Dipolarophiles olefinic

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 course and orientation of 1,3-cycloadditions will be illustrated by listing examples of actual reactions. Most dipolarophiles have carbon-carbon unsaturated bonds, and give derivatives of 1,2,3-triazole, pyrazole, isoxazole and pyrrole according to the following reactions (unless otherwise indicated, reference is made to monosubstituted dipolarophiles olefins and acetylenes usually, but not always, behave similarly) ... 

Aryne Dipolarophiles Olefinic Dipolarophiles Carbonyl Compounds Thiocarbonyl Compounds Oxygen... 

Few reactions of sulfonylfuroxans with olefins have been reported. Depending on the substituents at the furoxan ring, nature of dipolarophile, and temperature, different types of products may be obtained. It is relatively simple to cyclore-vert disulfonylfuroxans to a-sulfonyl nitrile oxides on thermolysis (81TL3371, 85T727). These nitrile oxides were trapped by dipolarophiles to yield sulfonyl-substituted isoxazole derivatives. For example, 3,4-bis(phenylsulfonyl)furoxan reacts with an excess of styrene in xylene under reflux to afford the corresponding isoxazoline 290 (Scheme 189). 

The class of 1,3-dipolar cycloadditions embraces a variety of reactions that can accomplish the synthesis of a diverse array of polyfunctional and stereochemically complex five-membered rings.3 The first report of a 1,3-dipolar cycloaddition of a nitrone (a 1,3-dipole) to phenyl isocyanate (a dipolarophile) came from Beckmann s laboratory in 1890,4 and a full 70 years elapsed before several investigators simultaneously reported examples of nitrone-olefin [3+2] cycloadditions.5 The pioneering and brilliant investigations of Huisgen and his coworkers6 have deepened our under-... 

As formal a, /i-unsaturated sulfones and sulfoxides, respectively, both thiirene dioxides (19) and thiirene oxides (18) should be capable, in principle, of undergoing cycloaddition reactions with either electron-rich olefins or serving as electrophilic dipolarophiles in 2 + 3 cycloadditions. The ultimate products in such cycloadditions are expected to be a consequence of rearrangements of the initially formed cycloadducts, and/or loss of sulfur dioxide (or sulfur monoxide) following the cycloaddition step, depending on the particular reaction conditions. The relative ease of the cycloaddition should provide some indication concerning the extent of the aromaticity in these systems2. 

Nitrones, reactive 1,3-dipoles, react with alkenes and alkynes to form isoxazolidines and isoxazolines, respectively. With monosubstituted olefinic dipolarophiles, 5-substituted isoxazolidines are generally formed predominantly however, with olefins bearing strongly electron-withdrawing groups, 4-substituted derivatives may also be formed.631... 

The ease with which nitrones undergo cycloadditions to a tetrasubstituted olefin like 3 must be related to the high energy of the HOMO of the dipolarophile (see Sect. 2.1.1). This factor renders comparable the reactivity of BCP (3) and MCP (1), which has a lower lying HOMO, despite the less steric hindrance of 1. 

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

Dipolarophiles D1 and D2. In the study of steric and electronic factors on regioselectivity and stereoselectivity of 1,3-cycloaddition of nitrones to olefins, 1-decene (734) and styrene derivatives (735) have been used. By comparative analyses of the kinetic and thermodynamic parameters in the 1,3-cycloadditions... 

Dipolarophiles Dll. In the 1,3-dipolar cycloadditions of electron-rich olefins, such as vinyl ethers, with nitrone (585), common palladium (II) catalysts were used (Fig. 2.45). Reactions proceeded smoothly under mild conditions and in good yield, affording isoxazolidines (646) (Scheme 2.283) (799). 

Regio- and stereoselectivity of the process depend on the nature of its participants and are determined by the character of the approach of the dipolarophile to the dipole. (In Scheme 3.127, this is demonstrated for the reaction of mono-substituted nitronates with monosubstituted olefins.)... 

Other Types of Nitronates in [3 + 2]-Cycloaddition Reactions with Olefins As mentioned above, of all known types of nitronates, only alkyl and silyl nitronates can be involved in [3 + 2]-cycloaddition reactions with olefins. However, furoxans (161), which can also be considered as cyclic nitronates, can react with active dipolarophiles under extreme conditions to give nitrosoacetals (162) (Scheme 3.131, Eq. 1). 

The authors (162) attempted to explain the stereochemical outcome of the reactions (Schemes 3.169 and 3.170) in the terms used earlier (337), that is, by steric factors, which destabilize the endo approach of a dipolarophile, and the electronic effect (secondary orbital interactions), which is most typical for electron-rich dipolarophiles and can slightly stabilize the endo approach of these olefins. 

An interesting observation was made in the study of BNO or ArNO addition to norbornene dipolarophiles 444 and 447, which contain C = N and C = C bonds. With BNO or ArNO, the isoxazoline regioisomers 445 and 446 were unexpectedly obtained by addition to the olefinic double bond. In the case of the exo isomers 447, addition took place to both the... 

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... 

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... 

Alternative doubly and singly activated olefinic dipolarophiles also underwent cycloaddition, generating the products 47-49 in 27-61% yields, although attempted use of an ot,p-unsaturated ketone furnished 50 in only 8% yield, while unactivated dipolarophiles were unreactive (Fig. 3.4). 

However, use of a less reactive reagent where [R = R =(CH2)4, (CH2)s, (CH2)20(CH2)2] led to the isolation of products 61 and 62, with a reduction in the yields of the desired cycloadducts. The product 62 arises from Michael addition of the liberated methanethiol to A-methylmaleimide. The protocol was further extended to olefinic dipolarophiles with dimethyl fiimurate, dimethyl maleate, fumaronitrile, and 2-chloroacrylonitrile leading to the corresponding adducts, although these dipolarophiles proved somewhat less reactive with reduced yields being observed. Where applicable, the alkene configuration was reflected in the relative stereochemistry of the cycloadducts (Fig. 3.5). 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

Epoxide 96 was prepared such that photolytic conversion to the carbonyl ylide could be followed by an intramolecular cycloaddition with the tethered pendant olefin. However, photolysis of epoxide 96 led only to the formation of the regio-isomer 97 and the aldehyde 98 with no evidence of the corresponding cycloadduct. It was presumed that 97 arose from the ylide by thermal recyclization to the epoxide while 98 could form through the loss of a carbene from the ylide. The failure of the tethered alkene to undergo cycloaddition may have resulted from a poor trajectory for the cycloaddition. An extended analogue (99) allowed greater flexibility for the dipolarophile to adopt any number of conformations. Photolysis of epoxide 99 did lead to formation of the macrocyclic adduct 100, albeit in modest yields. 

Nair et al. (87,88) achieved a synthesis of spirooxindole-containing molecules by adding isatins to various carbonyl ylides (Scheme 4.46). There has been relatively little research regarding the efficiency of C=0 of 1,2-dicarbonyl compounds as dipolarophiles relative to their olefinic counterparts. As anticipated, Nair found that the more electrophilic carbonyl of the isatin 187 (non-amide carbonyl) reacted smoothly with the carbonyl ylide formed from diazoketone 186 to give the spirocyclic adduct 188. Nair s yields were moderate to good (44—83%), but were based on recovered isatin. 

Muthusamy et al. (89) approached the formation of decahydrobenzocarbazoles 191 utilizing an indolic five-membered olefin 190 as the dipolarophile in reaction with a carbonyl yhde derived from 189. This intermolecular approach is strategically similar to an intramolecular approach to aspidosperma alkaloids developed by Padwa (Scheme 4.47). 

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