Diels-Alder DA Cycloaddition Reactions

Describe the main criteria that should be satis ed for a reaction to be called a click reaction How would you justify the inclusion of the following reactions into the pantheon of click reactions (a) Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions (b) strain-promoted azide-alkyne coupling (SPAAC) reactions (c) Diels-Alder (DA) cycloaddition reactions (d) thiol-ene (TE) reactions and (e) thiol-yne (TY) reactions ... 

Figure 12.7 All four possible transition states of the highly diastereoselective Diels-Alder (DA) cycloaddition reaction employed for the synthesis of the [12]collarene 12.18b. The superb diastereoselectivity of the reaction is explained by the DFT (B3LYP/6-31G ) transition-state energies, which have been plotted relative to the energy of the starting materials.

Diels-Alder (DA) cycloadditions are one convenient route for the formation of carbon-carbon bonds via a facile reaction under undemanding conditions [57]. As a thermoreversible reaction, DA cycloaddition does not require the addition of chemicals/catalyst to promote reaction [58]. This property makes it an ideal reaction for the synthesis of self-healing polymers. 

The synthesis (Scheme 12.8) of the first [l2]collarene molecular belt (12.18b) was achieved in our laboratory through the repeated application of Diels-Alder (DA) cycloadditions between the dienophile 12.20 and the diene 12.21, which proceeds with extraordinarily high diastereoselectivity. While the DA reaction between 12.20 and 12.21 could, potentially, lead to four different diastereoisomeric products, only a single diastereoisomer was actually observed in this reaction. This especially high diastereoselectivity is dictated primarily by electronic effects, which kinetically favor attack on the diene 12.21 from the endo face, while attack on the dieneophile 12.20 is preferred from the exo side. Density functional theoiy (DFT) calculations (Figure 12.7) reveal that the observed diastereoselectivity has its cause in the selective stabilization of the endo-exo transition state (12.19a). 

Diels Alder (DA) and 1,3-dipolar cycloaddition (1,3-DC) reactions are simple and very versatile transformations to introduce a wide range of substituents at the meso- and beta-pyrrolic positions of porphyrins, thus leading to promising derivatives obtained in many cases in one-pot transformations. 

The generation of six-membered ring systems by means of cycloaddition reactions can be divided into two main approaches. The first is the cyclotrimerizationofalkynes utilizing low-valent iron catalyst systems, whereas the second approach is the Diels-Alder (DA) reaction of a diene and a dienophile. The latter reaction can itself be divided into three subclasses DA reactions with normal, neutral and inverse electron demand are known. The electronic structure of the educts dictates the oxidation state of the catalyst system required to perform the diverse classes of DA reactions. Nevertheless, for each subclass examples can be found. 

An intriguing competition arises in the context of cation radical cycloadditions (as in the context of Diels-Alder cycloadditions) which involve at least one conjugated diene component. Since both cyclobutanation and Diels-Alder addition are extremely facile reactions on the cation radical potential energy surface, it would not be surprising to find a mixture of cyclobutane (CB) and Diels-Alder (DA) addition to the diene component in such cases. Even in the cyclodimerization of 1,3-cyclohexadiene, syn and anti cyclobutadimers are observed as 1 % of the total dimeric product. Incidentally, the DA dimers have been shown not to arise indirectly via the CB dimers in this case [58]. The cross addition of tw 5-anethole to 1,3-cyclohexadiene also proceeds directly and essentially exclusively to the Diels-Alder adducts [endo > exo). Similarly, additions to 1,3-cyclopentadiene yield essentially only Diels-Alder adducts. However, additions to acyclic dienes, which typically exist predominantly in the s-trans conformation which is inherently unsuitable for Diels Alder cycloaddition, can yield either exclusively CB adducts, a mixture of CB and DA adducts or essentially exclusively DA adducts (Scheme 26) [59]. 

Although there are many natural products 1-4 (Scheme 3 and 4) which may formally derive from [4 + 2]-cycloadditions, and although the Diels-Alder (DA) reaction is of great value and is irreplaceable for synthetic chemists, there is no definitive proof for Diels-Alder reactions occurring in biosynthesis. At the same time cell-free extracts, for instance, from the fungus aleternaria solani, accelerate Diels-Alder reactions by a factor of 4.1 and reverse the normally observed ewdo-selectivity. Still, there is no... 

Cycloaddition reactions, most commonly the Huisgen 1,3-dipolar cycloaddition, but also the Diels-Alder (DA) reaction. 

The Diels-Alder (DA) reaction is a pericyclic [4 -I- 2]-cycloaddition reaction where a 47t electron system (a diene) reacts with a 2jt electron system (a dienophile), yielding a new six-membered ring product. The reaction is stereospecific, where the stereochemistry of the starting compounds is preserved in the products. In a DA reaction with normal electron demand, the dienophile typically bears an electron withdrawing substituent, while the diene is electron-rich. The case of the reverse situation, where an electron-poor diene reacts with an electron-rich dienophile, is known as the Diels-Alder reaction with inverse electron demand. 

Reactions between a diene and a dienophile yielding cyclohexene derivatives through carbon-carbon or carbon-heteroatom bond formation are referred to as Diels-Alder (DA) reactions. The concerted [4 + 2] cycloaddition was first described in 1928 by Diels and Alder, ° and can be adapted for the efficient conjugation of peptides and proteins to synthetic polymers. Despite being recognized as highly selective and additive-free, DA reactions require elevated temperatures to obtain the desired product. Furthermore, the reversibility of the reaction limits its application in materials science. ... 

Even azide moieties are capable of entering DA cycloaddition reactions with oxanorbornadiene derivatives, yielding triazole products. For example, the tandem [3 + 2]/Diels-Alder cycloreversion (CrDA) was used for the PEGyZatzon of an N-terminally azido functionalized peptide (GGRGDG). Furthermore, labeling of oxanorbornadiene-modified hen egg-white lysozyme with fluorescent coumarine was demonstrated. The release of furan... 

Das has described the cycloaddition of camptothecin (92), an alkaloid with potent antitumor activity, with maleic anhydride under the action of microwave irradiation in a commercial microwave oven for 9 min [78]. Two unprecedented adducts, 93 and 94, were produced. The first was formed by involvement of the B-ring in a hetero Diels-Alder reaction whereas the second was formed by involvement of the C-ring, probably through Diels-Alder reaction of intermediate 95 (Scheme 9.28). 

Evans DA, Chapman KT, Bisaha J (1984) New asymmetric Diels-Alder cycloaddition reactions. Chiral a,fS-unsaturated carboximides as practical chiral acrylate and crotonate dienophile synthons. J Am Chem Soc 106 4261-4263... 

Alves, C. N., Romero, O. A. S., Da Silva, A. B. F. Theoretical study on the stereochemistry of intramolecular hetero Diels-Alder cycloaddition reactions of azoalkenes. Int. J. Quantum Chem. 2003, 95, 133-136. 

Microwaves were shown to affect both reactivity and selectivity. The effect on yield is rather limited in the Diels-Alder reaction and found to be higher in the Michael addition. This process was even more favored by use of acetic acid as the solvent. These results can be explained by the natural assumption that the transition state leading to Michael addition (M) much more polar than that leading to Diels-Alder cycloaddition (DA). 

In the past few years solvent-free DA reactions have been regularly performed successfully under microwave irradiation conditions, reducing reaction times to a few minutes compared with several hours under conventional reflux conditions [3j]. Scheme 11.3, mentioned above, shows two recent examples of Diels-Alder cycloadditions performed by microwave dielectric heating [42, 43]. In both examples the diene and dienophile were reacted neat under solvent-free conditions. 

In the field of sustainability, atom economy is an important asset and cycloaddition is an interesting way to build functionalised cycles with simultaneous creation of new stereocentres without production of waste/ The use of immobilised Lewis-acids to catalyse this pericyclic rearrangement renders it much more attractive for environmental considerations and such effort has been made in the titanium-catalysed Diels-Alder reaction (DA), hetero-Diels-Alder reaction (HDA) ° and 1,3-dipolar cycloaddition. 

The classical DA reaction is a [4+2] cycloaddition between a conjugated diene and a second component ( dienophile ) to give a stable cyclohexene derivative ( adduct ) [ 1 -5]. This reaction displays a thermally reversible character, which allows decoupling of the adduct to occur by increasing the temperature. Hence, the equilibrium is displaced to the left with regeneration of initial reagents (Scheme 7.1). The reverse reaction is called the retro-Diels-Alder (retro-DA) reaction [1-5]. 

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