Acrylic acids Diels-Alder reactions

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. 

Diels-Alder reactions in the presence of Lewis acids represent a case in which the Lewis acid is often used in catalytic quantities. The complexed ester (ethyl acrylate in the example given below) is substantially more reactive than the uncomplexed molecule, and the reaction proceeds through the complex. The reactive complex is regenerated by exchange of the Lewis acid from the adduct. 

The Diels-Alder reactions of the methyl or ethyl ester of benzenesulfonylindole-2-acrylic acid with several l-alkoxycarbonyl-l,2-dihydropyridines are reported and only a single stereoisomer was obtained, as in the case of l-methoxy(ethoxy)-carbonyl-1,2-dihydropyridines. However, when the Diels-Alder reaction of 17 was carried out with 8g[R = (CHsjsC], a mixture of two stereoisomers 18gand25were obtained in a 1 1 ratio (65% total yield). The bulky rerr-butyl group creates sufficient steric interference with the indole ring to cause the loss of stereochemistry ... 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

A similar study performed by Welton and co-workers studied the rate and selec-tivities of the Diels-Alder reaction between cyclopentadiene and methyl acrylate in a number of neutral ionic liquids [44]. It was found that endo. exo ratios decreased slightly as the reaction proceeded, and were dependent on reagent concentration and ionic liquid type. Subsequently, they went on to demonstrate that the ionic liquids controlled the endo. exo ratios through a hydrogen bond (Lewis acid) interaction with the electron-withdrawing group of the dienophile. 

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. 

Chloroaluminate ionic liquids (typically a mixture of a quaternary ammonium salt with aluminum chloride see Table 6.9) exhibit at room temperature variable Lewis acidity and have been successfully used as solvent/catalyst for Diels-Alder reactions [57]. The composition of chloroaluminate ionic liquids can vary from basic ([FMIM]C1 or [BP]C1 in excess) to acidic (AICI3 in excess) and this fact can be used to affect the reactivity and selectivity of the reaction. The reaction of cyclopentadiene with methyl acrylate is an example (Scheme 6.31). 

The ene reaction of fuUerene (C o) with 3-methylene-2,3-dihydrofuran gives an easily isolated addition product in good yield <96JOC2559>. There is a continuous need for chiral acrylate esters for asymmetric Diels-Alder reactions with high diastereoselectivity. Lewis acid promoted Diels-Alder reactions of acrylate esters from monobenzylated isosorbide 28 (or isomannide) and cyclopentadiene provided exclusively e db-adducts with good yields and high diastereoselectivity <96TL7023>. 

However, none of these compounds can be easily resolved except TM (16) Itself. Me prefer to resolve as early as possible, (page T 94), so It is better to carry out the Diels-Alder reaction with acrylic acid and resolve acid (19) before adding the phenyl group by a Grignard reaction. The benzylic alcohol group in (20) can be taken out by metal-anunonia reduction. Syrithesis ... 

Scott Oakes et al. (1999a, b) have shown how adoption of SC conditions can lead to a dramatic pressure-dependent enhancement of diastereoselectivity. In the case of sulphoxidation of cysteine derivatives with rert-butyl hydroperoxide, with cationic ion-exchange resin Amberlyst-15 as a catalyst, 95% de was realized at 40 °C and with SC CO2. By contrast, with conventional solvents no distereoselectivity was observed. Another example is the Diels-Alder reaction of acrylates with cyclopentadiene in SC CO2 at 50 °C, with scandium tris (trifluoromethanesulphonate) as a Lewis acid catalyst. The endoiexo ratio of the product was as high as 24 1, while in a solvent like toluene it was only 10 1. 

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). 

Nitrodienes are conveniently prepared by elimination of benzoic acid from P-nitro-P-l-cy-clopentenyl-a-benzoyloxyethane. They undergo the Diels-Alder reaction with methyl acrylate (Eq. 8.17).28... 

Enantioselective Diels-Alder reactions proceed smoothly in the presence of a chiral Sc catalyst, prepared in situ from Sc(OTf)3, R)- I )-l,l -bi-2-napluhol [(R)-BINOL], and a tertiary amine in dichloromethane.58 The catalyst is also effective in Diels-Alder reactions of an acrylic acid derivative with dienes (Scheme 14). 

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... 

Although the above demonstrated that product control could be achieved in scC02, the difference in selectivity was relatively small. However, later work using a Lewis acid catalyst, scandium triflate, on the Diels-Alder reaction of n-butyl acrylate and cyclopentadiene (Scheme 7.7) showed that the endo exo ratio was again found to rise to a maximum and then decrease again as the pressure, and hence density, was increased (Figure 7.3) [19]. 

Carbohydrates have found widespread use as chiral auxiliaries in asymmetric Diels-Al-der reactions156. A recent example is a study conducted by Ferreira and colleagues157 who used carbohydrate based chiral auxiliaries in the Lewis acid catalyzed Diels-Alder reactions of their acrylate esters 235 with cyclopentadiene (equation 66). Some representative results of their findings, including the ratios of products 236 and 237, have been summarized in Table 9. The formation of 236 as the main product when diethylaluminum chloride was used in dichloromethane (entry 3) was considered to be the result of an equilibrium between a bidentate and monodentate catalyst-dienophile complex. The bidentate complex would, upon attack by the diene, lead to 236, whereas the monodentate complex would afford 236 and 237 in approximately equal amounts. The reversal of selectivity on changing the solvent from dichloromethane to toluene (entry 2 vs 3) remained unexplained by the authors. 

Ci.v-1 -(arylsulfonamido)indan-2-ols have been shown to be excellent chiral auxiliaries for asymmetric Diels-Alder reactions191. Some results obtained in the Lewis acid catalyzed Diels-Alder reaction of 1 (p-lohicnc sulfonamido)indan-2-yl acrylate (303) with cyclopentadiene (equation 84) have been depicted in Table 17. The reaction conducted in the absence of a Lewis acid did not afford any facial selectivity and only moderate endo/exo selectivity. However, when a Lewis acid was added, excellent de values and almost complete endo selectivities (cf. 304) were observed, almost independent of the type and amount of Lewis acid added. 

Furthermore, regioselectivities89 as well as the diastereofacial selectivities90,91 may be increased in the presence of Lewis acids (Table 8). For instance, AICI3 OEt2 improves the ewrfo-selectivity of the reaction of cyclopentadiene and methyl acrylate from 82% to 98%87. The astonishing rate accelerations, the improved yields and higher selectivities make the Lewis acid catalysed Diels-Alder reaction one of the most important organic reactions. 

SCHEME 8. Stereodichotomy of the Lewis acid catalysed Diels-Alder reactions of a chiral acrylic ester and cyclopentadiene... 

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. 

A review of Diels-Alder reactions of fullerenes with acyclic and cyclic dienes has been presented. The addition of substituted pyrimidine o-quinodimethanes (75) to [60]fullerenes yields novel organofullerenes (76) bearing a pyrimidine nucleus covalently attached to the Ceo cage (Scheme 26). The Diels-Alder dimerization of cyclopenta[/]phenanthrene (77) with isobenzindene (78) yields the dimer (79) in 85% yield (Scheme 27). Further evidence has been supplied to support an early reorganization of the r-network in the dimerization of 2-methoxycarbonylbuta-1,3-diene. The Lewis acid-catalysed Diels-Alder reactions of acrylate derivatives of new carbohydrate-based chiral auxiliaries with cyclohexadiene show excellent endo. exo... 

Also the use of moisture stable ionic liquids as solvents in the Diels-Alder reaction has been carried out, and in all examples an enhanced reaction rate was observed [182,183]. The application of pyridinium-based ionic liquids allowed the utilization of isoprene as diene [184]. The chiral ionic liquid [bmim][L-lactate] was used as a solvent and accelerated the reaction of cyclopentadiene and ethyl acrylate, however, no enantiomeric excess was observed [183]. In addition several amino acid based ionic liquids have been recently tested in the Diels-Alder reaction. Similar exo. endo ratios were found but the product was obtained as racemate. The ionic liquids were prepared by the addition of equimolar amounts of HNO3 to the amino acids [185]. Furthermore, an enantiopure imidazolium salt incorporating a camphor motive was tested in the Diels-Alder reaction. No enantiomeric excess was found [186]. 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

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. 

Yamamoto had earlier reported that Lewis acid activation of valine-derived oxazaborolidine 60 yielded a highly reactive and moisture-tolerant LLA catalyst 61 for the Diels-Alder reaction (Scheme 5.76) [145]. In later studies, activation of 60 with the super Bronsted acid, C,sF5CHTf2, was found to produce the even more reactive catalytic species BLA 62. During studies toward an enantioselective route to Platensimycin [146], BLA 62 was found to catalyze the Diels-Alder reaction between various monosubstituted dienes and ethyl acrylate to afford adducts... 

Approaches to oseltamivir phosphate (1) that were independent of ( )-shikimic acid as the raw material were also evaluated. The furan-ethyl acrylate Diels-Alder approach is shown in Scheme 7.8 (Abrecht et al., 2001, 2004). The zinc-catalyzed Diels-Alder reaction between furan and ethyl acrylate was heated at 50°C for 72 h to provide a 9 1 mixture favoring exo-isomer rac-43 over the enJo-isomer. The enJo-isomer was kinetically preferred, but with increased reaction times an equilibrium ratio of 9 1 was achieved favoring the thermodynamically preferred exo-isomer rac-43. The optical resolution of rac-43 was achieved via enantioselective ester hydrolysis using Chirazyme L-2 to give (—)-43 in 97%... 

The Diels-Alder reaction of a-phellandrene with acrylic acid derivatives has been examined, apparently superficially in contrast to the re-investigation of the reaction with benzalbisurethane, catalysed by BF3,Et20-CuBr. The 1,4-adducts (161 endo exo/31 63) may result effertively from the concerted [4 -I-2 ] addition involving the immonium ion (PhCH=NHC02Et) however, with the corresponding unsubstituted immonium ion, formal 1,3-addition to a-phellandrene occurs essentially via the isomerized a-terpinene and isoterpinolene to yield [(162) (163)/84 16]. ... 

The enedione (15), a tetracyclic intermediate on a synthetic route to fusidic acid, has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3). This compound (24) has also been prepared by degradation of fusidic acid. Attempts to introduce the C-11 oxygen function necessary for the synthesis of fusidic acid have not been very... 

The oxazoline ring acts as an electron-withdrawing group for a substituent at the 2-position. Thus, the ot-protons of a 2-alkyloxazoline exhibit some acidity and can be abstracted by a base. A 2-alkenyloxazoline can be viewed as a masked acrylic acid derivative and is capable of undergoing Michael addition and Diels-Alder reactions. These reactions can often be carried out stereoselectively using a chiral oxazoline. Other types of chiral auxilliaries, most notably oxazolidinones, are also very effective for these types of applications. However, they are outside the scope of this chapter. The discussion in this section will focus on the new developments with oxazolines. 

Figure 3.5-3 The hydrogen bond (Lewis acid) interaction of an imidazolium cation with the carbonyl oxygen of methyl acrylate in the activated complex of the DIels-Alder reaction. 

Furo[3,4-J]pyridazines have also been used in Diels-Alder reactions (331a with maleic anhydride, acrylic acid, 1,4-naphthoquinone, dibenzoyl-ethylene, 1,4-benzoquinone, benzo[c]furandione ° 331c with maleic anhydride) 331a has been shown to be more reactive than 331c. 1,3-Diphenylfuro[3,4-b]quinoxaline (335) has been obtained from phthalide 334 (Eq. 17) as a green crystalline, quite stable solid (mp 244-246°C). In DMSO (deep blue solution), 335 reacts instantaneously with such dienophiles... 

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