Dipolarophiles reactions

Strained bicyclic compounds can be obtained e.g. when cyclopropenes are used as dipolarophiles. Reaction of 3,3-dimethylcyclopropene 7 with diazomethane 4 gives the heterobicyclic cycloaddition product 8 in 85% yield ... 

Aldimines, Ketimines, and Related Compounds as Dipolarophiles Reactions of aldimines with nitrile oxides proceed readily to give 1,2,4-oxadiazolines independently of the nature of substituents both in dipole and dipolarophile molecules. 1,2,4-Oxadiazolines were prepared by the regiospe-cihc 1,3-dipolar cycloaddition of nitrile oxides with fluoro-substituted aldimines (295). Phosphorylnitrile oxides gave with azomethines, PhCH NR, phosphory-lated 1,2,4-oxadiazolines 129 (296). Expected 1,2,4-oxadiazolines were also obtained from azomethines, derived from 4-formylcoumarine (179) and 1,3-diphenylpyrazole-4-carbaldehyde (297). 

The publications that appeared up to 1975 on the transformations of oxiranes into other heterocyclic compounds are reviewed in detail in the monograph by van der Plas and the relevant chapters of other reviews. Accordingly, we merely supplement the earlier data with more recently reported results and, at the same time, present some of the varied transformations of the oxiranes. The possibility of stereoselective synthesis of heterocyclic systems was broadened considerably by 1,3-dipolar cycloaddition reactions. Heterocycles are formed if the ylide intermediates produced from oxiranes in photolytically or thermally induced reactions are made to react intramolecularly or with external dipolarophiles. Reactions of these types will be treated in Sections IV.8 and IV.9. 

The transition state of the concerted 1,3-dipolar cycloaddition reaction is controlled by the frontier molecular orbitals of the substrates. Hence, the reaction of dipoles with dipolarophiles involves either a LUMO-dipole/ HOMO-dipolarophile reaction or a HOMO-dipole/LUMO-dipolarophile interaction, depending on the nature of the dipole and the dipolarophile. 

Potts et al. (333) condensed dipolarophiles (DMA, dibenzoylacetylene, ethyl propiolate) with ylides (81) obtained by quaternization of 4-methyl-thiazole with an a-bromoketone or ester and subsequent deprotonation. In fact the 1 1 molar adduct obtained (82) rearranged to a pyr-rolothiazine (83). One example of this reaction is described Scheme 49. 

A versatile method for the synthesis of a variety of five-membered heterocycles and their ring-fused analogs involves the reaction of a neutral 47r-electron-3-atom system with a 27T-electron system, the dipolarophile, which is usually electron deficient in nature. Available evidence, e.g. retention of dipolarophile stereochemistry in the product and solvent polarity exerting only a moderate influence on the reaction, indicates that the cycloaddition proceeds via a concerted mechanism 63AG(E)565, 63AG(E)633, 68JOC2291) and may be represented in general terms by the expression in Scheme 8. 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Formation of ring-fused systems by reactions of this type can be achieved in two ways in one the heterocycle to which ring annulation is to occur acts as the dipolarophile the alternative mode utilizes incorporation of the 1,3-dipole into the heterocyclic ring for reaction with the dipolarophile. Both approaches have been investigated intensively. 

Anhydro-3-hydroxy-2-phenylthiazolo[2,3-6]thiazolylium hydroxide (407) underwent ready thermal reaction with alkynic and alkenic dipolarophiles in refluxing toluene. With the former dipolarophile sulfur was lost from the intermediate 1 1 cycloadduct (408) to give the substituted 5H-thiazolo[3,2- i]pyridin-5-ones (409). With the latter, the intermediate (410) lost H2S, also forming (409). 

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

Cycloaddition reactions of aziridines with a wide assortment of dipolarophiles have been studied. The reaction of dialkyl azodicarboxylates with the cf5-aziridine (27) is stereospecific... 

The photochemical behavior of the isomeric 3-methyl-2-phenyl-2-allyl-l-azirine (66) system was also studied. Irradiation of (66) in cyclohexane gave a quantitative yield of azabicyclohexenes (67) and (68). Control experiments showed that (65) and (66) were not interconverted by a Cope reaction under the photolytic conditions. Photocycloaddition of (66) with an added dipolarophile afforded a different 1,3-dipolar cycloadduct from that obtained from (65). The thermodynamically less favored endo isomer (68b) was also formed as the exclusive product from the irradiation of azirine (66b). 

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 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Reactions of fluorinated dipolarophiles. Electron-deficient unsaturated species generally make better dipolarophiles, therefore, fluonnated alkenes become better dipolarophiles when vinylic fluonnes are replaced by perfluoroalkyl groups For example, perfluoro-2-butene is unreactive with diazomethane, but more highly substituted perfluoroalkenes, such as perfluoro-2-methyl-2-pentene, undergo cycloadditions in high yields [5] (equation 2) Note the regiospecificity that IS observed in this reaction... 

The high reactivity of monoperfluoroalkyl-substituted alkenes was demonstrated prior to 1972 via the facile reaction of diazomethane with 3,3,3-tnfluoro-propene [9] More recently, such dipolarophiles were found to be similarly reactive... 

Polyfluoroalkyl- andperfluoroalkyl-substituted CO and CN multiple bonds as dipolarophiles. Dmzo alkanes are well known to react with carbonyl compounds, usually under very mild conditions, to give oxiranes and ketones The reaction has been interpreted as a nucleophilic attack of the diazo alkane on the carbonyl group to yield diazonium betaines or 1,2,3 oxadiazol 2 ines as reaction intermediates, which generally are too unstable to be isolated Aromatic diazo compounds react readily with partially fluorinated and perfluorinated ketones to give l,3,4-oxadiazol-3-ines m high yield At 25 °C and above, the aryloxa-diazolines lose nitrogen to give epoxides [111]... 

The types of cycloadditions discovered for enamines range through a regular sequence starting with divalent addition to form a cyclopropane ring, followed by 1,2 addition (i) of an alkene or an alkyne to form a cyclo-cyclobutane or a cyclobutene, then 1,3-dipolar addition with the enamine the dipolarophile 4), and finally a Diels-Alder type of reaction (5) with the enamine the dienophile. 

Azides can use enamines as dipolarophiles for ],3 cycloadditions to form triazolines. These azides can be formate ester azides (186), phenyl azides (187-195), arylsulfony] azides (191-193,196), or benzoylazides (197,198). For example, the reaction between phenyl azide (138) and the piperidine enamine of propionaldehyde (139) gives 1 -phenyl-4-methy l-5-( 1 -piperidino)-4,5-dihydro-l,2,3-triazole (140), exclusively, in a 53% yield (190). None of the isomeric l-phenyl-5-methyl product was formed. This indicates that the... 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

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). 

This type of reaction is represented by 1,3-dipolar cycloadditions, corresponding to one of the Huisgen categories (69MI1). The 1,3-dipolar cycloaddition corresponds to the interaction between a 1,3-dipole and a multiple system five-membered ring closure (Scheme 1). 

The ease with which the dipolarophile interacts with vinylacetylenes depends mainly on a spatial factor. The study of the reactions of alkylthiobuten-3-ynones-l and their selenic and telluric analogs with DPNT shows that, in this case, nitrilimine also acts as a nucleophilic agent with a nucleophilic center on the carbon atom of the 1,3-dipole and always adds to the terminal carbon of the enyne system to form l,3-diphenyl-5-/ -2-pyrazolenines. The oxidation of the latter with chloranil leads to alkynylpyrazoles (65ZOR51). 

It was found that the reaction of 5-acetoxy- and 5-benzoyloxy-2(5//)-furanones 174 with aryl nitrile oxides afforded only one cycloadduct, the condensed isox-azoline 233 (88TL5317). In principle, there are four possible cycloadducts 233 and 234 resulting from the anti approach of the 1,3-dipolarophile to the acetoxy group (with exo configuration of the acetoxy substituent), and two further isomers... 

Kobayashi and co-workers reported similar enantioselectivity switch in the bi-nol-yterrbium(III) triflate complex-catalyzed cycloaddition reactions [69] between N-benzylidenebenzylamine N-oxide and 3-crotonoyl-2-oxazolidinone [70]. The reaction in the presence of MS 4 A showed an exclusively high enantioselectivity of 96% ee, while that in the absence of MS 4 A (-50% ee) or in the presence of pyridine N-oxide (-83% ee) had the opposite enantioselectivity (Scheme 7.24). This chirality switch happens generally for the combination of a wide variety of nitrones and dipolarophiles. 

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