Polycyclic compounds Diels-Alder reaction

Compounds containing a double or triple bond, usually activated by additional unsaturation (carbonyl, cyano, nitro, phenyl, etc.) In the ap position, add to the I 4-positions of a conjugated (buta-1 3-diene) system with the formation of a ax-membered ring. The ethylenic or acetylenic compound is known as the dieTwphile and the second reactant as the diene the product is the adduct. The addition is generally termed the Diels-Alder reaction or the diene synthesis. The product in the case of an ethylenic dienophile is a cyctohexene and in that of an acetylenic dienophile is a cyctohexa-1 4-diene. The active unsaturated portion of the dienophile, or that of the diene, or those in both, may be involved in rings the adduct is then polycyclic. 

Under different conditions [PdfOAcj2, K2CO3, flu4NBr, NMP], the 1 3 coupling product 86 with 4-aryl-9,10-dihydrophenanthrene units was obtained. The product 86 was transformed into a variety of polycyclic aromatic compounds such as 87 and 88[83], The polycyclic heteroarene-annulated cyclopen-tadicnc 90 is prepared by the coupling of 3-iodopyridine and dicyclopentadiene (89), followed by retro-Diels Alder reaction on thermolysis[84]. 

The allenyl moiety (2,3-aikadienyl system) in the carbonylation products is a reactive system and further reactions such as intramolecular Diels-Alder and ene reactions are possible by introducing another double bond at suitable positions of the starting 2-alkynyl carbonates. For example, the propargylic carbonate 33 which has l,8(or 1.9)-diene-3-yne system undergoes tandem carbonylation and intramolecular Diels-Alder reaction to afford the polycyclic compound 34 under mild conditions (60 C, 1 atm). The use of dppp as ligand is important. One of the double bonds of the allenyl ester behaves as part of the dieneflSj. 

Since diazaquinones are among the most powerful dienophiles, they undergo [4+2] cycloaddition (Diels-Alder) reactions with a great variety of dienes to give various heterocyclic systems accessible with difficulty by other methods. Diazaquinone reacts with butadiene and substituted butadienes, carbocyclic and heterocyclic dienes, 1-vinylcycloalkenes, polyaromatic compounds and vinylaromatic compounds to afford bicyclic and polycyclic bridgehead diaza systems, including diazasteroids (Scheme 56). 

Tamariz and coworkers [42] have described a versatile, efficient methodology for preparing N-substituted-4,5-dimethylene-2-oxazolidinones 42 (Figure 2.5) from a-diketones and isocyanates and have also studied their reactivity in Diels-Alder reactions. This is a method for synthesizing polycyclic heterocyclic compounds. Some of the reactions of diene 42 are summarized in Scheme 2.18. The nitrogen atom seems to control the regiochemistry of the reaction. 

Indole-2,3-quinodimethanes [44] 44 are bicyclic outer-ring dienes that are widely used to prepare a variety of heterocyclic polycyclic compounds. These dienes, generated by extrusion of CO2 from lactones, are then trapped by dienophiles. Some examples of Diels Alder reactions of the dienes 44 are reported in Scheme 2.19. 

Dihydrovinylphenanthrenes are more reactive than the corresponding vinyl phenanthrenes and undergo Diels-Alder reactions easily. They have been used in the synthesis of polycyclic aromatic compounds and helicenes. Examples of cycloaddition reactions of the 3,4-dihydro-1-vinylphenanthrene (70), [61] 3,4-dihydro-2-vinylphenanthrene (71) [68] and l,2-dihydro-4-vinylphenanthrene (72) [69] are reported in Equation 2.22 and Schemes 2.27 and 2.28. 

There is another type of multiple thermal Diels Alder reaction in which the initial monoadduct is involved, either directly or after one transformation, in a second cycloaddition that affords the final polycyclic compounds. These methodologies have been used especially in the synthesis of polycyclic cage compounds. Paquette was the first to report the conversion of 9,10-dihydroful-valene into polyfused cyclopentanoid systems [124],... 

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). 

Azulene quinones [49b] are compounds related to the family of tropones and are considered to possess great biological and physiological potential. Several polycyclic compounds have been prepared by high pressure (3kbar, PhCl, 130°C, 15h) Diels-Alder reaction of 3-bromo-l,5-azulene quinone (137) and 3-bromo-l,7-azulene quinone (138) with several dienophiles. The cycloadditions were regioselective and afforded cycloadducts in reasonable to good yields (Scheme 5.20). 

Deslongchamps P. Transannular Diels-Alder Reaction on Macrocycles a General Strategy for the Synthesis of Polycyclic Compounds A Idrichimica Acta 199124 43-56... 

Intramolecular versions of the Diels-Alder reaction are well known, and this is a powerful method for the synthesis of mono- and polycyclic compounds.There are many examples and variations. One interesting internal Diels-Alder reaction links the diene and dienophile by a C—O—SiR2—or a C—O—SiR2—O—C linkage. Internal cyclization to give a bicyclic product is followed by cleavage of the O-Si unit to give a monocyclic alcohol. 

Examples Compound <35) is a double diene, capable of Diels-Alder reactions on the simple diene and on the furan ring and it was required to try out a route to polycyclic compounds using both these reactions, Wittig disconnection direct to available aldehyde (36) and easily made (37) is possible, but the alternative Wittig disconnection to (38) takes advantage of the known simple and high yielding condensation of acetone with (36). 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

It is not quite clear which step takes place first - the Co-catalyzed [2+2+1] cycloaddition of the outer alkyne moiety, or the Diels-Alder reaction of the diene with the inner alkyne to form a 1,4-cyclohexadiene, which then undergoes a Pauson-Khand reaction with the remaining alkyne. Recently, it has been shown that a domino reaction can also be performed using 1 mol of a 1,7-diphenyl-1,6-diyne 6/4-20 and a 1,3-diene 6/4-21 in the presence of Co/C at 150 °C under 30 atm CO, to give the polycyclic compounds 6/4-22 as sole product (Scheme 6/4.7) [282]. 

Furanophane 8 is reactive and undergoes interesting reactions with dienophiles. The reaction of 8 with dimethyl acetylenedi-carboxylic acid gave a polycyclic compound, as shown in the following equation. The compound was derived by intramolecular Diels-Alder reaction of the initially formed 1 1 adducts (38). 

In the highly competitive arena surrounding the Pfizer compounds CP-263,114 and CP-225,917 (Figure 4.2), Nicolaou and co-workers employed a hydrozirconation—iodination sequence to produce vinyl iodide 4 [17]. Lithium—halogen exchange and subsequent conversion to enone 5 sets the stage for a Lewis acid assisted intramolecular Diels—Alder reaction affording polycyclic 6 as the major diastereomer (Scheme 4.3). 

The forward reaction is extremely easy bevause of aromaticity recovery. These aspects of the intramolecular Diels-Alder reaction are generally very useful and able to provide polycyclic fused six-membered ring compounds which are otherwise difficult to realize. The controlling factors, geometry and mechanism of intramolecular Diels-Alder reactions have been comprehensively reviewed elsewhere i°4,106), and it is not our intention to discuss these in details. However, the synthetic utility of the reaction is demonstrated by the following examples107). 

As a part of a broad study dealing with the development of synthetic methods for polycyclic aromatic compounds, Minuti and colleagues77 prepared some [5]phenacenes and fluorenoanthracenes via Diels-Alder reactions between dienes such as 59 and several activated dienophiles. Oxidation of the primary adducts with DDQ afforded the desired polycyclic aromatic compounds. Equation 21 shows the reaction between 3,4-dihydro-1-vinylanthracene (59) and in situ generated 2-inden-l-one (60) which afforded a 3 1 mixture of regioisomers 61 and 62 with 51% overall yield. 

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. 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

Since the publication of CHEC-II(1996) <1996CHEC-II(6)1>, in which thermally induced [4+2] cycloadditions have been reviewed, significant progress has been realized in this strategy, especially for the synthesis of polycyclic heterocycles. Cyclophanes 12 containing pyridazine and indole units were used for the synthesis of pentacyclic compounds 13 via a thermally induced transannular inverse-electron-demand Diels-Alder reaction (Equation 2) <20020L127, 2002AGE3261>. 

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