Cycloadditions, Diels-Alder Reactions

Three reactions are of great importance [2 + 2] cycloaddition, 1,3-dipolar cycloaddition and Diels-Alder reactions ([4 + 2] cycloadditions), which lead to four-, five- and six-membered rings, respectively. [3 + 3] Cycloadditions are known (see Section 4.3.8.2) but are of less importance. 

The thermal Diels-Alder reaction ([4 + 2] cycloaddition) is widespread in the synthesis of fullerene derivatives. In contrast, only a few examples of the photochemical Diels-Alder reaction in solution or in the solid state are known. The first example is described by Tomioka and coworkers [249], Irradiation of ketone 73 and C6o at 10°C with a high pressure mercury lamp through a Pyrex filter led to the formation of 61-hydroxy-61-phenyl-l,9-(methano[l,2]benzenomethano) fullerene 75 (Scheme 29). This compound is unusually unstable and yields the monoalky 1-1,2-dihydrofullerene 76 either by silica gel chromatography or upon heating. 

The last two bonds are formed by a Diels-Alder reaction ([4 + 2] cycloaddition) between the C9=C10 it bond and the diene from C14 to C17. 

An excellent catalytic system is based on (R)- and (5)-2,2 -dihydroxybinaphthoPThe newly designed enantiomerically pure ( + )-(/ )-3,3 -bis(triarylsilyl)binaphthol reacts with trimethyl-aluminum to produce a chiral organoaluminum reagent 15 which is a very efficient catalyst for the hetero-Diels-Alder reaction. [4 + 2] Cycloaddition of aliphatic and aromatic aldehydes 2 to dienes 14 in the presence of 10 mol% of 15 yields m-dihydropyrones 3 together with a few percent of the trans-isomers with a diastereoselectivity as high as d.r. 98.5 1.5. 

The Diels-Alder reaction ([4+2] cycloaddition) [8] provides one of the most powerful methods for the constmc-tion of PAHs because it affords one-step formation of the six-membered ring framework, the basic unit of these derivatives. This chapter, based on the results of our work, will highUght the synthesis of substituted oligoacenes including anthracene (1), tetracene (2), and pentacene (3) cores by Diels-Alder reactions using arynes and quinones as dienophile components and furans, thiophene-1,1-dioxides, and o-quinodimethane as diene components. The synthetic methodology will be accompanied by discussions on molecular and packing stmctures as weU as solid-state optical properties. 

The simplest of all Diels-Alder reactions cycloaddition of ethylene to 1 3 butadi ene does not proceed readily It has a high activation energy and a low reaction rate Substituents such as C=0 or C=N however when directly attached to the double bond of the dienophile increase its reactivity and compounds of this type give high yields of Diels-Alder adducts at modest temperatures... 

Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels-Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. 

Exocyclic double bonds at cyclic systems, which contain cross-conjugated double bonds, cannot be considered as a subgroup of radialenes and shall therefore be treated separately, although many of the structural features are comparable. However, in these systems the exocyclic and endocyclic double bonds are competing with each other as sites for Diels-Alder reactions, cycloadditions and electrophilic attacks. The double bond character of both, as measured by its distance, can provide some evidence for the selec-tivities. If no strain and conjugation are expected, the double bonds should be comparable... 

Fig. 4.10 A normal Diels-Alder reaction, cycloaddition of ethane and 1,3 butadiene.

Hayashi, Y. Catalytic asymmetric Diels-Alder reactions. Cycloaddition Reactions in Organic Synthesis 2002, 5-55. 

Kobayashi, S. Catalytic enantioselective aza Diels-Alder reactions. Cycloaddition Reactions in Organic Synthesis 2002,187-209. Jorgensen, K. A. Hetero-Diels-Alder reactions of ketones - a challenge for chemists. Eur. J. Org. Chem. 2004, 2093-2102. 

Diethyl 2-oxo-3-alkenylphosphonates, which are readily accessible from diethyl 2-oxopropylphos-phonate, are useful heterodienes in Diels-Alder reactions. Cycloaddition reactions with vinyl ethers in ( I I in a sealed tube at 85-130°C give satisfactory yields (57-88%) of dihydro-27/-pyrans. The products are isolated as a mixture of 2,4-tra .v and 2,4-czT isomers. When treated with 4 M HCl in THF, the dehydropyran hemiacetal moiety is readily hydrolyzed to provide diethyl 5-formyl-2-oxopentylphosphonates in excellent yields (72-92%, Scheme 5.59). When R> = R =H, the aldehyde undergoes smooth cyclization leading to diethyl 2-oxocyclohexenephosphonate. ... 

Keywords Diels-Alder reaction. Cycloaddition, Lewis acids, Enantioselective catalysis... 

Since cycloadditions of tetrazines follow the inverse electron demand in Diels-Alder reactions, cycloadditions to electron-rich enamines usually proceed easily and under mild conditions. In general, elimination of amine takes place from the initially formed dihydropyridazine to give the fully conjugated pyridazines as products. 

Kobayashi S (2002) Catalytic enantioselective aza Diels-Alder reactions. Cycloaddit React Org Synth 187-209... 

Nitroethene and vinyl sulfoxides have also been employed as ketene equivalents. Nitroethene is an excellent dienophile and oxidation of the initial nitro-adduct gives the corresponding ketone. However, the thermal instability of nitroethene limits its appUcation to cycloadditions with reactive dienes. An attractive feature of vinyl sulfoxides as ketene equivalents is that they can be obtained in optically active form because of the chirality of the sulfoxide group, thus allowing enan-tioselective Diels-Alder reactions. Cycloaddition of p-tolyl vinyl sulfoxide with cyclopentadiene requires heat and gives a mixture of all four (two exo and two... 

Although less reactive than most cyclic conjugated dienes, pyran-2-ones can be used in the Diels-Alder reaction/ Cycloaddition with alkynyl dienophiles is followed by loss of carbon dioxide to give benzene derivatives. Thus pyran-2-one itself reacts with dimethyl acetylene-dicarboxylate to give dimethyl phtha-late (3.46). 

Aza-Diels-Alder reactions, where the nitrogen is part of the diene component, have also featured prominently this year. Fowler and co-workers, in a continuation of their studies of the formation and trapping of 1-aza-dienes generated by thermal elimination of acetic acid from hydroxamic acid derivatives, have now described an application of the reaction to the total synthesis of the quino-lizidine alkaloid (-)-deoxynupharidine (288) (Scheme 25). Reaction to give (286) and (28 ) probably proceeds via exo, chair transition states where the major product (286) is derived from the transition state which has the methyl group on the connecting chain in an equatorial position. Kametani and co-workers have reported a useful extension to their earlier work on the Intramolecular aza-Diels-Alder reaction. Cycloaddition can now be carried out under much milder conditions than those previously described by using a trialkylsilyl trifluoromethanesulphonate as catalyst. BenzoCa ]-quinolizidine (290), for example, is obtained in excellent yield from the enamide (289). ... 

Effect of Substituents on the Reactivity of the Dienophile The simplest of aU Diels-Alder reactions, cycloaddition of ethylene to 1,3-butadiene, has a high activation energy and a low reaction rate, so does not proceed readily. However, electron-attracting substituents such as C=0 and C=N, when attached directly to the double bond, activate the dienophile toward cycloaddition. Aaolein (H2C=CHCH=0), for example, reacts with 1,3-butadiene to give a high yield of the Diels-Alder adduct at a modest temperature. 

Chiral oxazaborolidine catalysts were applied in various enantioselective transformations including reduction of highly functionalized ketones/ oximes or imines/ Diels-Alder reactions/ cycloadditions/ Michael additions, and other reactions. These catalysts are surprisingly small molecules compared to the practically efficient chiral phosphoric acids, cinchona alkaloids, or (thio)ureas hence, their effectiveness in asymmetric catalysis demonstrates that huge substituents or extensive hydrogen bond networks are not absolutely essential for successful as5unmetric organocatalysis. 

Thiophene 1,1-dioxides can behave as a dienophile toward 4it components and, therefore, can also be used for preparing bis-adducts through Diels-Alder reaction. Cycloaddition of dienes to thiophene 1,1-dioxide 109 afforded monoadducts 110, which were reacted with other dienes to give bis-adducts 111-116. The bis-adducts 111 and 112 and 113 and 114 were obtained as mixtures of stereoisomers, depending on the reaction conditions. Regio- and stereochemical features of the cycloaddition products were revealed by X-ray analyses (Scheme 103) [122]. 

Winterfeldt and co-workers discovered that ergosterol acetate 35 can be used to prepare macrocycle 37 by Diels-Alder/retro-Diels-Alder reactions. Cycloaddition of ergosterol acetate 35 to propargylic aldehyde in the presence of tungsten hexachloride as a Lewis acid catalyst produced a.jS-unsaturated aldehyde 36. When it was heated in toluene, the macrocyclic benzaldehyde 37 was obtained in 85% yield (Scheme 16.5). This skeletal... 

Breslow supported this suggestion by demonstrating that the cycloaddition can be further accelerated by adding anti cliaotropic salts such as lithium chloride, whereas chaotropic salts such as guanidium chloride led to a retardation " "" ". On the basis of these experiments Breslow excluded all other possible explanations for the special effect of water on the Diels-Alder reaction " . 

Alternatively, authors have repeatedly invoked the internal pressure of water as an explanation of the rate enhancements of Diels-Alder reactions in this solvent ". They were probably inspired by the well known large effects of the external pressure " on rates of cycloadditions. However, the internal pressure of water is very low and offers no valid explanation for its effect on the Diels-Alder reaction. The internal pressure is defined as the energy required to bring about an infinitesimal change in the volume of the solvents at constant temperature pi = (r)E / Due to the open and... 

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. 

Mechanistic investigations have focused on the two pericyclic reactions, probably as a consequence of the close mechanistic relation to the so successful aqueous Diels-Alder reaction. A kinetic inquest into the effect of water on several 1,3-dipolar cycloadditions has been performed by Steiner , van... 

As final examples, the intramolecular cyclopropane formation from cycloolefins with diazo groups (S.D. Burke, 1979), intramolecular cyclobutane formation by photochemical cycloaddition (p. 78, 297f., section 4.9), and intramolecular Diels-Alder reactions (p. 153f, 335ff.) are mentioned. The application of these three cycloaddition reactions has led to an enormous variety of exotic polycycles (E.J. Corey, 1967A). 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Two types of cycloaddition reactions have found application for the Synthetic elaboration of indoles. One is Diels-Alder reactions of 2- and 3-vinylindoles which yield partially hydrogenated carbazoles. The second is cycloaddition reactions of 2,3-indolequinodimethane intermediates which also construct the carbazole framework. These reactions arc discussed in the following sections. 

Scheme 99) (416). The 4-acetyloxy-5-ary]thiazo]e or 4-methoxy-5-arylthiazole, which are models of the protomer (174b) do not give cycloaddition products under the same experimental conditions. This rules out the possibility of a Diels-Alder reaction involving the protomer (174b) (416). 

The alkene that adds to the diene is called the dienophile Because the Diels-Alder reaction leads to the formation of a ring it is termed a cycloaddition reaction The prod uct contains a cyclohexene ring as a structural unit... 

Contrast the Diels-Alder reaction with a cycloaddition reaction that looks superfl cially similar the combination of two ethylene molecules to give cyclobutane... 

Vinylboranes are interesting dienophiles in the Diels-Alder reaction. Alkenylboronic esters show moderate reactivity and give mixtures of exo and endo adducts with cyclopentadiene and 1,3-cyclohexadiene (441). Dichloroalkenylboranes are more reactive and dialkylalkenylboranes react even at room temperature (442—444). Dialkylalkenylboranes are omniphilic dienophiles insensitive to diene substitution (444). In situ formation of vinyl-boranes by transmetaHation of bromodialkylboranes with vinyl tri alkyl tin compounds makes possible a one-pot reaction, avoiding isolation of the intermediate vinylboranes (443). Other cycloadditions of alkenyl- and alkynylboranes are known (445). 

Cycloaddition Reactions. Methacrylates have been widely used as dienophiles in Diels-Alder reactions (22—24). 

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