Heterocyclic derivatives cycloaddition

Inter- and intramolecular 1,3-dipolar cycloadditions of nitrones under microwave irradiation have been reported to give heterocyclic derivatives. 

Heterocyclic derivatives can be prepared by this route when one of the tether atoms is a nitrogen or an oxygen. Again this route is more efficient than the corresponding intramolecular ketene cycloaddition method for monosubstituted ketenes. Examples are the formation of 17,17 18,18 19 and 20,19 21,19 and 22.19... 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

Although the number of Diels-Alder cycloadditions with open-chain and alicyclic dienes is very large, the number of examples with aromatic heterocyclic compounds is relatively small. The introduction of a vinyl group as a substituent onto a heterocycle increases the number of possibilities of reaction. This new possibility, however attractive for synthetic purposes, is successful, with a few exceptions, only with 7r-excessive five-membered heterocyclic derivatives. As is usual in this kind of reaction, Michael additions, ene reactions, [2 + 2]-cycloadditions, and polymerization compete with the Diels-Alder cycloaddition. 

The first chapter is devoted to the formation and subsequent modification of three-membered heterocycles—aziridines. Synthesis and properties of aziridinyl ketones, bi- and tricyclic aziridine derivatives, cycloaddition and photochemical reactions are described. The second chapter deals with... 

Among the reactions applied in the synthesis of fullerene derivatives cycloaddition reactions such as [2 + 1]-, [2 + 2]-, [3 + 2] and [4 + 2] cycloadditions play a dominant role. In these reactions ring-fused fullerene derivatives are obtained, at least with incorporation of heteroatoms such as oxygen, nitrogen, or silicon. In this section photochemical reactions leading to cycloalkyl ring-fused fullerene adducts will be presented. Photocycloaddition reactions leading to C6o-fused heterocycles will be discussed later. 

Arrieta et al. (1998) illustrated the synthesis of (4,3 )-bipyrazole (3) by utilizing the mixture of dimethylhydrazone and ethyl phenylpropiolate under microwave irradiation. They also described the microwave-assisted 1,3-dipolar cycloadditions with electron-dehcient dipolarophiles to afford the corresponding cycloadducts. The use of pyrazolyl hydrazones led to valuable compounds, such as bipyrazoles (4), in good yields, providing a new approach to the preparation of these heterocyclic derivatives. 

Transition metal complexes in synthesis of heterocycles 80KGS147. Tropone derivatives, cycloaddition reactions with sulfenes or ketenes... 

Also in this field, Larock et al. have described that sydnones 29 undergo [3+2] dipolar cycloadditions with arynes affording 2//-indazoles 30 nndo" mUd reaction conditions. These heterocyclic derivatives are formed by a spontaneons extmsion of CO from the initial cycloadduct (Scheme 12.19) [30]. The same authors have developed a simple route to pyrido[l,2-f>]indazoles 31 via an aryne [3+2] cycloaddition with A(-tosylpyridininm imides and subsequent flnoride-induced elimination of the tosylate anion (Scheme 12.19) [31]. 

The synthetic potential of the obtained phosphonates has been demonstrated in electron-deficient iminophosphonates by their easy functionalisation to afford various acyclic and heterocyclic derivatives with an aminophosphonic fragment by the use of reductive nucleophilic addition reactions, direct aminoallg lation of electron-rich heterocycles, cyclocondensations, and dipolar cycloaddition reactions. In the subsubsection devoted to reactions of phosphonates, ketophosphonates, vinylphosphonates, alkinylphosphonates, vinyl- and vinylidenebisphos-phonates were widely used as organophosphorus reagents. 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

The preparation of isoxazolidine derivatives was first reported by Bodforss in 1918 (18CB192). The major synthesis of isoxazolidines involves the cycloaddition of nitrones with alkenes, and isoxazolidines have also enjoyed an increasing use as key intermediates in the synthesis of natural products and other heterocycles (79ACR396, 1892CB1498, 1892CB3291, 1882CB2105). 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

Dipolar cycloaddition in the synthesis of fullerene Ceo derivatives containing heterocyclic fragments 98KGS291. 

The preparation of 5-ACETYL-l,2,3,4,5-PENTAMETHYLCYCLO-PENTADIENE is of value in the synthesis of pentamethyleyclo-pentadiene and many pentamethylcyclopentadienyl metal carbonyl derivatives that are more soluble in organic solvents than those derived from cyclopentadiene. Simple preparations of 5,6-DIHYDRO-2-PYRAN-2-0NE and 2-//-PYRAN-2-ONE make these hitherto rather inaccessible intermediates available for cycloaddition and other reactions. The already broad scope of the Michael reaction has been widened further by including an efficient preparation of ETHYL (E)-3-NITROACRYLATE. Workers in the field of heterocyclic chemistry will find a simplified method for the preparation of 2,3,4,5-TETRA-HYDROPYRIDINE of help. 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

Iwasawa et al. also developed a new reaction involving a three-component coupling process which affords five-membered heterocycles. This [2s+2sh-1c] cycloaddition reaction supposes the consecutive addition of an alkynyllithium derivative to a Fischer carbene complex followed by the addition of a third component which can be an aldehyde, an imine, an isocyanate, or C02 [119] (Scheme 74). 

Intramolecular cycloadditions of chiral nitrones provide a useful tool for the preparation of bioactive heterocyclic compounds.63 Shing et al. demonstrated that 1,3-dipolar cycloaddition of nitrones derived from 3-0-allyl-hexoses is dependent only on the relative configuration at C-2,3, as shown in Scheme 8.16. Thus 3-0-allyl-D-glucose and -D-altrose (both with threo-configuration at C-2,3) produce oxepanes selectively, whereas 3-O-allyl-D-allose and -D-man-nose (both with erythro-configuration at C-2,3) give tetrahydropyranes selectively.80... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Compound 318 used as dipolarophile with ylide 315 (Ar = 2,4,6-Me3C6H2) gives spiro compound 319 (Equation 46) <2001HCA3403>. The 1,3-dipolar cycloaddition of 3-oxo-2-pyrazolidinium ylide 315 (Ar = Ph) with buckminsterfullerene Cgo yields new heterocyclic fullerene derivatives <1995TL2457>. 

The fused heterocycles 58 have been synthesized via cycloaddition of 1-phenylisobenzofuran 467 (prepared in situ from 466) and methyl a-phenylselenoacrylate. The cycloaddition was carried out in toluene at 80 °C for 2 h to give adduct 468. Hydrogen peroxide on reaction with 468 at —40 °C provided product 469. The [3+2] cycloaddition between 469 and an amine-derived dipole has been accomplished under acidic conditions <1985CPB2762> to provide the heterocycle 58 as a single diastereomer (Scheme 105) <20000L923>. 

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