Retro “inverse electron-demand

A strained azo-bridged tricyclic system (1) undergoes a selective retro inverse electron-demand Diels-Alder reaction on heating, leading through a cascade of tautomeric and sigmatropic shifts to the pyridazine derivative (2) (Scheme 2).16 The proposed mechanism was supported by quantum chemical calculations and experimental evidence. 

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 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). 

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). 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

Triethyl l,3,5-triazine-2,4,6-tricarboxylate and 2,4,6-tris(methylsulfanyl)-1,3,5-triazine react in an inverse electron demand Diels-Alder reaction with several electron-rich dienophiles.6 The tricarboxylate 9 (R1 = C02Et) undergoes a well-defined [4 + 2] cycloaddition reaction with ynamines and enamines. In the case of ynamines, the [4 -1- 2] cycloaddition is followed by a retro Diels - Alder reaction at 40 100 °C with direct formation of the substituted pyrimidines 11. In the case of enamines, the cycloaddition provides stable, isolable [4 + 2] adducts 12. The subsequent retro Diels-Alder reaction and the final aromatization step is catalyzed by a mixture of hydrochloric acid and dioxane, anhydrous p-toluencsulfonic acid or acetic acid. This two-step process can be reduced to a single operation by conducting the reaction in a solution of dichloromethane and acetic acid at 40-100 °C.6 Electron-deficient dienophiles like dimethyl acetylenedicarboxylate or 1,4-naphthoquinone do not react with this triazine. 

Intramolecular Diels-Alder reactions with the inverse electron demand of cyclic azadienes can be set up in pyrimidines which have a dienophilic side-chain such as a terminal alkyne group (360) (Scheme 60). Upon heating, an intramolecular Diels-Alder reaction (361) and a subsequent retro Diels-Alder reaction with loss of HCN take place to yield annelated pyridines (362). This reaction is exemplified by the preparation of furo[3,4-i]pyridin-7(5//)-one (363). The reactivity of intramolecular Diels-Alder reactions is strongly related to the conformational properties of the side-... 

INVERSE ELECTRON DEMAND AND THE RETRO DIELS-ALDER... 

The initial product 2 loses N2 in a retro-DiELS-Alder reaction forming the 3,4-dihydropyridine 3, which aromatizes giving the pyridine derivative 4 by elimination of amine or alcohol. The geometry of the transition state of this [4+2] cycloaddition with inverse electron demand follows from the reaction of 3- or 6-phenyl-1,2,4-triazine 5 or 8 with enamines of cyclopentanone. It is apparently influenced by the secondary orbital interaction between the amino and phenyl groups. 3-Phenyl-1,2,4-triazine 5 favours the transition state 11. It leads first to the 3,4-dihydropyridine 6 which, on oxidation followed by a Cope elimination, affords the 2-phenyldihydrocyclopenta[c]pyridine 7. However, 6-phenyl-1,2,4-triazine 8 favours the transition state 12 leading to 3,4-dihydropyridine 9. Elimination of amine yields 5 -phenyldihydrocyclopenta[c]pyridine 10 ... 

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... 

L-Pro has been used as an organocatalyst in an inverse-electron-demand Diels-Alder reaction of ketones with 1,2,4,5-tetrazines to furnish pyrazines with medicinal interest.The transformation proceeds by the reaction of the diene 1,2,4,5-tetrazine with the enamine formed in situ from the ketone and L-Pro. A retro-Diels-Alder step eliminates nitrogen and forms the pyr-azine product after catalyst elimination. The transformation is, however, not regioselective with unsymmetrical ketones. 

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). 

Wang, et al. reported an organocatalylic direct inverse electron demand Diels-Alder reaction of ketones 140 with l,2,4,5-tetrazinesl41, Scheme 3.46 [62]. Examination of the results of catalyst screening revealed that L-proline seems to be the best organocatalyst tried in this process. Several steps were involved in the cascade reactions inverse electron demand Diels-Alder reaction of 1,2,4,5-tetrazines 141 with the enamines, derived from ketones and L-proline, followed by a subsequent retro-Diels-Alder process to extrude and elimination to afford pyridazines 142. 

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. 

Taylor used an inverse electron demand Diels-Alder/retro-Diels-Alder/aromatization cascade for the synthesis of bicyclic pyridines. Beginning with 1,2,4 triazine 33, reaction with electron-rich dienophile 34 yields cycloadduct 35, which eliminates N2 on a retro Diels-Alder reaction. 

Inverse electron demand Diels-Alder reactions also have applications in biological systems. Fox reported that electron poor tetrazine diene 39 successfully forms a bioconjugate with the protein thioredoxin modified to contain a rara-cyclooctene (38). In an example of this Diels-Alder reaction in the absence of thioredoxin, tetrazine 39 combines with /ra -cyclooctene to yield cycloadduct 40 in quantitative yield. Like the synthesis of 37 described above, this reaction proceeds via a Diels-Alder/retro Diels-Alder cascade with elimination of N2. The reaction works well in organic solvents, water, and cellular media with 41 generated as the final product in protic solvents. ... 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

In comparison, the inverse-electron-demand Diels-Alder (lEDA) reaction between a tetrazine and a strained alkene or allg ne followed by retro-Diels-Alder elimination of nitrogen offers a highly selective alternative, yielding stable dihydropyridazine or pyridazine products. Studies on, e.g., ra s-cyclooctene have revealed rate constants up to 2x10 s , which are much higher than... 

Bromley WJ, Gibson M, Lang S et al (2007) Tandem inverse electron demand diels-alder retro-diels-alder and intramolecular diels-alder sequences one-pot synthesis of diaza-polycycles. Tetrahedron 63 6004-6014... 

Tetrazines 1 undergo regioseleetive inverse electron demand Diels-Alder reactions with a variety of electron-rich dienophiles to yield 1,2-diazines in good yield. The process takes place in three steps (a) [4+2] cycloaddition, (b) elimination of the electron-donating group, (c) extrusion of N2 by means of a retro-Diels-Alder process. 

The tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of 1,3,4-oxadiazoles developed by Boger and coworkers (Scheme 16.1) are also well represented. In this process, a 1,3,4-oxadiazole acts as an electron-poor heterodiene and engages in an inverse-electron-demand [4 + 2] cycloaddition. This step is followed by a retro-[3 + 2] cycloaddition that generates a dipole, reacting further via a [3 + 2] cycloaddition step. This cycloaddition has been used as the key step in the total syntheses of several Vinca alkaloids. Only tandem cascade cycloadditions of this type have been reported. 

An interesting transannular Diels-Alder/retro-Diels-Alder reaction cascade was employed in a formal total synthesis of ( )-strychnine by Bodwell and Li (Scheme 20.5). ° The reaction cascade involved a transannular inverse-electron-demand Diels-Alder (lEDDA) reaction of cyclophane 12 to form 13, which spontaneously expelled a molecule of nitrogen by the retro-Diels-Alder reaction to give 14 in quantitative yield. This led to a formal total synthesis of strychnine after 14 was converted into a common... 

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