Dipolarophiles cycloadditions

A23-22-Oxo steroids 424 have been synthesized via 1,3-dipolar cycloaddition of steroidal nitrile oxides to low-molecular dipolarophiles. Cycloaddition of 2-propynyl bromide to 20-carbonitrile oxide, followed by hydrogenation of the isoxazole derivative, gives 22-enamino-24-keto steroid. The latter has then been converted into the target enones in several steps (465). 

Another very elegant reaction is the synthesis of carbon-silylated isoxazoles213 by means of a 1,3-dipolarophilic cycloaddition of nitrile oxide with silylated acetylenes (7), (12) (Scheme 52). If mesitylnitrile oxide (361) and 3,3-dimethyl-3-sila-l, 4-pen-... 

A well-established pathway for the synthesis of silylated heteroarenes is the 1,3-dipolarophilic cycloaddition of alkynylsilanes (97a/189) with diazo compounds (261) or (262). Thus, TMS-phenylacetylene (97a) and diazomethane (261) form 3-TMS-4-phenylpyrazole (263), whereas bis(TMS)-acetylene (189) and 261 afford 3,4-bis-(TMS)-pyrazole (264). Ethyl diazoacetate (262) plus 189 give rise to 3,4-bis(TMS)-5-ethoxycarbonylpyrazole (265) in good yields (equation 121)151. The sterospecific formation of 263 via 1,3-dipolarophilic cycloaddition from 97a and 261 can be considered as... 

Finally, a very helpful synthetic pathway to silylisoxazoles is the 1,3-dipolarophilic cycloaddition of TMS-nitrile oxide (294) with alkenes such as styrene which gives rise to, e.g., 3-TMS-4,5-dihydro-5-phenylisoxazole (295) (equation 134)158. 

Some 1,3-dipoles, such as azides and diazoalkanes, are relatively stable, isolable compounds however, most are prepared in situ in the presence of the dipolarophile. Cycloaddition is thought to occur by a concerted process, because the stereochemistry E or Z) of the alkene dipolarophile is maintained trans or cis) in the cycloadduct (a stereospecihc aspect). Unlike many other pericycUc reactions, the regio- and stereoselectivities of 1,3-dipolar cycloaddition reactions, although often very good, can vary considerably both steric and electronic factors influence the selectivity and it is difficult to make predictions using frontier orbital theory. 

Reactivity involving the mesoionic protomer has been investigated very recently (562). It was known that fixed mesoionic structures undergo cycloaddition with various dipolarophiles (473) and that such a reactivity Ph. 

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. 

Dipolarophiles utilized in these cycloadditions leading to five-membered heterocycles contain either double or triple bonds between two carbon atoms, a carbon atom and a heteroatom, or two heteroatoms. These are shown in Scheme 9 listed in approximate order of decreasing activity from left to right. Small rings containing a double bond (either C=C or C=N) are also effective dipolarophiles, but these result in six- and seven-membered ring systems. 

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). 

Small unsaturated rings are usually very reactive undergoing ring opening in a number of ways, and this characteristic has been utilized in heterocyclic synthesis. In their role as dienophiles or dipolarophiles, the initial cycloaddition is usually followed by a valence tautomerism resulting in a six-membered or larger ring system. Several examples exist, however, where this does not occur, and these are described below. 

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. 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

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... 

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 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... 

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). 

Dipolar cycloadditions of dihydropyrimidine-fused mesomeric betaines 389, 391 and 394 with different dipolarophiles afforded 6-oxo-6H-pyrido[l,2-n]pyrimidine-3-carboxylates 390, 392, 393 and 396 (97JOC3109). 

The use of chiral dipolarophiles, such as the nitrile oxide additions to chiral furanones, have received much interest. The cycloaddition of various 1,3-dipolar reagents to the enantiomeric ally pure furanones 170 and 227 showed excellent diastereofacial control by the menthyloxy substituent, especially in nitrone and nitrile oxide additions (cf. Table II) (88TL5317). 

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