Dienophile electron-rich

D-A rxns with electron deficient dienes and electron rich dienophiles also work well. These are refered to as reverse demand D-A rxns. 

Fluorine-substituted heterodienes are particularly prone to inverse electron demand Diels-Alder reactions with electron-rich dienophiles, as can be seen from the examples in equations 94-97 [113, 114, 115, 116, 117]... 

More recently, Neunhoeffer showed that 1,3,5-triazines 16 could react with electron rich dienophiles, such as 17, to produce pyrimidines 18. 

The total syntheses of fredericamycin 71 and camptothecin 72 made use of similar strategies. N-Sulfonyl-l-aza-1,3-butadienes in conjunction with electron rich dienophiles participated in the inverse electron demand Diels-Alder reaction to afford pyridines after treatment with base. 

Besides nucleophile-induced transformations the Hetero Diels-Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. They can occur either by a reaction of an electron-poor pyrimidine system with an electron-rich dienophile (inverse HDA reactions) or by reacting an electron-enriched pyrimidine with an electron-poor dienophile (normal HDA reactions) (see Section II.B). 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

Extension of this work by reacting 5-nitropyrimidine with 0,0-ketene acetals and with other cyclic and non-cyclic enamines showed that also with these electron-rich dienophiles the addition is regioselective and gives rise to the formation of 2-mono- or 2,3-disubstituted 5-nitropyridines (Scheme 30). Thus, reaction of 5-nitropyrimidine with the cyclic N,S-ketene acetals 4,5-dihydro-1 -methyl-2-methylthiopyrrole and 4,5,6,7-tetrahydro-1 -methyl-2-methylthioazepine gives in low yields 2,3-dihydro-1-methyl-5-nitropyr-olo[2,3-h]pyridine and the 5,6,7,8-tetrahydro-9-methyl-3-nitropyrido [2,3-Z)]azepine, respectively (89T2693) (Scheme 30). 

Equation 2.13), undergo slow but very clean regioselective cycloaddition reactions, under carefully controlled thermal conditions with both electron-poor and electron-rich dienophiles. 

Sauer and Heldmann [97] recently reported an interesting application of ethynyltributyltin as an electron-rich dienophile in an inverse electron-demand Diels-Alder reaction with the electron-deficient triazine derivative 94. This method is interesting because the reaction is highly regioselective and the trialkylstannyl group is easily replaced by several groups under mild conditions, leading to substituted pyridines 95 (Scheme 2.41). 

The inverse electron demand Diels-Alder reaction has also been used to provide expedient access to unnatural 6-carboline alkaloids from 1,2,4-triazines, prepared by microwave-assisted MCR [92]. One-pot reaction of an acyl hydrazide-tethered indole 73, 1,2-diketone and ammonium acetate in acetic acid provided triazines 74 (see Sect. 3.2, Scheme 22), bearing an electron-rich dienophilic indole moiety (Scheme 31). By carrying out the... 

Nakayama and coworkers reported that 3,4-di-tert-butylthiophene 1-oxide 114 is thermally stable but still an extremely reactive substrate. They reported that the Diels-Alder reactions of 114 with varieties of electron-deficient and electron-rich dienophiles took place exclusively at the syn-n-face of the diene with respect to the S=0 bond (Scheme 53) [62, 63]. 

The benzthiazole (62), an example of a stabilised 1-azabuta-1,3-diene, undergoes Inverse type Diels-Alder reactions with electron-rich dienophiles under extremely mild conditions. 

Pyrones are useful dienes, although they are not particularly reactive. The adducts have the potential for elimination of carbon dioxide, resulting in the formation of an aromatic ring. Pyrones react best with electron-rich dienophiles. Vinyl ethers are frequently used as dienophiles with pyrones. The regiochemical preference places the dienophile donor ortho to the pyrone carbonyl. 

Elimination of nitrogen from D-A adducts of certain heteroaromatic rings has been useful in syntheses of substituted aromatic compounds.315 Pyrazines, triazines, and tetrazines react with electron-rich dienophiles in inverse electron demand cycloadditions. The adducts then aromatize with loss of nitrogen and a dienophile substituent.316... 

Another combination of hetero-Diels-Alder reactions and a [3+2] cycloaddition of a nitroalkene was described by Avalos and coworkers [46]. Using the chiral substrate 4-134 derived from a sugar, the domino process can be performed as a three-component transformation using an electron-rich dienophile and an electron-poor... 

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

Another method for pyrazine preparation is the cycloaddition of oxadiazinones with dienophiles. The oxadiazinone 208 undergoes cycloadditions with electron rich dienophiles such as 2,3-dihydrofuran to produce lumazines 209 <00JHC419>. 

Waldmann et al. used tyrosinase which is obtained from Agaricus bisporus for the oxidation of phenols to give ortho-quinones via the corresponding catechols in the presence of oxygen (scheme 33).1881 A combination of this enzymatic-initiated domino process with a Diels-Alder reaction yields the functionalized bicyclic components 164 and 165 as a 33 1 mixture starting from simple p-methyl-phenol 160 in the presence of ethyl vinyl ether 163 as an electron rich dienophile via the intermediates 161 and 162 in an overall yield of 77%. 

Af-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4+2] cycloaddition with alkenes and alkynes.15 The reaction has been utilized as a useftil method for the construction of heterocycles and acyclic amino alcohols. The reaction can be explained in terms of an inverse electron demand Diels-Alder type process that involves an electron-deficient hetero-diene with an electron-rich dienophile. Af-Acyliminium ions generated by the cation pool method were also found to undergo [4+2] cycloaddition reaction to give adduct 7 as shown in Scheme 7.16 The reaction with an aliphatic olefin seems to proceed by a concerted mechanism, whereas the reaction with styrene derivatives seems to proceed by a stepwise mechanism. In the latter case, significant amounts of polymeric products were obtained as byproducts. The formation of polymeric byproducts can be suppressed by micromixing. 

The interactions of the occupied orbitals of one reactant with the unoccupied orbitals of the other are described by the third term of the Klopman-Salem-Fukui equation. This part is dominant and the most important for uncharged reaction partners. Taking into account that the denominator is minimized in case of a small energy gap between the interacting orbitals, it is clear that the most important interaction is the HOMO-LUMO overlap. With respect to the Diels-Alder reaction, one has to distinguish between two possibilities depending on which HOMO-LUMO pair is under consideration. The reaction can be controlled by the interaction of the HOMO of the electron-rich diene and the LUMO of the electron-poor dienophile (normal electron demand) or by the interaction of the LUMO of an electron-poor diene and the HOMO of an electron-rich dienophile (inverse electron demand cf Figure 1). 

The number and position of electron-withdrawing substituents on the 1,2,4-triazine nucleus and the reactivity of the electron-rich dienophile determine the mode of cycloaddition (additions across C-5/N-2 as well as C-3/C-6 of the 1,2,4-triazine nucleus have been observed) as well as the... 

This procedure describes the preparation of an electron-deficient heterocyclic azadiene suitable for use in inverse electron demand (LUMOd gpg controlled) Diels-Alder reactions with electron-rich dienophiles. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

The [4 + 2] heteio Diels-Alder reaction of in sifti-generated chlorodiazadienes 127 with various electron rich dienophiles (such as enamines) yielded a series of substituted pyridazines 128 after aromatization <99JHC301>. In this publication. South noted that the use of trichlorohydrazones 126 (X = Cl) gave rise to chloro-substituted pyridazines 128, although not through the [4 + 2] mechanism. 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

The principal reaction described above (i.e., the Diels-Alder cycloaddition) has been employed with great success to prepare l,3-dithiolo[3,4-, ]-l,4-dithiones. For example, reacting 277 with cyclohexene 278 affords 279 (Equation 36) <1991KGS1317>. The molecule is active toward both electron-poor and electron-rich dienophiles <1998RUP95252, 2003TL3127>. 

Since no cycloaddition reactions between 1,3-diazadienes and electron-rich dienophiles, e.g., enamines, were previously recorded in the literature, we studied the inverse-electron demand [4 + 2] cycloaddition of 357 with acyclic and cyclic enamines derived from pyrrolidine or morpholine (89TL4573 90TH1) (Scheme 80). Thus, pyrimidinones and -thiones 359... 

Despite the concerted nature of most Diels-Alder reactions, substituent effects are evident. Electronic compatibility of the reaction partners is of paramount importance, therefore while a normal Diels-Alder reaction is characterized by the union of an electron-rich diene and an electron-poor dienophile, the Diels-Alder reaction with inverse electron demand features an electron-poor diene and electron-rich dienophile. 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

Inverse electron demand Diels-Alder/retro-Diels-Alder-type reactions, of di- and especially poly-azines with electron-rich dienophiles, interconvert six-membered rings. 1,2,4-Triazines react with enamines and enol ethers to give pyridines (Scheme 76) (CHEC-n(5)242). 

The five-membered ring systems can also behave as electron-rich dienophiles in [n4 + 2] reactions. Indole and 1,2,4,5-tetrazines yield indolopyridazines (262) via [ 4 + 2] cycloaddition followed by extrusion of nitrogen and aromatization, whilst the dihydro adduct,... 

Triazines react also with electron-rich dienophiles such as ethyl vinyl ether (401 R = Et) or vinyl acetate (401 R = Ac) in boiling dioxane to yield the pyridine derivatives (376). After the usual [4 + 2] cycloaddition and nitrogen elimination from the bicyclic compound (402), the dihydropyridines (403) eliminate ethanol or acetic acid to give the aromatic pyridines (376). The dienophiles (401) can therefore be used as alkyne equivalents (69TL5171). 

---