Demand DA reactions

The inverse electron demand DA reaction of 1,2,4,5-tetrazines has continued to be the most important reaction of this system. 

The o-quinone heterodienes generated electrochemically from pyrogallols undergo in situ regiospecific inverse electron demand DA reactions with enamines leading to a wide range of... 

Chiral Al-salen complexes enable pyranoquinolines to be obtained with high diastereoselectivity by an inverse electron demand DA reaction between dihydropyran and benzylidene aniline <04BMCL2035>. Sulfamic acid effects the one-pot reaction between benzaldehyde, an aromatic amine and dihydropyran which leads to the same products (Scheme 3). An intramolecular version of the latter variant involves the imines derived from O-prenylsalicylaldehyde and gives isochromanoquinolines <04S69> and sulfamic acid is also a suitable catalyst for the Pechmaim synthesis of coumarins <04SL1909>. 

It is proposed that the benzo[c]pyrylium cation 39, produced from o-alkynylbenzaldehydes by AuBra catalysis, behaves as the 4n component in an inverse electron demand DA reaction with enols. Dehydration and bond rearrangement leads to naphthalene derivatives. Simple a, 3-unsaturated aldehydes can also be benzannulated in this way <04JA7458>. 

An asymmetric total synthesis of ent-(-) roseophilin has been reported involving an inverse electron demand DA reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate <01JA8515>. The electron deficient character of the diazadiene system of 1,2,4,5-tetrazines has been used to obtain epibatidine analogs (7-azabicyclo[2,2,l]heptane derivatives) through an inverse type DA reaction <01JMC47>. 

The synthesis of the ultra highly electron-deficient pyrrolo[3,4-inverse-electron-demand DA reaction of the pyrrole-2,5-dione 50 with furyl- or thienyl-decorated tetrazine 51 was applied for preparation of new electrochromic materials with good optical contrast, fast-switching speed, and high coloration efficiency (140L6386). 

Diels-Alder (DA) reaction is one of the most useful chemical transformations. This reaction typically proceeds slowly in the absence of a catalyst, but can be accelerated with the use of Lewis acids [75], It is characterized by high yield under various conditions, has less sensitivity against solvents, and does not produce byproducts. It is characterized by high yield under various conditions, insensitive toward solvent polarity, and little byproducts. Indeed, the tetrazine/trani-cy-clooctene based inverse electron-demand DA reaction has become the most popular bioorthogonal reaction in the literature because of its fast reaction kinetics [76]— second-order rate constant as high as 2.8 x 10 s has been reported [77], So... 

Normally the polarity of the normal electron demand DA process has been studied by means of global electrophilicity index difference between reactants and the regioselectivity of the normal electron demand DA reaction using the local electrophilidty index for dienophiles (electrophiles in the reaction) and the local nudeophilicity index for dienes (nucleophiles in the reaction). 

Taking into account that the reactivity of a DA reaction depends on the HOMO-LUMO energy separation of the reactants, and that in a normal electron demand DA reaction the strongest interaction takes place between the HOMO of the diene and the LUMO of the... 

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. 

Scheme 9.27 Benchmark transformation for DA reaction with normal electron demand.

Scheme 9.30 Iron-catalyzed DA reaction with neutral electron demand.

So far, only a single report, by Gorman and Tomlinson of an iron-catalyzed DA reaction with inverse electron demand, has appeared [86]. The transformation of a 4-oxobutenoate (43) as a rather electron-poor hetero-1,3-diene and an enol ether as the electron-rich dienophile can be seen as an extreme example of a diastereoselective hetero-DA reaction controlled by an iron catalyst (Scheme 9.32). 

The yields for this transformation are good and the diastereoselectivities are generally excellent however, the scope of the iron-catalyzed DA reaction with inverse electron demand seems to be limited. 

The 1,2,4-triazines usually attract much greater attention than their 1,2,3-relatives. Due to the abundance of nitrogen atoms in the cycle and electron deficiency, they are widely explored in reactions of nucleophilic substitution, inverse-electron-demand DA cycloaddition and other ring transformations, as coordinating ligands for metal ion binding and bioactive agents. So, the points of interest involve 1,2,4-triazine synthesis, their transformation and functionalization, and further studies for different applications. 

Inverse-electron-demand DA cycloaddition reactions retain the top position in synthetic research on 1,2,4-triazines (12CHC1153). There are several new examples of the use of the reaction for 1,2,4-triazine ring transformation. Thus, a new route to prepare pyridine derivatives 23 and 24 based on inverse-electron-demand DA/retro-DA reactions of ketones with 1,2,4-triazines 25 using the enolates of methyl ketones direcdy as a dienophile without enamine intermediates is reported, which is complementary to the classical Boger procedure (14RSCA59218). 

The HOMO activation of dienophiles (reversed electron demand DA) was reported by Chen and co-workers [32]. They found that the catalytic reaction of crotonaldehyde with prolinol ether 46 resulted in formation of a 1,3-dieneamine 49 that selectively reacted as a dienophile on the terminal double bond in a reversed electron demand Diels-Alder reaction with electron-deficient dienes 48 to give access to highly diastereo- and enantioenriched cyclohexen derivatives 50 (Scheme 6.12). 

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. 

The most commonly employed dienophiles in DA reactions with normal electron demand are maleimide derivatives. These electron-poor alkenes react smoothly with various conjugated dienes to form the respective bicyclic cycloadducts under mild conditions (Fig. 14a). One drawback of maleimides that limits their widespread use in bioconjugation is their ability to react with naturally occurring nucleophiles,... 

The reversibility of the DA reaction, known as the retro Diels-Alder reaction, can hamper the utilization of this chemistry for bioconjugation when the formation of thermally stable products is absolutely necessary. This limitation can be conveniently overcome by the use of dienes that form stable cycloadducts during the reaction. One such example is the inverse electron-demand Diels-Alder reaction of heterodienes with strained alkenes and alkynes. 

The DFT analysis of the global properties of the interacting pair diene/dienophile illustrates the normal electron demand character of these DA reactions. It is possible to show that the local indexes provide useful clues about the regiodirector effects, particularly of the nitro group. The presence of a solvent (molecular or neoteric) as the reaction media does not... 

The reversibility of the conventional Diels-Alder reaction makes it a prime candidate for the synthesis of smart materials that exhibit a temperature-dependent transition between two physical properties (such as viscosity or color). However, many applications (such as biological labeling) require irreversible conjugation chemistry that also is very fast under mild and dilute reaction conditions. Eor such purposes, the inverse electron-demand Diels-Alder (IVED-DA) reaction between electron-deficient tetrazine derivatives and various alkenes is incredibly efficient. 

Only one study detailing DTDA reactions of the pseudo-acyclic 1,1- or 3,3-cyclo[3]dendralenes has been reported, most likely owing to the difficulties associated with DA reactions of such highly substituted dienes. The prototypical, and not yet reahzed, DTDA cascade of l,l-cyclo[3]dendralene 17 is presented in Scheme 12.12. If the first DA reaction occurs at the more sterically demanding exocyclic diene site, spiro-bicycle 65 is produced, which could react further to generate the... 

The generally observed identity of the r value for solvolysis reactivity and gas-phase stability AAG(c+> of the corresponding carbocation leads to an important prediction concerning the solvolysis transition state. In a typical (limiting) two-step SnI mechanism with a single dominant transition state, the r values of transition states for the various nucleophile-cation reactions should be essentially controlled by the intrinsic resonance demand of the intermediate cation the substituent effect should be described by a single scale of substituent constants (a) with an r value characteristic of this cation. In a recent laser flash-photolysis study (Das, 1993) on the recombination of stable trityl and benzhydryl cations with nucleophiles and solvents, McClelland et al. (1986, 1989) have treated the substituent effects on solvent-recombination processes by (2). 

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