Diels-Alder reactions, intermolecular intramolecular

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels—Alder reactions. The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN. The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzoluroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine A-oxide adducts (138) and (139) together with a bis(dihydrooxazine 7V-oxide) product (140) in the presence of excess ethyl vinyl ether (Scheme 52). The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-d]pyrimidines. The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced 17/-imidazo[4,5-c]pyridines and the rearranged 37/-pyrido[3,2-J]pyrimidin-4-... 

Methods for the synthesis of central hydroisoquinolines or pyrrolo-hydroisoquinoHnes of manzamine A can be classified into 11 types of reactions (1) intermolecular Diels-Alder reaction, (2) intramolecular Diels-Alder reaction, (3) photochemical reaction, (4) radical reaction, (5) ionic cyclization, (6) intramolecular Michael reaction, (7) intramolecular Maimich reaction, (8) intramolecular [3 + 2] cycloaddition, (9) intermolecular [3 + 2] cycloaddition, (10) Pauson-Khand reaction, and (11) eneyne metathesis. 

The chiral copper reagent 24 is an effective catalyst not only for intermolecular, hut also for intramolecular Diels-Alder reactions, as shown in the following schemes (Scheme 1.41, 1,42, 1.43). Synthetically useful octalin and decalin skeletons were synthesized in high enantio- and diastereoselectivity. The synthetic utility of this intramolecular Diels-Alder reaction has been demonstrated hy a short total synthesis of isopulo upone [23, 33d]. 

A domino reaction,in this case consisting of an inter- and an intramolecular Diels-Alder reaction, is a key step in the synthesis of the hydrocarbon pago-dane 30, reported by Prinzbach et al When the bis-diQnQ 27 is treated with maleic anhydride 4, an initial intermolecular reaction leads to the intermediate product 28, which cannot be isolated, but rather reacts intramolecularly to give the pagodane precursor 29 ... 

The Diels-Alder cycloaddition is the best-known organic reaction that is widely used to construct, in a regio- and stereo-controlled way, a six-membered ring with up to four stereogenic centers. With the potential of forming carbon-carbon, carbon-heteroatom and heteroatom-heteroatom bonds, the reaction is a versatile synthetic tool for constructing simple and complex molecules [1], Scheme 1.1 illustrates two examples the synthesis of a small molecule such as the tricyclic compound 1 by intermolecular Diels-Alder reaction [2] and the construction of a complex compound, like 2, which is the key intermediate in the synthesis of (-)chlorothricolide 3, by a combination of an intermolecular and an intramolecular Diels-Alder cycloaddition [3]. 

The Diels-Alder reaction can be intermolecular or intramolecular and can be carried out under a variety of experimental conditions that will be illustrated in detail in the following chapters. 

There are many types of Diels-Alder reactions that are carried out under thermal conditions. This chapter will deal with the most significant developments, the potential and range of applications of this methodology of both the intermolecular and intramolecular cycloadditions in organic synthesis. 

The /zetero-Diels-Alder reaction permits heterocyclic-six- membered rings to be constructed by the interaction of heterodienes and/or heterodienophiles. Both the intermolecular and intramolecular versions of the /zctcro-Diels Alder reaction are, therefore, very important methods for synthesizing heterocyclic compounds. 

Lewis-acid catalysis is effective in intermolecular as well as intramolecular /zomo-Diels-Alder reactions. Thus, complex polycyclic compounds 93 have been obtained in good yield by the cycloaddition of norbornadiene-derived dienynes 92 by using cobalt catalyst, whereas no reaction occurred under thermal conditions [91] (Scheme 3.18). 

To avoid problems with the separation of regiomers, dimethyl acetylene dicarboxylate (DMAD) was chosen as a dienophile. The intermolecular Diels-Alder reactions were performed in refluxing dichlorobenzene (bp 132 °C), while the intramolecular reaction of alkyne tethered pyrazinone required a solvent with a higher boiling point (bromobenzene, bp 156 °C). In the case of 3-methoxy or 3-phenyl pyrazinones a mixture of pyridinones and pyridines was obtained, while for the alkyne tethered analogue only the di-hydrofuropyridinone was isolated as the single reaction product. 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The combination of two successive [4+2] cycloadditions has already been described by Diels and Alder [la] for the reaction of dimethyl acetylenedicarboxylate with an excess of furan. A beautiful, more modern, example is the synthesis of pagodane (4-5) by Prinzbach [2], in which an intermolecular Diels-Alder reaction of 4-1 and 4-2 to give 4-3 is followed by an intramolecular cycloaddition. The obtained 4-4 is then transformed into 4-5 (Scheme 4.1). 

Another intramolecular ene-yne metathesis followed by an intermolecular metathesis with an alkene to give a butadiene which is intercepted by a Diels-Alder reaction was used for the synthesis of condensed tricyclic compounds, as described by Lee and coworkers [266]. However, as mentioned above, the dienophile had to be added after the domino metathesis reaction was completed otherwise, the main product was the cycloadduct from the primarily formed diene. Keeping this in mind, the three-component one-pot reaction of ene-yne 6/3-94, alkene 6/3-95 and N-phenylmaleimide 6/3-96 in the presence of the Grubbs II catalyst 6/3-15 gave the tricyclic products 6/3-97 in high yield (Scheme 6/3.28). 

A one-pot, four-component process involving the in situ formation of an azadiene followed by an intermolecular or intramolecular Diels-Alder reaction for the synthesis of highly functionalized piperidone scaffolds has been reported [81]. The compounds were obtained in good yields and diastereoselectivities (Figure 5). 

This chapter deals with [2 + 2]cycloadditions of various chromophors to an olefinic double bond with formation of a four-membered ring, with reactions proceeding as well in an intermolecular as in an intramolecular pattern. Due to the variety of the starting materials available (ketones, enones, olefins, imines, thioketones, etc.. . .), due to the diversity of products obtained, and last but not least, due to the fact that cyclobutanes and oxetanes are not accessible by such a simple one-step transformation in a non-photo-chemical reaction, the [2+2]photocycloaddition has become equivalent to the (thermal) Diels-Alder reaction in importance as for ring construction in organic synthesis. 

Intermolecular cycloadditions or Diels-Alder reactions have proved to be a successful route to several valuable intermediates for natural product syntheses. In creating new chiral centers, most of these reactions apply single asymmetric induction. As mentioned in Chapter 3, in the asymmetric synthesis of the octa-hydronaphthalene fragment, the Roush reaction is used twice. Subsequent intramolecular cyclization leads to the key intermediate, the aglycones, of several natural antitumor antibiotics. On the other hand, the Diels-Alder reaction of a dienophile-bearing chiral auxiliary can also be used intramolecularly to build... 

Apart from its application in intermolecular Diels-Alder reactions, chiral acyloxy boron (CAB) can also be used to effect intramolecular Diels-Alder reactions with excellent stereoselectivity (Scheme 5-45).73... 

Bicyclic derivatives. Polyhydroxylated carbo-bicyclic derivatives may be regarded as carbasugars with the rigid structure resulting from the presence of the additional carbocyclic ring. The most convenient way for construction of the bicyclic skeleton consists of the Diels-Alder reaction of properly functionalized trienes (intramolecular version) or dienes and olefins (intermolecular). 

Several other intramolecular reactions showed only slight rate accelerations or retardations (VanderJagt et al., 1970). Of potential synthetic use, it has been found that both intramolecular and intermolecular Diels-Alder reactions can be catalysed by /3-CD (Sternbach and Rossana, 1982 Breslow and Guo, 1988). 

Dailey and colleagues109 employed a domino Diels-Alder reaction to synthesize the complex hexacycle 146. The intermolecular reaction of tetracycle 143 with maleic anhydride 144 afforded a single adduct (145) which immediately underwent an intramolecular Diels-Alder reaction to give 146 (equation 42). This reaction is similar to a reaction performed previously by Prinzbach and colleagues110. Prinzbach observed that when alkynes were used as dienophiles, either domino or pincer Diels-Alder reactions occurred. In the latter type, the triple bond reacts with both diene units. 

Intramolecular Diels—Alder reactions without prior 1,4-addition of oxygen (cf. previous section) have similarly been postulated for a number of [2.2]paracyclophane analogs. When [2](2,5)furano[2](l,4)naphthalen-ophane (42) is heated in excess dimethyl acetylenedicarboxylate at 100 °C, a polycyclic compound of structure 134 is formed. The mechanism of formation of 134 is most probably as follows 101> the furan moiety reacts as active diene component in an intermolecular Diels—Alder reaction to give 135. This is followed by further intramolecular 1,4-addition with the unsubstituted naphthalene ring as diene component to give the product 133, which has been isolated. 

Except for Yamada s synthesis, all total syntheses feature the venerable Diels-Alder reaction as a key transformation, in either an intermolecular or intramolecular fashion or in a combination of both. 

In a rather elegant approach towards colombiasin A (36) Flynn et al. [47] would access the tetracyclic carbon skeleton through an enantioselective intermolecular Diels-Alder sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence between double-diene 166 and quinone 167 (Scheme 26). A key element of the proposed approach would be the chiral sulfoxy group in 167 which controls both the regio and facial selectivity of the intermolecular Diels-Alder reaction and eliminates generation of the dienophile for the IMDA reaction. 

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

This section is devoted to cyclizations and cycloadditions of ion-radicals. It is common knowledge that cyclization is an intramolecular reaction in which one new bond is generated. Cycloaddition consists of the generation of two new bonds and can proceed either intra- or intermolecularly. For instance, the transformation of 1,5-hexadiene cation-radical into 1,4-cyclohexadienyl cation-radical (Guo et al. 1988) is a cyclization reaction, whereas Diels-Alder reaction is a cycloaddition reaction. In line with the consideration within this book, ring closure reactions are divided according to their cation- or anion-radical mechanisms. 

Bicyclopropylidene (1) does not undergo an intermolecular Diels-Alder reaction with furan and 2-methoxyfuran even under high pressure. Intramolecular cycloadditions of compounds 160 with a furan tethered to bicyclopropylidene, however, were easily brought about under high pressure (10 kbar) and gave cycloadducts 161 stereoselectively in yields ranging from 32 to 95% (Scheme 35) [58]. 

Lewis acid catalysis usually substantially improves the stereoselectivity of intramolecular Diels-Alder reactions, just as it does in intermolecular cases. For example, the thermal cyclization of 1 at 160°C gives a 50 50 mixture of two stereoisomers, but the use of Et2AlCl as a catalyst permits the reaction to proceed at room temperature, and endo addition is favored by 8 l.69... 

As can be seen in the intramolecular cycloaddition (Section 8.03.5.1), the intermolecular Diels-Alder reactions between functionalized 2(l/f)-pyrazinones 83 and dimethyl acetylenedicarboxylate (DMAD) forming bicyclo adducts 84 has been shown to be significantly rate enhanced and increased in yields by using controlled microwave irradiation compared to the conventional thermal protocols (Scheme 21) <2002JOC7904>. The microwave-assisted Diels-Alder reactions of substituted 2(l//)-pyrazinones with ethene are significantly more effective utilizing prepressurized (up to 10 bar) reaction vessels <20040BC154>. 

An interesting one-pot, five-component domino process using an intermolecular Diels-Alder reaction of furans with AT-phenylmaleimide as its final step has been used to construct the central core of indolo[2,3- ]carbazoles (Equation 86) <2002AGE4291>. Thus, aminooxazoles produced from an Ugi three-component reaction undergo acylation/intramolecular Diels-Alder/retro-Diels-Alder cycloreversion with pentafluorophenyl arylprop-2-ynoates to give furan derivatives. Subsequent Diels-Alder cycloaddition at elevated temperatures with A -phenylmaleimide produces carbazoles in good yields (Table 5). 

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