Cycloaddition examples

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). 

Disubstituted 1,2,3-triazoles are formed in 1,3-dipolar cycloaddition of alkynylmagnesium reagents to azides. This reverse regioselectivity is also achieved in ruthenium-catalyzed cycloadditions. Examples of such reactions can be found in Section 5.01.9. 

Reactions at ring atoms consist mainly of electrophilic attack at nitrogen and cycloadditions. Examples of the reaction of 2-substituted 1,3,4-oxadiazoles with bifunctional compounds at both ring nitrogen and at the substituent, leading to cyclic systems, are included in Section 4.06.5.2 irrespective of where the initial point of attack took place. A few examples of nucleophilic attack at unsubstituted carbon are described, the more common nucleophilic attack at substituted carbon being included under reactions of the appropriate substituent (Sections 4.06.7.1-7.5). 

The 1,3-dipolar cycloadditions of 1,3-dipoles with chiral alkenes has been extensively reviewed and thus only selected examples will be highlighted here. We have chosen to divide this section on the basis of the different types of alkenes rather than on the basis of the type of 1,3-dipole. For 1,3-dipolar cycloadditions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is located as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently apphed in asymmetric 1,3-dipolar cycloadditions. Examples of the application of alkenes with the chiral center localized two or more bonds apart from the alkene will also be mentioned. Application of chiral auxiliaries for alkenes is very common and will be described separately in Section 12.3. 

In a [2 + 2] cycloaddition example, 1,2-dichloroethene was reacted with readily available dimethyl 7,8-bis(trifluoromethyl)-9-oxatricyclo[4.2.1.02 5]nona-3,7-diene-3,4-dicarboxylate in a photochemical reaction, from which dimethyl 4,5-dichloro-9,10-bis(trifluoromethyl)-ll-oxa-tetracyclo[6,2.1.02 7.03,6]undec-9-ene-3,6-dicarboxylate (22) was isolated in 72% yield.29... 

Selenaaromatic rings in selenazolium and selenopyrylium salts are transformed to other rings in reactions other then cycloaddition. Examples are conversion of 1,2,4-selenadiazolium salt (67) to 1,3,5-selenadiazine (68) (Scheme 17), oxidative ring contraction of selenopyrylium salt (81) to selenophene (82), or replacement of selenium in the 2-selenachromylium salts (83) by two nitrogen atoms resulting in formation of benzodiazepines (84) (Scheme 21) [116],... 

This approach has proven to be quite useful in a number of applications two cycloaddition examples are examined here. 

In some instances it has been demonstrated that oxidation is complete before coupling occurs, the second step thus being nonoxidative. Such cases (Scheme 5) involve oxidation to a quinone or a quinone methide whose further reactions may involve nucleophilic addition, e.g. by phenol, or cycloaddition. Examples are given below. 

Diels-Alder reactions. This vinyl sulfoxide undergoes Diels-Alder reactions at 110-130° usually with simultaneous extrusion of CgHsSOH. It thus behaves as an equivalent of acetylene, which is unreactive in [4 + 2]cycloadditions. Examples ... 

Only relatively few examples of interesting target molecules containing rings are known. These include caryophyllene (E.J. Corey, 1963 A, 1964) and cubane (J.C. Barborak, 1966). The photochemical [2 + 2]-cycloaddition applied by Corey yielded mainly the /ranr-fused isomer, but isomerization with base leads via enolate to formation of the more stable civ-fused ring system. 

As final examples, the intramolecular cyclopropane formation from cycloolefins with diazo groups (S.D. Burke, 1979), intramolecular cyclobutane formation by photochemical cycloaddition (p. 78, 297f., section 4.9), and intramolecular Diels-Alder reactions (p. 153f, 335ff.) are mentioned. The application of these three cycloaddition reactions has led to an enormous variety of exotic polycycles (E.J. Corey, 1967A). 

A few typical examples indicate the large variety of five-membered heterocycles, which can be synthesized efficiently by [2 + 3]-cycloadditions. [2 + 2]-Cycloadditions are useful in the synthesis of certain four-membered heterocycles (H. Ulrich, 1967), e.g. of 8-lactams (J.R. 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

The Diels-Alder cycloaddition is one example of a pencyclic reaction, which is a one step reaction that proceeds through a cyclic transition state Bond formation occurs at both ends of the diene system and the Diels-Alder transition state involves a cyclic array of six carbons and six tt electrons The diene must adopt the s cis conformation m the transition state... 

Epoxidation of alkenes (Sec tion 6 18) IS another example of a cycloaddition... 

The importance of both electronic and steric effects is clear in cycloadditions as in cross-oxidations. One example is a heterocycHc modification leading to the thermodynamically less stable natural form of juglone derivatives such as ventiloquinones JT [124917-64-2] (84) and I [124917-65-3] (85) (83). The yields are 97% (84) from 6-chloro-2,3-dimethoxy-l,4-ben2oquinone [30839-34-0] and 100% (85) upon hydrolysis. 

Characteristic reactions of singlet oxygen lead to 1,2-dioxetane (addition to olefins), hydroperoxides (reaction with aHyhc hydrogen atom), and endoperoxides (Diels-Alder "4 -H 2" cycloaddition). Many specific examples of these spectrally sensitized reactions are found iu reviews (45—48), earlier texts (15), and elsewhere iu the Engchpedia. 

The ring opening of 2//-azirines to yield vinylnitrenes on thermolysis, or nitrile ylides on photolysis, also leads to pyrrole formation (B-82MI30301). Some examples proceeding via nitrile ylides are shown in Scheme 92. The consequences of attempts to carry out such reactions in an intramolecular fashion depend not only upon the spatial relationship of the double bond and the nitrile ylide, but also upon the substituents of the azirine moiety since these can determine whether the resulting ylide is linear or bent. The HOMO and second LUMO of a bent nitrile ylide bear a strong resemblance to the HOMO and LUMO of a singlet carbene so that 1,1-cycloadditions occur to carbon-carbon double bonds rather than the 1,3-cycloadditions needed for pyrrole formation. The examples in Scheme 93 provide an indication of the sensitivity of these reactions to structural variations. 

There are several useful syntheses which effectively commence with the cycloaddition of oxygen, a nitroso compound, an azo compound or a sulfinylamine to a 1,3-diene leading to the corresponding 1,2-dioxins, 1,2-oxazines, pyridazines or 1,2-thiazines. Examples of the transformation of these adducts into five-membered heterocycles are shown in Scheme 114 together with leading references. 

Thiatriazolin-5-imines undergo a variety of cycloaddition reactions with the elimination of Nt. 1,3-Dithiolylium-4-olates undergo cycloaddition reactions, e.g. as in Scheme 36 80AHC(27)i5l). Scheme 37 gives an example of cycloaddition in the oxathiazole series. 

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. 

---