Acrylic acid, Diels-Alder cycloaddition

The Diels-Alder cycloaddition of furan and acrylic acid, in the presence of hydroquinone as a polymerization inhibitor, provided enrfo-7-oxabicy-clo[2.2.1]hept-5-ene-2-carboxylic acid - (29) in a yield of 45%. Compound 29 was found to be the most accessible and important starting-material for the synthesis of various racemic carba-sugars, as well as their enantiomers. 

Clifford and Rayner have reported enhanced selectivities for Lewis acid catalyzed Diels-Alder cycloadditions in sc C02 relative to organic solvents. It is well known that Lewis acids catalyze Diels-Alder reactions and can improve their rate and selectivity (Dell, 1998 Santelli, 1996). The endo exo product selectivity for the Sc(Otf)3-catalyzed reaction between cyclopenta-diene and alkyl acrylates (eq. 2.3) could be optimized to 24 1 by controlling the density of sc C02 (Clifford et al., 1997, 1998 Oakes et al., 1999), whereas in toluene the endo exo ratio was 10 1. 

Cycloadditions of Acrylate Derivatives. Acrylate derivatives undergo highly stereoselective Diels-Alder cycloadditions with 1,3-dienes when promoted by a Lewis acid, Dichlorotitanium Diisopropoxide or Jitanium IV) Chloride (eq 2). With the latter, care must be taken to avoid... 

Esterification of 19 with acrylic acid chloride made diene 20 available. Subsequent stereoselective Diels-Alder cycloaddition with cyclopentadiene proceeded with complete diastereoselectivity in 55% yield. The asymmetric product 21 was cleaved from the polymer by exposure to light (Scheme 12.11). 

Applications of chirally modified titanium Lewis acids have been reported most cases use various acetal diols derived from tartrate as the chiral auxiliary26 33,31 90. Various methods of catalyst preparation are known, as well as the use of different types of dienes (open-chained, cyclopentadiene) and dienophiles (acroleins, acrylates, crotonates, fumarates and amides derived from oxazolidinone), including intramolecular cycloaddition30. Addition of 4 A molecular sieves can improve asymmetric induction31,34 (as observed with the Sharpless epoxidation, loc. cit 31 in ref 6) and shows remarkable solvent effects on enantioselectivity. This method has been applied to the asymmetric Diels-Alder cycloaddition of cyclopentadiene and open-chain dienes to acrylamides28, 35. 

Supported liquid acrylic esters have been prepared from hydroxylated imidazolium-based TSILs and used neat in (4-1-2) Diels-Alder cydoadditions. First, Handy et al. [31] used a fructose-derived ionic liquid to support acryUc acid and performed the Diels-Alder cycloaddition with several dienes induding cydopenta-and cydohexadienes and butadiene derivatives at 120 °C for 12 h in the presence of hydroquinone (Scheme 5.5-25). 

Norbornene-2-carboxylic acid (8) was obtained in acceptable ee by the use of a chiral auxiliary. Optically active tetrahydropyrimidones 6 underwent Diels-Alder cycloadditions with cyclopentadiene (5) in water at room temperature. Subsequent removal of the auxiliary was achieved by boiling the carboxamide 7 in water (Scheme 5.2). The cycloaddition conversions were at least 90% and the endo adduct was the prevalent diastereoisomer. Using 70% aqueous ethanol as reaction medium, both the endo/exo ratio and ee were lower than in pure water. Since tetrahydropyrimidones 6 can be prepared in water from L-asparagine and a suitable aldehyde and subsequent acylation with acryloyl chloride, the entire synthesis of 8 was performed in water by one-pot procedure. The yield was fair, but the ee of norbornene carboxylic acid 8 was lower than that obtained by using a step-by-step procedure. This result was probably due to some acryloyl chloride being hydrolyzed to acrylic acid, which then reacted with 5 in a non-stereo-biased manner. 

Finally, the corresponding acrylate derivatives have been reported to undergo stereoselective Lewis acid-catalysed Diels-Alder cycloadditions (Scheme 6.21). ... 

Several multicomponent cascade reactions involving a critical Diels-Alder cycloaddition have been recently described by Huang and Xu. Thus, a one-pot preparation of isoindoles such as 172 involves an Ugi four-component coupling of furfural (167a) with benzyl amine (168a), 2-(phenylselanyl)acrylic acid (169a), and benzylisonitrile... 

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Good yields and high diastereoselectivities were obtained by using zeolites in combination with Lewis-acid catalyst [21]. Table 4.7 illustrates some examples of Diels-Alder reactions of cyclopentadiene, cyclohexadiene and furan with methyl acrylate. Na-Y and Ce-Y zeolites gave excellent results for the cycloadditions of carbocyclic dienes, and combining these zeolites with anhydrous ZnBr2 further enhanced the endo diastereoselectivity of the reaction. An exception is the cycloaddition of furan that occurred considerably faster and with better yield, in comparison with the classic procedure [22], when performed in the presence of sole zeolites. 

Although the metathesis of ene-ynes is a valuable method for the preparation of 1,3-butadienes, and may be used for Diels-Alder reactions, a problem arises from the need to employ either a high temperature or a Lewis add to accelerate the cycloaddition, which is usually not feasible with the Grubbs catalyst Therefore, the combination of metathesis and cycloaddition is usually performed in sequential fashion (as just shown, and highlighted earlier) [264]. However, Laschat and coworkers [265] have shown the Lewis acid BC13 to be compatible with the Grubbs I catalyst (6/3-13). Reaction of 6/3-92 and ethyl acrylate using a mixture of 2.5 equiv. of the Lewis acid and 10 mol% of 6/3-13 led to 6/3-93 in 60% yield (Scheme 6/3.27). 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

For the Diels-Alder reaction, polymer-bound acrylic acid ester (73) was treated with cyclopentadiene. The cycloaddition product (74) was formed with an endo/exo ratio of 2.5 1 and with quantitative conversion. The subsequent enzymatic release delivered the corresponding alcohols (72, 75) in high yield and purity. 

Other 2-substituted cyclopropylideneacetates of type 3-X also entered this cycloaddition (Scheme 15) [19]. The endolexo selectivity is low but usually still higher than that of simple acrylic acid esters. The relative Diels-Alder reactivities of dienophiles 1-Me and 3-X as determined by competition experiments (Scheme 15) suggest a mechanism involving either diradicals or zwitterions as intermediates [19]. Surprisingly, the 2-fluoro derivative 3-F is less reactive than the parent compound 3-H. The 2-chloro and 2-bromo derivatives 1-Me and 3-Br have similar reactivities and cycloadd to furan (57) about 16 times faster than methyl acrylate. 

The highly ordered cyclic transition state of the Diels-Alder reaction permits design of reaction parameters which lead to a preference between the transition states leading to diastereomeric or enantiomeric adducts. (See Part A, Section 2.3, to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.56 The cycloaddition proceeds to give two diastereomeric products which can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best enantioselectivity is often observed in catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useftd because the chiral auxiliary can be easily recovered upon hydrolysis of the adduct to give the enantiomerically pure carboxylic acid. 

Cycloaddition reactions.l This surfactant increases the rate of Diels-Alder reactions. In addition, the endo/exo ratio is improved in the addition of acrylic acid derivatives to cyclopentadiene. 

Diels-Alder reactions.1 The diene undergoes uncatalyzed [4+2]cycloaddition with very reactive dienophiles, but generally a Lewis acid catalyst (ZnCl, or C2H5A1C12) is required. Thus, the catalyzed reaction of 1 with methyl acrylate proceeds at 0° to afford, after silyl ether cleavage, the cycloadducts 2 and 3. 

The non-selective thermal Diels-Alder reaction of hexa-2,4-dienol with methyl acrylate is made enantioselective by using the Lewis acid template (86) to assemble the reagents for cycloaddition.91 The Me2AlCl-catalysed intramolecular Diels-Alder... 

The high simple diastereoselectivities seen in Figures 15.29 and 15.30 are due to the same preferred orientation of the ester group in the transition states. The stereostructure of the cycloadduct shows unequivocally that the ester group points underneath the diene plane in each of the transition states of both cycloadditions and not away from that plane. Figure 15.31 exemplifies this situation for two transition states of simple Diels-Alder reactions of 1,3-butadiene A shows a perspective drawing of the transition state of the acrylic acid ester addition, and B provides a side view of the addition of ethene, which will serve as an aid in the following discussion. Both structures were determined by computational chemistry. 

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