Intramolecular 1,1-cycloaddition reactions

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. 

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]-... 

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. ... 

When allenyl aziiidinylimines 40 were heated to 110 C in toluene, as anticipated, only one aUenyl aziridinyUmine 40a gave the tetraquinane product 38a successfully through TMM diyl [2+3] cycloaddition reaction. Intramolecular [2+3] cycloaddition reaction of diazo compotmd with the allene moiety produced methylenepyrazole structure and the pyrazole ring lost a... 

As final examples, the intramolecular cyclopropane formation from cycloolefins with diazo groups (S.D. Burke, 1979), intramolecular cyclobutane formation by photochemical cycloaddition (p. 78, 297f., section 4.9), and intramolecular Diels-Alder reactions (p. 153f, 335ff.) are mentioned. The application of these three cycloaddition reactions has led to an enormous variety of exotic polycycles (E.J. Corey, 1967A). 

Simple olefins do not usually add well to ketenes except to ketoketenes and halogenated ketenes. Mild Lewis acids as well as bases often increase the rate of the cyclo addition. The cycloaddition of ketenes to acetylenes yields cyclobutenones. The cycloaddition of ketenes to aldehydes and ketones yields oxetanones. The reaction can also be base-cataly2ed if the reactant contains electron-poor carbonyl bonds. Optically active bases lead to chiral lactones (41—43). The dimerization of the ketene itself is the main competing reaction. This process precludes the parent compound ketene from many [2 + 2] cyclo additions. Intramolecular cycloaddition reactions of ketenes are known and have been reviewed (7). 

Another synthetically intriguing method of ring formation is based upon the intramolecular cycloaddition reaction formulated in Scheme 28 (82CC613). The initially formed adduct will undergo cleavage to the carbazole on heating. 

In an intramolecular 1,3-cycloaddition reaction, 3-butynyl carbonocyanidate //-oxide (340) was constrained to give exclusively the 4-substituted isoxazole (341) (80JHC609). 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

Intramolecular cycloaddition reactions of allylic cations with participation and/ or formation of heterocycles, mainly [4+3]-cycloaddition to furan system 97T6235. 

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

The intramolecular variant leads to formation of more than one ring an interesting example is the formation of an intermediate in the synthesis of tetraasterane 16 by Musso and coworkers from 3,6-dihydrophthalic anhydride 15 by two subsequent [2 + 2] cycloaddition reactions, an intermolecular step followed by an intramolecular one ... 

Several elegant synthetic strategies have been devised for biotin (1) this chapter describes one of the total syntheses developed at Hoffmann-La Roche. This insightful synthesis employs a derivative of L-cysteine, a readily available member of the chiral pool,2 as the starting material, and showcases the powerful intramolecular nitrone-olefin [3+2] cycloaddition reaction. 

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

The total synthesis of biotin (1) described in this chapter provides an impressive example of the intramolecular nitrone-olefin [3+2] cycloaddition reaction. Aiming for a practical process, the Hoff-mann-La Roche group utilized relatively simple and inexpensive starting materials, and ingeniously controlled the crucial [3+2] cycloaddition reaction to give only one stereoisomer by confining the cycloaddition precursor to a ten-membered ring. 

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

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