Isoprene Diels—Alder reactions

Synthesis The Diels-Alder reaction is simply the dimerisation of isoprene to giye the naturally occurring terpene A. Now we haye to cleaye one double bond and leaye the other alone. It turns out that epoxidation is selectiye in this case. 

Isoprene is highly reactive both as a diene and through its allyhc hydrogens, and its reactions are similar to those of butadiene (qv) (8). Apart from polymerisation, the most widely investigated isoprene reactions are the formation of six-membered rings by the Diels-Alder reaction ... 

Maleic anhydride has been used in many Diels-Alder reactions (29), and the kinetics of its reaction with isoprene have been taken as proof of the essentially transoid stmcture of isoprene monomer (30). The Diels-Alder reaction of isoprene with chloromaleic anhydride has been analy2ed using gas chromatography (31). Reactions with other reactive hydrocarbons have been studied, eg, the reaction with cyclopentadiene yields 2-isopropenylbicyclo[2.2.1]hept-5-ene (32). Isoprene may function both as diene and dienophile in Diels-Alder reactions to form dimers. 

Another chiral titanium reagent, 11, was developed by Corey et al. [17] (Scheme 1.24). The catalyst was prepared from chiral ris-N-sulfonyl-2-amino-l-indanol and titanium tetraisopropoxide with removal of 2-propanol, followed by treatment with one equivalent of SiCl4, to give the catalytically-active yellow solid. This catalyst is thought not to be a simple monomer, but rather an aggregated species, as suggested by NMR study. Catalyst 11 promotes the Diels-Alder reaction of a-bro-moacrolein with cyclopentadiene or isoprene. 

The Diels-Alder reaction catalyzed by this chiral titanium catalyst 31 has wide generality (Scheme 1.53, 1.54, Table 1.22, 1.23). Acryloyl- and fumaroyl-oxazolidinones react with isoprene giving cycloadducts in high optical purity. 2-Ethylthio-l,3-buta-diene can also be successfully employed as the diene [42]. 

Sequential radical cyclizations are also featured in an efficient and clever synthesis of the cedrane framework 83 (see Scheme 15).30 Compound 81, the product of a regioselective Diels-Alder reaction between isoprene (79) and nitroethylene (80), participates in a nitroaldol reaction (Henry reaction) with 5-methyl-4-hexenal in the presence of a basic resin to give 82. Because the nitro group in... 

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). 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

The presence of two substituents at C-4 also strongly influences the regios-electivity as shown in the cycloaddition of dienone 13 with isoprene (2) (Equation 3.1). In violation of the para-rule for Diels-Alder reaction, only metfl-adduct was obtained [19,20]. 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

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. 

The ability of zeolites to control the regioselectivity of Diels-Alder reaction has been investigated for the cycloaddition of isoprene with various dienophiles [20bj. Some results are reported in Table 4.6. All the zeolites tested afforded high regioselectivity but the reaction yield was generally low and depended on the zeolite as well as on the dienophile. 

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. 

Recently Nafion-H was successfully used in the Diels-Alder reaction of olefin acetals with isoprene and cyclopentadiene (Scheme 4.27). The reactions work well in DCM at room temperature and Nafion-H did not cleave the acetal group [96]. The recovered Nafion-H was used four or five times without affecting the yield of the cycloadducts. 

Zeolite and Lewis-acid catalysis in Diels-Alder reactions of isoprene [20b]... 

A convenient alternative to LP-DE is lithium trifluoromethanesulfonimide (LiNTf2) in acetone or diethyl ether (LT-AC, LT-DE). Representative examples are the Diels-Alder reactions of citraconic anhydride with cyclopen-tadiene and of dimethyl acetylenedicarboxylate with isoprene [47] (Scheme 6.26). 

The effect of pressure on the rate constant of the Diels-Alder reaction between maleic anhydride and isoprene was investigated in SC-CO2 at 35 °C and at pressures ranging from 90 to 193 bar. For comparison purposes, the reaction was also carried out in an apolar solvent such as propane under... 

The Diels Alder reactions of maleic anhydride with 1,3-cyclohexadiene, as well the parallel reaction network in which maleic anhydride competes to react simultaneously with isoprene and 1,3-cyclohexadiene [84], were also investigated in subcritical propane under the above reaction conditions (80 °C and 90-152 bar). The reaction selectivities of the parallel Diels-Alder reaction network diverged from those of the independent reactions as the reaction pressure decreased. In contrast, the same selectivities were obtained in both parallel and independent reactions carried out in conventional solvents (hexane, ethyl acetate, chloroform) [84]. 

The combination of Lewis-acid catalysis and sc-COi has also been investigated. One of these studies involved the AlCls-catalyzed Diels Alder reaction of isoprene and maleic anhydride in sc-COi at 67 °C and at 74.5-78.5 bar [89]. The reaction rate was enhanced with respect to the uncatalyzed reaction and an unconcerted two-step mechanism was suggested [89]. 

In the same area, a (5)-tryptophan-derived oxazaborolidine including a p-tolylsulfonylamide function has been used by Corey et al. to catalyse the enantioselective Diels-Alder reaction between 2-bromoacrolein and cyclo-pentadiene to form the corresponding chiral product with an unprecedented high (> 99% ee) enantioselectivity (Scheme 5.27)." This highly efficient methodology was extended to various 2-substituted acroleins and dienes such as isoprene and furan. In addition, it was applied to develop a highly efficient total synthesis of the potent antiulcer substance, cassiol, as depicted in Scheme 5.21... 

The Diels-Alder reactions of alkyl-substituted benzoquinones with penta-1,3-diene and isoprene were also studied in aqueous cyclodextrin solutions. Highly enhanced ortho- and mefa-regioselectivities were observed (Eq. 12.11).48... 

It was also well established that silenes could take part as the dienophile in Diels-Alder reactions. In many cases, particularly with unsymmetric dienes such as isoprene, the reactions were not clean because, in addition to formation of the [2+4] cycloadduct 61, the possibility exists for the formation of it regioisomer 62, products of an ene reaction 63, and conceivably the [2+2] cycloaddition product 64, as shown in Eq. (23). Wiberg... 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

Recently, much attention has been paid to hetero Diels-Alder reactions as powerful tools for the construction of heterocyclic compounds. For example, cycloaddition of 2,3-dimethylbuta-l,3-diene 41a with 1,2-thiazinylium salt 95, in acetonitrile at room temperature, resulted in the exclusive formation of product 76a resulting from cycloaddition across the C—S1 bond (see entry 1 in Table 15 and Equation 26) <1999TL1505>. Similarly, isoprene 41b and... 

Rare-earth-metal triflates are efficient catalysts in Diels-Alder reactions, and Sc(OTf)3 is clearly more effective than Ln(OTf)3 as a catalyst.45,53-55 In the presence of 10mol.% Y(OTf)3 or Yb(OTf)3, only a trace amount of the adduct was obtained in the Diels-Alder reaction of methyl vinyl ketone (MVK) with isoprene. In contrast, the reaction proceeded smoothly to give the adduct in 91% yield in the presence of 10mol.% Sc(OTf)3 (Scheme 13).45 Sc(OTf)3 has also proved to be an efficient catalyst for the Diels-Alder reaction of imines (aza Diels-Alder reactions).56,57... 

Tab. 7.2 Diels-Alder reactions with 2,3-dimethylbutadiene (12) and isoprene (13) by use of the GS/MW process [27, 30, 31],...

The reactions of 4-nitrobenzodifuroxan 242 with a series of common dienes, such as cyclopentadiene, cyclohexa-diene, isoprene, 2,3-dimethylbutadiene, and 1-acetoxybutadiene, with ethoxymethyleneacetylacetone were found to proceed very readily to afford stable cycloadducts, which are the result of highly stereoselective normal electron-demand (NED) Diels-Alder reactions. Due to the additional activation provided by the two adjacent furoxan rings, the nitroalkene double bond of compound 242 is also prone to undergo NED reactions with less reactive dienic structures, such as the enol form of ethoxymethyleneacetylacetone and the in situ generated 2-ethoxy-4-(2-furfur-yl)buta-l,3-diene <2004TL1037, 2005T8167>. 

Many Diels-Alder [4 + 2] cycloadditions show a powerful pressure-induced acceleration, which is often turned to good synthetic purpose as discussed in Section III.A.2. Table 1 illustrates the effect of pressure on the Diels-Alder reaction of isoprene with acrylonitrile as a representative example. This reaction is accelerated by a factor of 1650 by raising the pressure from 1 bar to 10 kbar28. 

TABLE 1. Pressure-induced rate acceleration of the Diels-Alder reaction of isoprene with acrylonitrile at 21 °C (AV = -35.4 cm3 mol-1, AV = -37.0 cm3 mol-1)28... 

Narasaka et al.16 reported that 53 catalyzes Diels-Alder reactions of 54-type substrates with diene in the presence of 4 A molecular sieves (Scheme 5-18). A remarkable solvent effect on the enantioselectivity is observed. High enantio-selectivity is attained using mesitylene as the solvent. As shown in Scheme 5-18, the reaction of 54a with isoprene proceeds smoothly in this solvent, affording product 55a with 92% ee. Other 3-(3-substituted acryloyl)-l,3-oxazolidin-2-ones 54b-d also give good results (75-91% ee) when reacted with cyclopentadiene. 

The complex [Cp2Zr(OTf)2(thf)] is a catalyst for the Diels—Alder reactions of 105 compared to the corresponding thermal reactions [82,83] (Scheme 8.45). The isomer ratio of the reaction products (endo/exo or regioisomers) is higher in catalyzed than in thermal reactions. However, because the zir-conocenium triflate is also a catalyst for the polymerization of 1,3-dienes, the Diels—Alder reaction is sometimes completely suppressed in the case of less reactive dienophile-diene combinations. 

Fig. 20 The deuterium and carbon-13 KIEs calculated for the Diels-Alder reaction between isoprene and maleic anhydride using the isotopic enrichment in the unreacted isoprene recovered from a reaction taken to 98.9% of completion. The numbers in parentheses represent the error in the KIE. Reproduced, with permission, from...

Ohfune and coworkers78 used Diels-Alder reactions between 2-trimethylsilyloxy-l,3-butadiene (63) and acrylate esters 64 to synthesize constrained L-glutamates which they intended to use for the determination of the conformational requirements of glutamate receptors. The reactions between 63 and acrylate esters 64a and 64b did not proceed. Changing the ethyl and methyl ester moieties into more electron-deficient ester moieties, however, led to formation of Diels-Alder adducts, the yields being moderate to good. In nearly all cases, the cycloadducts were obtained as single diastereomers, which is indicative of a complete facial selectivity (equation 22, Table 1). Other dienes, e.g. cyclopentadiene and isoprene, also showed a markedly enhanced reactivity toward acrylate 64g in comparison with acrylate 64a. 

---