1.3- dipolar cycloaddition reactions dipolarophile

There is a large elass of reactions known as 1,3-dipolar cycloaddition reactions that are analogous to the Diels-Alder reaction in that they are coneerted [4jc -I- 2jc] eyeloaddi-tions. ° These reactions can be represented as in the following diagram. The entity a—b—c is called the 1,3-dipolar molecule and d—e is the dipolarophile. 

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 ... 

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

Dipolar cycloaddition reaction of suitable dipolarophiles to azomethine imines is a well-known method leading to the pyrazolo[l,2-tf]pyrazole ring system and the methodology was duly reviewed in CHEC-II(1996) <1996CHEC-II(8)747>. During the covered period, some new applications have appeared. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

Benzocyclobutene, when generated by oxidation of its iron tricarbonyl complex, can function as the dipolarophile in 1,3-dipolar cycloaddition reactions with arylnitrile oxides (Scheme 113).177 Unfortunately the synthetic versatility of this type of process is limited because of the unreactivity of other 1,3-dipolar species such as phenyl azide, benzonitrile N-phenylimide, and a-(p-tolyl)benzylidenamine N-oxide.177... 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Iodoacetylene (prepared in situ from ethynylmagnesium bromide or tributyl (ethynyl)tin with iodine) was used as a dipolarophile in the 1,3-dipolar cycloaddition reactions with nitrile oxides to produce 2-(5-iodoisoxazol-3-yl)pyridine and 3-(4-fluorophenyl)-5-iodoisoxazole in good yield (70%-90%). Subsequently,... 

The carbon-nitrogen triple bond of aryl thiocyanates acts as a dipolarophile in 1,3-dipolar cycloadditions. Reactions with nitrile oxides yield 5-arylthio-1,2,4-oxadiazoles 227 (X = O Y = S). Aryl selenocyanates behave similarly forming 5-arylseleno-l,2,4-oxadiazoles 227 (X = 0 Y = Se). Reactions of 5-aryl-... 

Dipolarophile D6. A complete theoretical study of the 1,3-dipolar cycloaddition reaction of D-glyceraldehyde nitrone (N) to methyl acrylate (MA) has been... 

The use of nitriles as dipolarophiles in 1,3-dipolar cycloaddition reactions is scarce because of their relative inertness in such reactions. Indeed, nitriles with electron-donor substituents do not react with nitrones even under harsh conditions. Hence, an additional activation of the reactants is required. This can be achieved, either by activating the nitrile (dipolarophile) or the nitrone (dipole), or both of them. For example, the reaction of electron-difficient nitriles such as... 

The general method, that has been widely used for the synthesis of perhydropyrrolo[1,2-6]isoxazoles, is based on a cycloaddition reaction of cyclic nitrones with dipolarophiles. The nitrone is easily available by oxidation of the corresponding hydroxylamine with mercuric chloride. The cycloaddition of nitrone to dipolarophiles is highly regioselective and stereoselective and have been often applied in the total synthesis of natural products <20010L1367, 2004BML3967, 2005JOC3157>. As one representative example of dipolar cycloaddition, reaction... 

Cycloaddition reactions are a fundamental class of processes in synthetic chemistry. Within this class, the 1,3-dipolar cycloaddition reaction (DCR) has found extensive use as an efficient method for the synthesis of different heterocyclic compounds. These type of reactions involve the addition of a 1,3-dipole to a multiple 7i-bond system (dipolarophile) leading to five-membered heterocycles (Scheme 1) [1]. 

On the other hand, reactions of nitrile oxides with 1,2-disubstituted olefins are slower and regioselectivity usually was not so high. For example, benzonitrile oxides, obtained from the corresponding chlorooximes 167, undergo 1,3-dipolar cycloaddition reaction with methyl cinnamate to produce the 5-phenyl 168 and 4-phenyl 169 regioisomers in approximately an 80 20 ratio °. However, use of A,iV-diethylcinnamamide as the dipolarophile... 

In addition to the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity. Norbomene, for example, is consistently more reactive than cyclohexene in 1,3-dipolar cycloadditions. Conjugated functional groups also usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enamines, enol ethers, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with a few 1,3-dipoles are given in Table 6.3. Scheme 6.5 gives some examples of 1,3-dipolar cycloaddition reactions. 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

The meso-ionic l,3-dithiol-4-ones (134) participate - in 1,3-dipolar cycloaddition reactions giving adducts of the general type 136. They show a remarkable degree of reactivity toward simple alkenes including tetramethylethylene, cyclopentene, norbomene, and norbor-nadiene as well as toward the more reactive 1,3-dipolarophilic olefins dimethyl maleate, dimethyl fumarate, methyl cinnamate, diben-zoylethylene, A -phenylmaleimide, and acenaphthylene. Alkynes such as dimethyl acetylenedicarboxylate also add to meso-ionic 1,3-dithiol-4-ones (134), but the intermediate cycloadducts are not isolable they eliminate carbonyl sulfide and yield thiophenes (137) directly. - ... 

The meso-ionic l,3>2-oxathiazol-5-ones (169) show an interesting range of reactions with nucleophiles including ammonia, primary amines, and aqueous alkali. They also react with l,3-dipolarophiles, including dimethyl acetylenedicarboxylate and methyl propiolate, yielding isothiazoles (171) and carbon dioxide. 1,3-Dipolar cycloaddition reactions with alkenes such as styrene, dimethyl maleate, and methyl cinnamate also lead to isothiazoles (171) directly. BicycUc intermediates (cf. 136) were not isolable these cycloaddition reactions with alkenes giving isothiazoles involve an additional dehydrogenation step. 

The formation of various 1 1 adducts from dehydrodithizone 413, R = R = Ph, and various 1,3-dipolarophiles has been reported. Thus, dimethyl acetylenedicarboxylate yields 419, X = COOMe, tetra-cyanoethylene yields 420, and e oxycarbonylmethylenetriphenylphos-phorane yields the betaine 421. These transformations have been considered as 1,3-dipolar cycloaddition reactions of a novel type. It seems to us rather unlikely that these transformations are concerted 1,3-dipolar cycloadditions the alternative that they are reactions involving dipolar intermediates (e.g., 422, 423, and 424) should also be considered. The... 

A full account of the preparation and 1,3-dipolar cycloaddition reactions of this class of meso-ionic heterocycle (105) has now been published. Using olefinic dipolarophiles or heterocumulenes, a number... 

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). 

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