Olefins as dipolarophiles

Aside from reactions involving heterocumulenes, processes involving simple activated olefins as dipolarophile partners have been only scarcely investigated. The popular 2-vinyloxiranes [27] as well as N-tosyl-2-vinylaziridinc 20 [28] have been shown to react with Michael acceptors having neces-... 

A direct and efficient route to imidazoline and pyrrolidine derivatives using copper(ll) triflate-mediated [3+2] cycloaddition of various aryl, alkyl, and cycloalkyl iV-tosylaziridines with nitriles and olefins as dipolarophiles has been reported <2006TL5399>. Formation of bicyclic imidazoline 334 with a /ra j-ring junction as a single product from aziridine 333 suggested that the reaction proceeded through an SN2-type pathway (Scheme 86). 

Olefins as dipolarophiles. The reactivity of 13 is also sufficient to cycloadd olefins such as dimethyl fumarate and maleate. The conservation of the cis- and trans-configuration of the olefins in products formed on N-protona-tion and insertion of CO into the Ru-N bond of the cycloaddition product indicates that the reaction is stereospecific and most likely to be a concerted process. The CO ligands in 13 are thermally labile, for which reason 13 is only stable in solution under an atmosphere of CO. ° It is therefore not surprising that the substitution products in which a CO is replaced by dimethyl fumarate or maleate are formed as side-products. 

Aldoximes derived from an o-protected vanillin 321, when treated with TCCA in the presence of olefins as dipolarophiles, afford nitrile oxides 322. Subsequent 1,3-dipolar cycloaddition generates the corresponding isoxazo-lines 323 (Scheme 72) <2001SC3075>. 

There have been few studies comparing the reactivity of various 1,3-dipoles. Quite a lot of work has been done, however, on comparing the reactivity of various olefins as dipolarophiles. Several generalizations have come from such studies ... 

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). 

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. 

However, an unprecedented result is obtained when maleimide, fumarates, maleate and dibenzoylethylene are used as dipolarophiles, as hydromethylenation of olefins results.405,406... 

A representative 1,3-dipolar cycloaddition process occurs with yV-aryl-C-(trifiuoromethyl)-nitrilimines, generated from the corresponding hydrazonoyl bromides, c.g. 4. under basic conditions. which can react with dimethyl fumarate and maleate,bicyclic olefins. and dipolarophiles containing cumulative double bonds. With sodium isocyanates as the dipolarophilc the cycloaddition reaction occurs across the C = N bond, while with potassium isothiocyanate it occurs through the C = S bond. ... 

Although the reaction mechanism depends upon the nature of the reacting anionic species (as illustrated in the scheme), a chelation between the lithium and the carbonyl oxygen of the dipolarophiles may be responsible for the exclusive regio- and endo selectivity. This chelation is so rigid that the high endo selectivity as well as the enhanced reactivity remains even when the a substituent of the ylide is a sterically bulky isopropyl group and the p substituent an olefinic methyl. On the other hand, the selectivity of cycloadditions of ylides 141 is very poor when the olefin dipolarophiles bear a noncarbonyl substituent (e.g., acrylonitrile) or when s-(rans-enones (e.g., 2-cyclopentenone) are used as dipolarophiles. 

Most of the efforts towards the stereocontrolled synthesis of 4,5-dihydroisoxazoles were based on the use of chiral alkenes as dipolarophiles. Among these, the reactions of chiral acyclic olefins featuring an allylic stereocenter are of interest from both the practical and theoretical points of view 1 25,1 37 - 157. (More recent examples can be found in references 356-387.)... 

Table 13 offers also the opportunity of a comparison of olefins and acetylenes as dipolarophiles. In some cases the C=C dipolarophile is more effective, for instance styrene appears more reactive than phenylacetylene in other cases the contrary is true, for instance acetylene dicarboxylic ester reacts faster than fumaric ester. When C=C and C N dipolarophiles were compared, the former were found to be more reactive for instance with diphenylnitrili-mine (in benzene, 80°C) phenylacetylene reacts 18 times as rapidly as benzo-nitrile . Nitriles also are less efficient than acetylenes as dienophiles (Section 4.1.3). 

The dipolarophile typically is an olefin, but diversity in the structure of the dipolarophile is one of the synthetically important features of 1,3-dipolar cycloaddition reactions. Many different types of unsaturated compounds have been employed as dipolarophiles. Likewise, structural diversity is the rule rather than the exception for compounds capable of acting as 1,3-dipoles. Variation in structure in both the 1,3-dipole and dipolarophile makes this a very versatile and useful reaction, particularly in the synthesis of heterocyclic compounds. The most significant structural feature of 1,3-dipolar compounds is that they possess a 7r-system containing four electrons over three atoms, and are isoelectronic with the allyl anion. Some typical 1,3-dipolar species are shown in Scheme 10.1. 

Acceptor-CH-substituted pyridinium-N-betaines 15 (accessible in situ by deprotonation of the corresponding N-alkylpyridinium salts 14) undergo 1,3-dipolar cycloaddition with activated alkynes and alkenes as dipolarophiles. With alkynes, the cycloadducts (16/19) dehydrogenate spontaneously to indolizines, which are either of the 1,2,3-trisubstituted type 17 or (indicating a regioselective cycloaddition) of the 1,3-disubstituted type 18. With olefinic substrates, the presence of an oxidant for additional dehydrogenation of the primary cycloadduct (20 -> 17) is required [219] ... 

Other reactive olefins, such as enamines and vinyl ethers also participate as dipolarophiles in their reaction with thiocarbonyl 5-imides. Even fulvenes undergo [3+2] cycloaddition reactions. 

The [3+2] cycloaddition reaction of azides with terminal olefins is of considerable interest in the modification of biomolecules, because the azide group is abiotic in animals. Especially, the Cu(i) catalyzed cycloaddition reaction of azides with terminal alkynes achieves regioselective formation of 1,4-disubstituted 1,2,3-triazoles and this reaction is currently referred to as click chemistry . In the thermal reaction of azides with terminal alkynes, about 1 1 mixtures of 1,4- and 1,5-disubstituted 1,2,3-triazoles are obtained. Likewise, disubstituted alkynes afford mixtures of the stereoisomers. In order to avoid the cellular toxicity caused by the copper catalyst, Cu-free click chemistry is of considerable interest. The use of strained cyclooctyne derivatives as dipolarophiles was proposed recently. In this manner a novel 6,7-dimethoxyazacyclooct-4-yne was constructed from a glucose analogue s. The disadvantage of this reaction is its significantly slower reaction rate but introduction of fluoro groups adjacent to the triple bond achieves some rate enhancement. ... 

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. 

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 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). 

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... 

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. - ... 

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). 

The relative rate constants (fe ) do not account for the fact that approach of the nitrile oxide to the 7i-bond can occur from both olefinic diastereofaces with two regioisomeric modes of reaction (Scheme 6.14). In the case of achiral 1-alkenes, only one regioisomer is formed. With chiral dipolarophiles, preference for one of the two is usually found (diastereodifferentiation). The relative diastereofacial reactivity (fejH) is used to evaluate this effect (121). With ethylene, there are four possibilities of attack (two for each face corresponding to the different regio-isomers), and the of each is set as 0.25. In diastereodifferentiating cycloadditions, such as those with a-chiral alkenes, the major isomer generally results... 

Confirmation was provided by the observation that the species produced by the photolysis of two different carbene sources (88 and 89) in acetonitrile and by photolysis of the azirine 92 all had the same strong absorption band at 390 nm and all reacted with acrylonitrile at the same rate (fc=4.6 x 10 Af s" ). Rate constants were also measured for its reaction with a range of substituted alkenes, methanol and ferf-butanol. Laser flash photolysis work on the photolysis of 9-diazothioxan-threne in acetonitrile also produced a new band attributed the nitrile ylide 87 (47). The first alkyl-substituted example, acetonitrilio methylide (95), was produced in a similar way by the photolysis of diazomethane or diazirine in acetonitrile (20,21). This species showed a strong absorption at 280 nm and was trapped with a variety of electron-deficient olefinic and acetylenic dipolarophiles to give the expected cycloadducts (e.g., 96 and 97) in high yields. When diazomethane was used as the precursor, the reaction was carried out at —40 °C to minimize the rate of its cycloaddition to the dipolarophile. In the reactions with unsymmetrical dipolarophiles such as acrylonitrile, methyl acrylate, or methyl propiolate, the ratio of regioisomers was found to be 1 1. 

---