Inverse electron demand Diels-Alder reactions, examples using

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Several examples exist of inverse electron demand Diels-Alder reactions involving electron-deficient sym-tetrazines acting as dienes. However, the neutral, electon-rich imino compounds involved in these cycloadditions do not generally e pear to be useful dienophiles with other types of dienes. 

An extensively investigated and useful hetero-2-azadiene system capable of 4it participation in Diels-Alder reactions is the vinylnitroso compounds.75-78 The complementary addition of electron-withdrawing substituents to the 3 position of the vinylnitroso system enhances the rate of diene participation in inverse electron demand Diels-Alder reactions with electron-rich or neutral dienophiles (simple olefins).75,76 Table 9-IV summarizes a series of representative examples of the 47r participation of vinylnitroso compounds in Diels-Alder reactions, and an extensive review has summarized much of this work.5,75... 

Probably the most useful and general reaction of all these systems is the inverse-electron demand Diels-Alder reaction with acetylenes (or equivalents) to produce either pyridines or diazines via elimination of hydrogen cyanide or nitrogen. Abnormal reactions occasionally occur through non-concerted mechanisms, as the last example shows. 

Fragmentation of an adduct with release of a nitrile, CO2 or N2 are most common and the latter provide an irreversible method for the formation of a new diene or aromatic compound. Cycloaddition of a pyran-2-one or a 1,2-diazine (pyridazine) with an alkyne gives an intermediate bridged compoimd that loses CO2 or N2 to generate a benzene derivative (see Scheme 3.46). Many other aromatic and heteroaromatic compounds can be prepared likewise. For example, a synthesis of lavendamycin made use of the inverse electron demand Diels-Alder reaction between the 1,2,4-triazine 116 and the enamine 117, followed by in situ elimination of pyrrolidine and retro Diels-Alder reaction, releasing N2 and the substituted pyridine 118 (3.88). 2... 

Sol 2. (c) This is an example of an inverse electron demand Diels—Alder reaction. The diene is electron-deficient and hence uses its LUMO, whereas the dienophile is electron-rich and will use its HOMO in the cycloaddition. Here, LUMO of the diene and HOMO of dienophile have the smallest energy gap and can have best overlap. 

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. 

To date, a few examples of iEDDA reactions on nucleic acids in vitro and in cells were reported. In 2010, Jaschke et al. [76] reported the first example of DNA modification by the inverse-electron-demand Diels-Alder reaction between nor-bomene dienophiles and tetrazine-derivatives. 3 - and 5 -terminal labeling, as well as internal modification of DNA with norbomenes and subsequent iEDDA reaction, was demonstrated [76]. Yields of 96 % are observed using a 1 1 stoichiometry of DNA and tetrazine derivative [76]. Lower reactant concentrations and considerably lower excess of labeling reagent (usually 1 3 stoichiometry) compared to CuAAC, as well as the absence of any toxic catalysts, shows the potential of this cycloaddition reaction for in cell and in vivo applications. 

As several novel reactions satisfying the criteria of click chemistry have been exposed in the last decade, we also mention the introduction of these new click reactions to the ground of polysaccharide chemistry, encompassing two metal-free [3 + 2] cycloaddition reactions, and the inverse electron-demand Diels-Alder reaction, In this section we emphasized on the chemistry of the reactions, and try to offer to readers a guide for executing such reactions. Simultaneously, the extremely diverse and controllable structures and functionalities of the click reaction products are established. Various types of chck reactions involved are illustrated in Fig. 4.4. In addition several examples of alkynes and azides generally used to functionalized polysaccharides are mentioned in Table 4.3. 

Indoles have been used in a variety of capacities in Diels-Alder type [+1-2] cycloaddition reactions. Most often, the indole ring or a derivative thereof has been incorporated as part of the diene moiety. However, there are also several examples reported in which the indole ring, in particular the 2,3-bond, served as the dienophUe component in the cycloaddition reactions. Due to the electron-rich nature of the indole 2,3-bond, its most widely reported synthetic applications as a dienophile are in inverse electron demand Diels-Alder (IDA) reactions. Nevertheless, a few reports on normal electron demand Diels-Alder cycloadditions of the indole 2,3-bond have also appeared in the more recent literature. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

In addition to the reaction of vinylcarbene complexes with alkynes, further synthetic procedures have been developed in which Fischer-type carbene complexes are used for the preparation of benzenes. Most of these transformations are likely to be mechanistically related to the Dbtz benzannulation reaction, and can be rationalized as sequences of alkyne-insertions, CO-insertions, and electrocycli-zations. A selection of examples is given in Table 2.18. Entry 4 in Table 2.18 is an example of the Diels-Alder reaction (with inverse electron demand) of an enamine with a pyran-2-ylidene complex (see also Section 2.2.7 and Figure 2.36). In this example the adduct initially formed eliminates both chromium hexacarbonyl ([4 -I- 2] cycloreversion) and pyrrolidine to yield a substituted benzene. 

Hanessian and Compain have also reported a Lewis acid-promoted inverse electron demand hetero-Diels-Alder reaction between dihydrofurans and dihydropyrans with a-keto-/3,7-unsaturated phosphonates to give stmcturally related products <2002T6521>. High-pressure OTr/o-selective hetero-Diels-Alder reactions between a,/3-unsaturated aldehydes and enol ethers in the presence of lanthanide catalysts have also been reported and give 3,4-dihydro-27/-pyrans. Examples include the use of cyclic enol ethers to give 2,3,4,4a,5,8a-hexahydro-277,577-pyrano[2,3-. ]pyrans <1995T8383>. 

The procedure describes the preparation and use of a reactive, electron-deficient heterocyclic azadiene suitable for Diels-Alder reactions with electron-rich, unactivated, and electron-deficient dienophiles. Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, because of its electron-deficient character, is ideally suited for use in inverse electron demand (LUMOdiene-controlled) Diels-Alder reactions. Table I and Table II detail representative examples of the reaction of dimethyl 1,2,4,5-tetrazine-3.6-... 

The LUMOdiene HOMOalkene interaction for butadiene and methyl vinyl ether is lower than the comparable HOMOdiene-LUMOaikene interaction in dienes bearing an electron-withdrawing group. In many cases, but not all, this leads to the inverse electron demand reaction mentioned above. Fleming uses the example of azonia salt 86, which reacted with diethyl ketene acetal to give 87. Similar reaction with allyl alcohol gave 88, and acrylonitrile gave 89.97a in all cases, the reaction proceeded to 75% completion, and it is clear from the relative rates of reactions provided with each transformation that the electron-rich alkenes reacted faster. The concept of inverse electron demand applies to a Diels-Alder reaction that is controlled by the LUMO of the diene and the HOMO of the alkene, which usually means that an electron-rich alkene reacts faster than an electron-poor alkene, the opposite of what is normally observed (see above). 

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