Diene synthesis inverse electronic demand

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). 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

The inverse electron demand Diels-Alder reaction between enamines and electron-deficient dienes is a useful method for the synthesis of six-membered rings. The process is considered LUMOdiene-controlled70 72, and its rate (as in the other Diels-Alder... 

The [4 + 2] cycloaddition of a,p-unsaturated aldehydes and ketones (1-oxa-1,3-dienes) to enol ethers (Diels-Alder addition with inverse electron demand) has been an attractive route for the synthesis of 3,4-dihydro-2 -pyrans [143-146], which can be converted into deoxy- and dideoxypyranosides [147,148]. 

In 2002, Bodwell and Li reported an elegant and efficient total synthesis of strychnine based on an intramolecular inverse-electron-demand Diels-Alder reaction that involves a pyridazine as diene. The required cyclophane 91 was built up via hydroboration of A-[2-(l-allyl-l/7-indol-3-yl)ethyl]-6-iodopyridazin-3-amine (90) followed by an intramolecular sp —sp coupling reaction [55]. 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

Tetrazines are highly reactive dienes in Diels-Alder reactions with inverse electron demand and have therefore been utilized as starting materials for the synthesis of theoretically or biologically interesting compounds. 

The most intensively studied reactions of 1,2,4,5-tetrazines are cycloaddition reactions with alkenes and alkynes, not only due to theoretical interest but also due to its importance in synthesis. The 1,2,4,5-tetrazines are diene components in this [4 + 2]-cycloaddition reaction while the alkynes and alkenes are the dienophiles. Kinetic studies have shown that these reactions should be classified as Diels Alder reactions with inverse electron demand. Therefore, 1,2,4,5-tetrazines with electron-withdrawing substituents (C02Me, CF3) and dienophiles with electron donating substituents are the most reactive compounds. However, dimethyl... 

The most extensively studied reaction of 1,2,4-triazines is the Diels-Alder reaction with inverse electron demand, in which the triazines behave as reactive electron-deficient dienes. Electron-rich alkenes and acetylenes have been most often used as dienophiles but alkenes with strained double bonds and nitriles can also react. Besides intermolecular Diels-Alder reactions, which were discussed in detail in CHEC-I, intramolecular cycloadditions have been studied widely and used in the synthesis of condensed heterocyclic systems. A review on intermolecular Diels-Alder reactions was published by Roger and Weinreb in 1987 , Sauer published an account of his studies in 1992 <92BSB52l>, and a summary by Taylor of his own work on intramolecular Diels-Alder reactions was published in 1988 <88BSB599>. 

This chapter will mainly describe new developments in the area of theoretical methods and experimental structural methods, and in the rapidly growing field of inter- and intramolecular Diels-Alder reactions of these electron-poor azadienes. Quantitative data for the reactivity of dienes and dienophiles in these (4 -1- 2) cycloadditions with inverse electron demand will be discussed. The synthesis and reactions of dihydro, tetrahydro, and hexahydro tetrazines cannot be discussed broadly beyond the scope of <84CHEC-I(3)53l>. Verdazyls, a well-known class of compound, cannot be treated in detail within the frame of this contribution (see Section 6.21.5.9). 

It should be noted, however, that there are a number of Diels-Alder reactions for which the above generalization does not hold, in which reaction takes place between an electron-rich dienophile and an electron-deficient diene. The essential feature is that the two components should have complementary electronic character. These Diels-Alder reactions with inverse electron demand, as they are called, also have their uses in synthesis, but the vast majority of reactions involve an electron-rich diene and an electron-deficient dienophile. 

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... 

Toward the biomimetic synthesis of chloropupukeananin, Kobayashi et al. [22] successfully implemented a domino sequence of two pericyclic reactions. Masked benzoquinone 59 as the diene reactant classifies the Diels-Alder reaction as inverse-electron-demanding one to which the vinylallene 58 can contribute its extra double bond forming a caged skeleton for the subsequent carbonyl-ene reaction. Longer reaction times and higher pressures were able to direct the reaction pathway toward the desired endo product 60 against the backdrop of numerous conceivable side mechanisms. Choosing the pure enantiomer of 59, as depicted in Scheme 6.12, furthermore increased the stereoselectivity and completed the synthesis of the model compound 61 in 70% yield. 

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. ... 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

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