part of an a,(I-unsaturated system, which reacts in a cycloaddition reaction with an electron-rich alkene. The inverse electron demand hetero-Diels-Alder reaction is primarily controlled by a LUMOdiene-HOMOdienophiie interaction, which can be found, for example, in the reactions... 

The high-pressure Diels-Alder reaction of ketones with 1-methoxybutadiene yields the masked a,/3-unsaturated aldehyde (30). ° Under similar conditions, the highly functionalized cyclohexene (31) may be obtained [equation (6)]."°... 

Most known chiral secondary-amine catalysts are effective only for less sterically hindered substrates such as a,p-unsaturated aldehydes. Asymmetric Diels-Alder reactions of acyclic a,p-unsaturated ketones represent a formidable challenge in this area. In 2002, MacMillan and coworkers accomplished the first general enanti-oselective Diels-Alder reactions of ketones by using chiral amine 26 [16]. As shown... 

Cyclic 1,3-diacetoxy-l,3-dienes can be generated in situ from cyclic 1,3-diketones under the influence of isopropenyl acetate. The dienes then undergo Diels-Alder reactions with maleic anhydride giving as products 1-acetoxybicycloalkane dicarboxylic anhydride derivatives (10). The procedure is also successful with cyclic 1,2- and 1,4-diketones as well as cyclic a,j3-unsaturated ketones. The products, after hydrolysis to... 

Anionic Diels-Alder reactions have been studied less extensively with the interest having been focused mainly on the cycloaddition of enolates of a,/l-unsaturated ketones with electron-poor olefins [24] (Equations 1.8 and 1.9). These reactions are fast and stereoselective and can be regarded as a sequential double Michael condensation, but a mechanism involving a Diels-Alder cycloaddition seems to be preferred [24b,f, 25]. 

Fluoboric acid is also an efficacious promoter of cyclic oxo-carbenium ions (Scheme 4.24) bearing an activated double bond which, in the presence of open-chain and cyclic dienes, rapidly undergo a Diels-Alder reaction [91]. Chiral a, -unsaturated ketones bearing a -hydroxy substituents, protected as acetals, react with various dienes in the presence of HBF4, affording Diels-Alder adducts that were isolated as alcohols by hydrolysis of the acetal group by TsOH. Some examples of reactions with isoprene are reported in Table 4.23. The enantios-electivity of the reaction is dependent on the size of the substituent R on the of-carbon high levels of asymmetric induction were observed with R = z-Pr (90 1) and R = t-Bu (150 1) and low levels with R = Me (2.7 1) and R = Ph (3.0 1). Scheme 4.24 shows the postulated reaction mechanism. 

The effectiveness of LP-NM with respect to LP-DE has also been proven by the cycloaddition of ketals of a,)S-unsaturated ketones with open-chain and cycloaliphatic dienes [46]. In 4.0m LP-NM the Diels-Alder reaction occurs with good yields and selectivities without using CSA, which is absolutely necessary when the reaction is performed in LP-DE (Section 6.2.1). Some examples are illustrated in Scheme 6.25. 

C. Reactions not involving P=0 or P=S Groups.—Enamine phosphine oxides (45) have been prepared by the addition of amines to 1-alkynyl-phosphine oxides, and the reactions of their anions with various electrophiles have been reported. - With ketones a Wittig-type reaction leads to the formation of a/3-unsaturated ketones, in 53—70% yield, while with epoxides cyclopropyl ketimines are formed. A Diels-Alder reaction of l-phenyl-A -phospholen-l-oxide (46) with 1,4-diacetoxybutadiene has been used in the preparation of l-phenyl-benzo[/>]phosphole (47), as... 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

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-... 

The cycloadduct of an a,a -dioxo-thioketone with antracene,84 treated at low temperature with the Nysted reagent and TiCl4, transforms a ketone group to the corresponding methylenic group. This product is thermically decomposed via retro Diels-Alder reaction into the unstable a, p-unsaturated-a -oxo derivative (Scheme 10). 

Kelly and colleagues91 explored the use of bisphenylenediol 103 as a catalyst in Diels-Alder reactions of a,/i-unsaturated carbonyl compounds. Activation of the dieno-phile occurred through double hydrogen bonding of the two hydroxyl functions on 103 to the carbonyl group on the dienophile. The reaction of cyclopentadiene with methyl vinyl ketone (equation 31) at ambient temperature showed, after a reaction time of 10 minutes, 3% of product formation in the absence of 103 against 90% of product formation in the presence of 0.4 equivalents of 103. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Additionally, investigations into imidazolidinone catalysed Diels-Alder reactions (Schemes 2 and 6) [234] have shown that iminium ions of a,P-unsaturated aldehydes and ketones have lower activation barriers for the Diels-Alder reaction with cyclopentadiene than the parent compound (13 and 11 kCal mol", respectively). It was also noted that transition structures show the formation of the bonds is concerted but highly asynchronous. 

The competition between Michael addition of a,(3-unsaturated ketones and Diels-Alder reactions involving furan and 2-methylfuran is affected by the catalyst used. Methyl vinyl ketone gives the alkylation product with furan and 2-methylfuran in the presence of silica gel (88TL175). Bis(alkylated) products have also been obtained in reactions of 2-methylene-1,3-dicarbonyl compounds (90H(31)1699). An intramolecular proton catalyzed alkylation reaction of an a,(3-unsaturated ketone provided a straightforward synthesis of norpinguisone (90TL4343) and in the example shown in Equation (4) the cyclization reaction involved an a,(3-y,8-dienone (94TL4887). 

A.2.4. Asymmetric Diels-Alder Reactions with Unsaturated Ketones... 

DFT has been used to investigate the Diels-Alder reactions of cyclopentadiene with a,/S-unsaturated aldehydes and ketones organocatalysed by MacMillan s chiral... 

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