Acrylates, cycloaddition

The diastereomeric excess increases steadily as the activity of the alumina increases, i. e. when its Lewis character increases. Results obtained for menthyl acrylate cycloaddition with cyclopentadiene were rather similar but not as important [36] endolexo increase from 2.4 to 8.1 changing non-activated alumina for a pre-heated one at 200°C). 

Acrylates. Cyclopentadiene is often used to evaluate selectivity in asymmetric Diels-Alder reactions. Table 6.4 lists the selectivities found for acrylate cycloadditions using the auxilieuies shown in Figure 6.13 under conditions that are optimized for each auxiliary. Note that there are four possible norbomene stereoisomers, two endo and two exo. In accord with Alder s endo rule, the endo is heavily favored in all these examples. Although several authors report selectivities in these reactions in terms of selectivity for one endo adduct over the other, the selectivities indicated in the table reflect the total diastereoselectivity of the major adduct over the other three, if this information could be deduced from the information provided in the paper. 

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. 

The benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2+2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-lrig cyclization on to the aromatic ring to give 404[279],... 

Methacryhc acid and its ester derivatives are Ctfjy -unsaturated carbonyl compounds and exhibit the reactivity typical of this class of compounds, ie, Michael and Michael-type conjugate addition reactions and a variety of cycloaddition and related reactions. Although less reactive than the corresponding acrylates as the result of the electron-donating effect and the steric hindrance of the a-methyl group, methacrylates readily undergo a wide variety of reactions and are valuable intermediates in many synthetic procedures. 

In the case of enamines derived from aldehydes a cycloaddition to give a cyclobutane occurs (48-50). Thus the enamine (16) reacted with methyl acrylate in acetonitrile to give a 91 % yield of methyl 2-dimethylamino-3,3-dimethylcyclobutane carboxylate (56). Similarly, treatment of (16) with diethylmaleate at 170° gave a 70% yield of diethyl 4-dimethylamino-3,3-dimethyl-l,2-cyclobutanedicarboxylate (57), and 16 and acrylonitrile gave a 65% yield of 2-dimethylamino-3,3-dimethylcyclobutanecarbonitrile (58). 

The reaction of methyl or ethyl acrylate with the enamine of an alicyclic ketone results in simple alkylation when the temperature is allowed to rise uncontrolled in the reaction mixture (7,34,35). If the reaction mixture is kept below 30°C, however, a mixture of the simple alkylated and cyclobutane (from 1,2 cycloaddition) products are obtained (34). Upon distillation of this mixture only starting material and simple alkylated product is obtained because of the instability of the cyclobutane adduct. 

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. 

Enamines have been observed to act both as dienophiles (46-48) and dienes (47,49) (dienamines in this case) in one-step, Diels-Alder type of 1,4 cycloadditions with acrylate esters and their vinylogs. This is illustrated by the reaction between l-(N-pyrrolidino)cyclohexene (34) and methyl t/-a i-2,4-pentadienoate (35), where the enamine acts as the dienophile to give the adduct 36 (47). In a competitive type of reaction, however, the... 

Vinyl ethers undergo many cycloaddition reactions similar to those which take place with enamines. In general, however, these cycloaddition reactions with vinyl ethers take place less readily than those with enamines. These reactions include cycloaddition of vinyl ethers with ketene (200-205), phenyl isocyanate (206), sulfene (207,208), methyl acrylate (209), diethyl acetylenedicarboxylate (210), and diphenylnitrilimine (183). 

Evans s bis(oxazolinyl)pyridine (pybox) complex 17, which is effective for the Diels-Alder reaction of a-bromoacrolein and methacrolein (Section 2.1), is also a suitable catalyst for the Diels-Alder reaction of acrylate dienophiles [23] (Scheme 1.33). In the presence of 5 mol% of the Cu((l )-pybox)(SbF5)2 catalyst with a benzyl substituent, tert-butyl acrylate reacts with cyclopentadiene to give the adduct in good optical purity (92% ee). Methyl acrylate and phenyl acrylate underwent cycloadditions with lower selectivities. 

The cycloaddition reaction of diazomethane 4 and an olefin, e.g. methyl acrylate 5, leads to a dihydropyrazole derivative 6 ... 

Figure 3.5-2 Diels-Alder cycloaddition between cyclopentadiene and methyl acrylate.

Di-tert-butylthiepin (9) undergoes a [4+2] cycloaddition with ethenetetracarbonitrile over two weeks at room temperature to give the 1 1 adduct 10 in 49% yield. Almost the same result was obtained at 60°C and 8500 atm over three days (46% yield). Methyl acrylate is inert to thiepin 9 under similar conditions.87... 

Other examples of acrylate additions have been reported298 and analogous [6 + 2] cycloadditions of the corresponding ethyl 17/-azepine-1-carboxylate-tricarbonylchrominium complex with alkynes have been achieved in good yields (63-68%).299... 

Danishefsky and coworkers using the same approach have synthesized substituted cyclohexadienones 563s65,666 (equation 361). A highly stereoselective (96%) cycloaddition of diastereoisomerically pure (Ss)-menthyl 3-(3-trifluoromethylpyrid-2-ylsulphinyl)acrylate 564 to 2-methoxyfuran 565 leads to the cycloadduct 566 which was elaborated by Koizumi and coworkers to glyoxalase I inhibitor 567667 (equation 362). 

It has been established that alkoxy alkenylcarbene complexes participate as dienophiles in Diels-Alder reactions not only with higher rates but also with better regio- and stereoselectivities than the corresponding esters [95]. This is clearly illustrated in Scheme 51 for the reactions of an unsubstituted vinyl complex with isoprene. This complex reacts to completion at 25 °C in 3 h whereas the cycloaddition reaction of methyl acrylate with isoprene requires 7 months at the same temperature. The rate enhancement observed for this complex is comparable to that for the corresponding aluminium chloride-catalysed reactions of methyl acrylate and isoprene (Scheme 51). 

The reaction of methyl acrylate and acrylonitrile with pentacarbonyl[(iV,iV -di-methylamino)methylene] chromium generates trisubstituted cyclopentanes through a formal [2S+2S+1C] cycloaddition reaction, where two molecules of the olefin and one molecule of the carbene complex have been incorporated into the structure of the cyclopentane [17b] (Scheme 73). The mechanism of this reaction implies a double insertion of two molecules of the olefin into the carbene complex followed by a reductive elimination. 

Clay-catalyzed asymmetric Diels-Alder reactions were investigated by using chiral acrylates [10]. Zn(II)- and Ti(IV)-K-10 montmorillonite, calcined at 55 °C, did not efficiently catalyze the cycloadditions of cyclopentadiene (1) with acrylates that incorporate large-size chiral auxiliaries such as cA-3-neopentoxyisobornyl acrylate (2) and (-)-menthyl acrylate (3, R = H) (Figure 4.1). This result was probably due to diffusion problems. 

Pagni and coworkers [18] have conducted in-depth investigations on the cycloadditions of cyclopentadiene with methyl acrylate on alumina of varing activity (200 300 400 800 °) showing that the diastereoselectivity of the... 

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. 

The importance of the relationship between the macrocycle cavity and the binding of two reagents is shown by the cycloadditions of cyclopentadiene with diethyl fumarate and ethyl acrylate in aqueous solution. The presence of jS-CD strongly accelerates the first cycloaddition, while it slows down the reaction rate of the second, probably because the cavity favors the binding of two molecules of either diene or dienophile [65c]. 

Cycloaddition reactions of (E)-l-acetoxybutadiene (18a) and (E)-l-methoxy-butadiene (18b) with the acrylic and crotonic dienophiles 19 were studied under high pressure conditions [9] (Table 5.1). Whereas the reactions of 18a with acrylic dienophiles regioselectively and stereoselectively afforded only ortho-enJo-adducts 20 in fair to good yields, those with crotonic dienophiles did not work. Similar results were obtained in the reactions with diene 18b. The loss of reactivity of the crotonic dienophiles has been ascribed to the combination of steric and electronic effects due to the methyl group at the )S-carbon of the olefinic double bond. 

The aqueous medium also has beneficial effects on the diastereoselectivity of the Diels-Alder reactions. The endo addition that occurs in the classical cycloadditions of cyclopentadiene with methyl vinyl ketone and methyl acrylate is more favored when the reaction is carried out in aqueous medium than when it is performed in organic solvents (Table 6.4) [2b, c]. 

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. 

The Diels-Alder reaction can be greatly enhanced by high pressure (Chapter 5) but the effect of pressure is generally weaker in aqueous medium than in organic solvent. Results of high pressure-mediated Diels-Alder reactions of furans and acrylates in water and dichloromethane are reported in Table 6.6 [32]. In aqueous medium the cycloadditions occur with lower yields and less diastereoselectivity than in dichloromethane and, in some cases, addition-substitution reactions were observed. 

Earle and coworkers [54] have performed Diels-Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except [BMIMJPF4, and gave almost quantitative yields after 18-24h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. 

The results of Diels-Alder reactions of cyclopentadiene with diethyl fumarate, diethyl maleate and ethyl acrylate carried out in SC-H2O are reported in Scheme 6.32 [79]. The cycloaddition of diethyl fumarate occurred with low yield. 

---