1,3-dipolar cycloaddition reactions electron-deficient dipolarophiles

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Azole approach. 5-JT[l,3,4]Thiadiazolo[3,2-a]pyridin-5-ones (723) can be prepared by 1,3-dipolar cycloaddition reactions between electron-deficient alkenic or alkynic dipolarophiles and the thiocarbonyl ylide dipole present in anhydro-5-hydroxy-2-methyl-6-phenylthiazolo[2,3-6][l,3,4]thiadiazolium hydroxide (720). Sulfur is extruded from the original acetylene adduct (722) whereas H2S is eliminated from the alkene adduct (721) to form the same product (723) (79JOC3808). 

The 1,3-dipolar cycloaddition of 7V-benzyl-C-ethoxycarbonylnitrone with (5)-5-hydroxymethyl-(577)-fiiran-2-one is regio- and stereo-selective. The intramolecular 1,3-dipolar cycloaddition of sugar ketonitrones (50) provides a convenient method for the stereoselective formation of carbohydrate derivatives (51) possessing nitrogenated quaternary centres. This methodology has been successfully used to prepare synthetic precursors of (—)-tetrodotoxin (52) (Scheme 18). The hydrophobic effect has been shown to influence the rate and selectivity of 1,3-dipolar cycloaddition reactions of C,iV-diphenylnitrone with electron-deficient dipolarophiles. ... 

Gowravaram and Gallop adapted the rhodium-catalyzed generation of isomunchnones from diazo imides to the solid-phase synthesis of furans, following a 1,3-dipolar cycloaddition reaction with alkynes. A variety of furans 492 were prepared in this fashion (Fig. 4.150). With unsymmetrical electron-deficient alkynes (e.g., methyl propiolate), the anticipated regiochemistry is observed, e.g., HOMO-dipole LUMO-dipolarophile, as seen previously. 

A competition experim Qt involving isomunchnone 502 and ethyl acrylate and ethyl vinyl ether afforded both cycloadducts, 505 and 506, although the former predominated (Fig. 4.153)- The authors concluded that similar FMO energetics are operating for both electron-rich and electron-deficient dipolarophiles in their 1,3-dipolar cycloaddition reactions with isomunchnones. 

Scheme 14). The regiochemical outcome of the 1,3-dipolar cycloaddition reactions of the cyclic five-membered ring carbonyl yUde 48 with a variety of acycUc and cycHc alkenes having activated or inactivated r-bonds can be ra-tionaUzed [78,79] on the basis of frontier molecular orbital considerations, with the HOMO and LUMO of the carbonyl ylides dominating the reactions with electron-deficient and electron-rich dipolarophiles, respectively (Scheme 14). 

Dipolarophiles which contain an electron-deficient substituent undergo smooth cycloaddition reactions with nitrile ylides. The relative reactivity of the nitrile ylide toward a series of dipolarophiles is determined primarily by the extent of stabilization afforded the transition state by interaction of the dipole highest-occupied (HO) and dipolarophile lowest-unoccupied (LU) orbitals. Substituents which lower the dipolarophile LU energy accelerate the 1,3-dipolar cycloaddition reaction. For example, fumaronitrile undergoes cycloaddition at a rate which is 189,000 times faster than methyl crotonate. Ordinary olefins react so sluggishly that their bimolecular rate constants cannot be measured. 

Gong et al. have confirmed that oxygen-linked bisphosphoric acid (274) provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of a-amino esters (275), aldehydes (276), and various electron deficient dipolarophiles (277). This reaction actually represents one of the most enantioselective catalytic... 

Hlasta and Ackerman (72) reported a synthesis of the triazoles 379, related to the human leuokocyte elastase inhibitor WIN 62225 (380), based on an inter-molecular 1,3-dipolar cycloaddition of the azide 378 with alkynes (Scheme 9.72). They also investigated in detail the effect of steric and electronic factors on the regioselectivity of the cycloaddition reaction. (Azidomethyl)benzisothiazolone (378) underwent smooth 1,3-dipolar cycloaddition with various disubstituted acetylenes to give the corresponding triazoles (379) in 37-84% yields. Electron-deficient acetylenic dipolarophiles reacted more rapidly with the azide to give the respective triazoles. 

Buckminsterfullerene C6o generally reacts as electron-deficient dienophile or dipolarophile in numerous Diels-Alder or i,3-dipolar cycloadditions . The rates of reaction are again enhanced by an increase of pressure so that the yields are usually better at high pressure than at atmospheric pressure (Scheme l2). 

An interesting example is the pressure-induced reaction of buckminsterfullerene Cfio with 1,3,5-cycloheptatriene [60]. Generally C o reacts as an electron-deficient dienophile or dipolarophile in numerous Diels-Alder or 1,3-dipolar cycloadditions and 1,3,5-cycloheptatriene as a diene. The reaction with C(,o is a rare example where both adducts derived from the norcaradiene as well as the cycloheptatriene are observed. 

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