Cycloaddition reactions intramolecular cycloadditions

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. 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-... 

Intramolecular Reactions Intramolecular 1,3-cycloaddition with high regio- and stereo-control seems to be an important instrument for an effective... 

The alternating electronic properties of the Co, and Cp atoms in the vinylidene ligand enable dipolar molecules to enter into cycloaddition reactions. Intramolecular [2 + 2]-... 

The development within the area of asymmetric 1,3-dipolar cycloadditions since the first edition of this series is too extensive to be completely covered in this chapter and we have therefore chosen selected examples to illustrate the different aspects of the subject. The examples have been chosen on the basis of general importance and also to complement recent monographs in the area. Special attention will be given to recent developments within the area of metal-catalyzed reactions. Intramolecular 1,3-dipolar cycloadditions are only briefly described. 

A major problem in the reaction of a,/3-unsaturated carbonyl compounds and alkenes proves to be the competition between hetero Diels-Alder and ene reactions. Intramolecular cycloadditions of 1,6- and 1,7-dienes with ester and cyano groups at the double bond yield the ene product nearly exclusively, but with alkylidene- and benzylidene-ketoesters and 1,3-diketones the Diels-Alder reaction is preferred under thermal conditions, however under Lewis acid catalysis also ene reactions occur [12]. 

M4604>. The synthesis of a fullerene embedded with a furan motif was reported, which was confirmed by a single crystal X-ray analysis <07OL1741>. Tandem Wittig reaction-intramolecular Diels-Alder cycloaddition of 2-furfural provided tricyclic furans, which may serve as precursors in the synthesis of furanosesquiterpenes <07TL3517>. 

Pcricyclic reaction intramolecular electrocyclic reaction (e.g., spiropyrans, spirooxazines, Mgides, etc.), cycloaddition (2 + 2) reaction. 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-4, 6-dihydrofuro[3,4-b]-furan-3-carboxylates 146 and 147. The results give further evidence of the potential of intramolecular Diels-Alder based multiple processes [129], 2-Substituted furans and thiophenes 148 and 149, heated in the presence of 3,6-di(pyridin-2 -yl)-,y-tetrazine, underwent intramolecular and intermolecular cycloadditions. The cycloadducts underwent double cycloreversion reactions with the loss of a nitrogen and dipyridyldiazine as illustrated in Scheme 2.55. The electron-deficient dipyridyltetrazine reacts with the isolated, electron-rich olefinic bond rather than with the bond conjugated with the methylcarboxylate. 

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... 

Our initial improvement in the synthesis of pyrrolidine acid 3 relied on a racemic 1,3 dipolar cycloaddition followed by resolution. Attempts to devise asymmetric protocols of this reaction using chiral auxiliaries were not productive. The results from our laboratories were consistent with literature findings, with a moderate diastereoselectivity of 3 to 4 1 at best obtained even when double chiral auxiliaries were used. Several other approaches, such as Aza-Cope/Mannich reaction, intramolecular C-H insertion, and asymmetric aryl 1,4 addition, did not bear fruit. 

Scheme 6-8 Diphosphatricyclooctenes - scope of application of the reaction sequence Diels-Alder reaction, ene reaction, intramolecular [4 -t 2]-cycloaddition. Mes, mesitylene.

Vinylmagnesium bromides. These reagents can be employed as alkene equivalents m Diels-Alder reactions. Their reaction with lithium alka-2,4-dienolates followed by heating at 130° leads to 2-cyclohexene-1-methanols. The Mg atom serves as a temporary tether to render the reaction intramolecular, so that highly substituted unactivated dienes and Jienophiles are coaxed to partake in cycloaddition. Even 4,4-disubstituted alkadienols become reactive. Unlike silicon atom tethers, the cycloadducts undergo protonolysis on workup. 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

Sammes and co-workers reported studies on an intramolecular variation on the Bradsher cycloaddition reaction. However, the Franck group,publishing on the construction of benz[c,c/]indole frameworks, reported an alternate structure for the product of their reaction. Intramolecular cycloaddition of the isoquinolinium salt 43 initially afforded adduct 44. This intermediate rapidly converted to 45, which gave 48 after acetylation. The Sammes group had assigned 47 to the final compound but the Franck group, based on NMR and crystal structure data from a related system, proposed the alternate structure 48. Thus this chemistry provided... 

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